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Review

The Role of Crosstalk between Adipose Cells and Myocytes in the Pathogenesis of Sarcopenic Obesity in the Elderly

by
Mauro Zamboni
1,*,
Gloria Mazzali
2,
Anna Brunelli
1,
Tanaz Saatchi
1,
Silvia Urbani
1,
Anna Giani
1,
Andrea P. Rossi
3,
Elena Zoico
2 and
Francesco Fantin
2
1
Geriatrics Division, Department of Surgery, Dentistry, Pediatric and Gynecology, Healthy Aging Center, University of Verona, 37126 Verona, Italy
2
Geriatrics Division, Department of Medicine, University of Verona, 37126 Verona, Italy
3
Geriatrics Division, Department of Medicine, AULSS2, Ospedale Ca’Foncello, 31100 Treviso, Italy
*
Author to whom correspondence should be addressed.
Cells 2022, 11(21), 3361; https://doi.org/10.3390/cells11213361
Submission received: 22 August 2022 / Revised: 8 October 2022 / Accepted: 14 October 2022 / Published: 25 October 2022
(This article belongs to the Collection Molecular Mechanisms and Current Treatment Strategy of Sarcopenia and Cachexia)
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Abstract

:
As a result of aging, body composition changes, with a decline in muscle mass and an increase in adipose tissue (AT), which reallocates from subcutaneous to visceral depots and stores ectopically in the liver, heart and muscles. Furthermore, with aging, muscle and AT, both of which have recognized endocrine activity, become dysfunctional and contribute, in the case of positive energy balance, to the development of sarcopenic obesity (SO). SO is defined as the co-existence of excess adiposity and low muscle mass and function, and its prevalence increases with age. SO is strongly associated with greater morbidity and mortality. The pathogenesis of SO is complex and multifactorial. This review focuses mainly on the role of crosstalk between age-related dysfunctional adipose and muscle cells as one of the mechanisms leading to SO. A better understanding of this mechanisms may be useful for development of prevention strategies and treatments aimed at reducing the occurrence of SO.

1. Introduction

Normally, bone, muscle and fat mass grow in harmony in the body. However, this linkage may be lost as a result of aging and in several chronic diseases, when a progressive decline of muscle mass in stable weight subjects occurs, configuring a condition called sarcopenia, or when a combination of decline of muscle mass together with an increase in fat mass in overweight or obese subjects occurs, a condition called sarcopenic obesity (SO). SO has been recently defined as the co-existence of excess adiposity and low muscle mass and function. Its prevalence increases with age and has been recognized to be strongly associated with greater morbidity and mortality [1].
Much evidence shows that the consequences of SO are clinically relevant [1,2,3]. SO has consistently been demonstrated to be a strong and independent risk factor for frailty, metabolic disorders, hospitalization and mortality in the older population (Figure 1).
Pathogenesis of SO is multi-factorial [3].
Gain in adipose tissue (WAT) and especially dysfunctional WAT may represent an independent determinant for the development of loss and dysfunction of muscle mass. In addition, a decline in muscle mass may facilitate WAT accumulation. SO is more frequently present in older adults, particularly because of the changes observed in body composition (i.e., changes in muscle mass and AT quantity and quality), which in general accompany the aging process.
Age-related changes in sex steroids should be also taken into account in the pathogenesis of SO in the elderly. In fact, in men as in women, age-related decline in sex steroids is strongly related to sarcopenia [4], in term of loss of muscle mass, quality and function, as well as to an increase of WAT and its redistribution (Figure 2) [5].
Both WAT and muscle have been identified as endocrine organs, which influence each other through several mechanisms [6,7]. Defects in the crosstalk between adipose cells and myocytes may be a cause of SO; an understanding of the interplay between adipose cells and myocytes may be crucial for SO prevention and/or treatment.

2. Adipose Tissue as Endocrine Organ

The concept that WAT, apart from serving as an energy storage and mechanical protection, acts as an endocrine organ, representing a source of countless adipokines, proteins, metabolites, lipid molecules, non-coding RNAs and extracellular vesicles (Evs), as involved in tissue crosstalk, has been widely accepted in recent years [6]. Besides adipocytes, WAT contains stromovascular cells and immune cells acting as an integrated unit, all of which contribute to its endocrine activity [8]. Several adipocyte-derived proteins with endocrine function have been detected since the discovery of leptin many years ago [6].
WAT, distributed in different depots in the body, expresses specific features in relation to cellular composition and functions [6]. Furthermore, the anatomical location is relevant when considering that hormones produced by the visceral adipose tissue (VAT) are released into the portal system and go directly to the liver, while the systemic circulation receives the molecules produced by the subcutaneous adipose tissue (SAT) [8,9].
Moreover, WAT is a dynamic organ that modifies in response to changes in nutritional state, through modifications of its metabolism and cellularity, and subsequent shifts in adipokine secretion. In the lean state, SAT is characterized by smaller cell size and by an increased number of adipocytes, which have a different pattern of adipokine secretion compared with VAT. Weight gain causes adipocyte hypertrophy, with differences across sex, age and fat depot. Weight gain in women, at least until menopause, characterized by the enhanced accumulation of SAT, is associated with a low risk of type 2 diabetes and cardiovascular diseases [10]. In contrast, weight gain in men usually accumulates more VAT, resulting in higher metabolic risk [9].
In subjects with overweight and obesity, changes in WAT depots and cellularity, with a prevalent pro-inflammatory adipokine secretion profile, may directly contribute to the development of metabolic and cardiovascular consequences of obesity [6,9].
Adiponectin and leptin are the two most widely studied adipocyte-derived factors. Most leptin is secreted by SAT [11,12], flows into the bloodstream, passes through the blood brain barrier and arrives in areas of the brain involved in regulating hypothalamic energy balance. The link between neuroendocrine and sympathetic control of WAT endocrine function, and the existence of negative feedback between the brain and WAT, have been widely studied [13]. In the last few decades, several studies have shown the association between leptin and cardiovascular diseases [14].
Adiponectin is an adipokine with described anti-atherogenic, anti-inflammatory and insulin-sensitizing properties [15]. Obesity is associated with reduced adiponectin expression in VAT, and adiponectin levels have been shown to negatively correlate with the amount of VAT [16], suggesting that the obesity-associated decline in adiponectin could contribute to the detrimental effects of excessive VAT accumulation on whole body metabolism [17].
VAT expansion also triggers other proinflammatory cytokine expressions as well as the recruitment of immune cells [18]. Expansion of VAT is accompanied by increased interleukin 6 (IL-6) and tumor necrosis factor (TNF) secretion, which lead to a crown-like structure formation, and augmented hypoxia-inducible factor 1α expression to promote angiogenesis, which contributes to local and systemic inflammation [19,20,21].
Moreover, great attention has recently been focused on WAT contribution in inter-organ communication, not only by producing signaling mediators but also by converting or degrading signaling mediators from other organs (“signal metabolism” and “signal catabolism”) [6]. Increasing and specific interest has been given to Evs (carrying protein, lipids, small coding and noncoding RNAs), which are now considered an eminent way of communication between WAT and other organs, as well as between different cell populations within WAT itself [6].

3. Adipose Tissue Changes across Aging

With aging, quantity, distribution, and function of WAT changes. Fat mass increases and reaches its peak at about 65–75 years for men, and later for women [22]. The increase in fat mass is independent from changes in body weight, and this is due to the concurrent decline in muscle mass: so-called sarcopenia [23]. Fat storage is progressively redistributed from the body’s periphery (i.e., loss of SAT, in particular, gluteo-femoral SAT) to the abdomen (i.e., increase of VAT), and such abdominal fat accumulation is independent of weight gain [24,25]. It has been shown that involuntary SAT loss, in the absence of a negative energy balance, is associated with triglyceride (TG) spillover, which determines ectopic deposition of TG in muscle, liver, bone marrow and heart, contributing to the dysfunction of these organs [24,25].
With aging, WAT also becomes dysfunctional, showing an increased profile of pro-inflammatory adipokines produced by adipose cells, greater infiltration of inflammatory cells in WAT, and preadipocytes and adipocyte incompetence, together leading to inflammaging [26].
In general, serum levels of the majority of adipokines are higher in older than in younger individuals [24]. The relationship between aging and the endocrine function of WAT is complex to study in humans. As aging is associated with changes in fat mass and its distribution, as well as with high prevalence of metabolic syndrome, insulin resistance and obesity, the effect of aging itself is difficult to isolate. Indeed, age-related VAT increase, obesity and metabolic syndrome are all factors that can induce an increase in inflammatory and a decrease in anti-inflammatory adipokine production.
Older subjects show higher leptin levels [27], whose activity seems to be reduced, thereby determining a phenomenon called leptin resistance, a phenomenon that is not completely understood in humans [28].
It has been determined that the amount of serum adiponectin rises as humans age [29], and higher levels of adiponectin have been found in centenarians [30]. Although the beneficial metabolic and anti-inflammatory effects of adiponectin have been confirmed by some scientific studies, adiponectin’s role in the elderly is still controversial [30,31]. Indeed, a significant positive relationship was found between adiponectin and risk of incident disability and all-cause mortality among the subjects of the Health ABC Study [32], but this relationship was not significant after adjusting for weight loss and physical performance at baseline.
In an in vitro model of chronological aging of adipocytes, we and other researchers observed that adipocyte secretion of proinflammatory cytokines, such as interleukin-6 and monocyte chemoattractant protein-1, was significantly higher in older than younger adipocytes [33,34,35]. We also found that in vitro aged adipocytes accumulate ROS, increase mRNA expression of key proteins related to the remodeling of the extracellular matrix and increase p53, p21 and p16 expression, compared to younger cells [34,35].
Moreover, dysfunction of WAT is also characterized by increased oxidative stress (OS), mitochondrial dysfunction, reduction in vascularization and hypoxia [36]. The age-related deregulation of WAT can initiate inflammatory cycles with monocyte recruitment and activation of macrophages. The ratio between pro-inflammatory M1 and anti-inflammatory M2 macrophages increases with aging [37,38], as well accumulation of CD3+ T and CD8+ T cells and activation of T and B lymphocytes [39,40]. Factors secreted by activated macrophages induce the release of fatty acids from adipocytes that inhibit differentiation of pre-adipocytes and cause de-differentiation of mesenchymal progenitors into mesenchymal adipocyte-like default cells [41]. These processes induce lipotoxicity both in WAT and in other organs, cause cellular stress responses, promote release of inflammatory cytokines, block adipogenesis and determine further release of lipotoxic fatty acid [42]. WAT in the elderly is also characterized by reduction of adipocyte size and increase of tissue fibrosis [43].
That adipocyte size is affected by aging was clearly shown by Donato et al., who observed significantly lower adipocyte areas from WAT in older than younger mice [44] and by the fact that a high fat diet was able to increase adipocyte diameter in young rats but not in old rats [45]. Furthermore, age-related decline of adipocyte capacity to stock TG has been shown to be related to fat infiltration inside the muscles, as well as to a deposition in muscles of toxic lipids such as ceramides [45]. Fibrosis, characterized by an increase in connective fiber content, may be due to an up-regulation of collagen protein [46]. The OS that occurs in WAT during aging causes oxidative damage to lipids, proteins and DNA. Finally, senescent cells are over-represented in aged WAT, providing a source of many pro-inflammatory cytokines and chemokines, impairing the production of extracellular matrix modifying proteases and further promoting the production of ROS [47,48].

4. Muscle as Endocrine Organ

Muscle has also been identified as having a secretory/endocrine function [7]. Cytokines and other peptides produced, expressed and released by muscle cells are called myokines. Proteomics analyses identified over 650 proteins and peptides produced by muscle cells, yet their precise biological role has been characterized only in a minority of cases [49]. Myokines act in an autocrine, paracrine or endocrine way. In fact, some myokines exert their effect on muscle itself, taking part in muscle hypertrophy and myogenesis, while other myokines are involved in the regulation of energy metabolism. There is now solid evidence that skeletal muscle, through the production of myokines, communicates with other key organs and regulates lipid mobilization from adipose tissue, liver endogenous glucose production, insulin secretion and thermogenesis [50].
Many myokines are produced in response to the contraction of muscle fibers and may indeed mediate protective effects of physical exercise and counteract the pathological consequences of a sedentary lifestyle.
Several myokines act precisely within skeletal muscle itself and are involved in muscle cell proliferation, differentiation, and regeneration [51,52]; others are involved in mediating energy supply during exercise (Table 1).
It is now believed that every stage of the myogenic process involves regulation by myokines, many of which contribute to myogenic regulation at different stages, from satellite cell proliferation to differentiation and cell survival [49,53].
The role of IGF-1 and IGF-2 as endocrine modulators of myogenesis has been extensively studied [54], as they seem indispensable for the initiation of differentiation [55]; IGF-1 leads to muscle hypertrophy by activating satellite cells and possibly inhibiting autophagy [56]. Impairment of IGF-1 signaling has been described in chronic disorders, and as such, represents a possible mechanism in muscle atrophy led by altered protein synthesis, autophagy, and impaired muscle regeneration [57].
Furthermore, IL-7 plays an essential role in myogenesis and may influence the differentiation of satellite cells into fully developed skeletal muscle cells [58].
On the other hand, TGF-beta has shown to be a strong inhibitor of myogenic differentiation in vitro [59]. Myostatin, the first discovered myokine, is a member of the TGF-beta superfamily and plays a key role in muscle growth and differentiation, by controlling the proliferation of myoblasts (as a major negative regulator of skeletal muscle growth) and suppressing satellite cell activation and myoblast proliferation [60,61]; it is known that the deletion of the myostatin gene causes massive muscle hypertrophy in animals [62,63].
More recently, follistatin and decorin have been identified as potent inducers of muscle hypertrophy with an anti-myostatin function [64]; in particular, decorin acts in an auto/paracrine manner as a direct antagonist of myostatin [65]. Although myokine IL-6 is mainly known for its role in the regulation of lipid and glucose metabolism, it has also been shown that it has an anabolic effect in the processes of myogenesis [66]. Leukemia inhibitory factor (LIF) also exerts an autocrine/paracrine action [67], and it has proven to be crucial for satellite cell proliferation and survival [67].
Apart from the regulatory effects on myogenesis, many myokines act on metabolic pathways in the modulation of energy metabolism. IL-6 [50] and brain-derived neurotrophic factor (BDNF) [68] are involved in activating fat oxidation in muscle cells. Indeed, IL-6 signaling within muscle cells appears to affect both glucose uptake and fat oxidation, and its role in GLUT4 translocation has been described [69]. In addition, several studies described an increase in intramyocellular and whole-body fatty acid oxidation in response to myokine IL-6 [69,70]. BDNF affects myogenesis through activation of satellite cells [71], especially in response to muscle injury; it has also been suggested as a regulator of neuromuscular function during the aging process, with possible implications in sarcopenia and SO [72]. Indeed, low levels of BDNF are described in subjects with obesity and T2D [73].
Table
Table 1. Selected myokine functions.
Table 1. Selected myokine functions.
FunctionMyokineAgingReferences
Myogenesis and muscle hypertrophymyostatin
LIF
IL-6
IL-7
IL-15
musclin
follistatin
decorin
myonectin
IGF-1
musclin 		⇑
?
⇑
⇓
⇓
?
⇓
⇓
⇓
⇓
?		[61,74]
[67]
[66,75]
[58]
[76]
[77]
[64,78]
[79,80]
[81]
[56]
[82]
Muscle-cell FFA oxidationIL-6
BDNF
irisin
myonectin 		⇑
⇓
⇓
⇓		[69,83]
[68]
[84]
[81]
Insulin sensitivityIL-6
IL-15
SPARC
LIF
BMP-7
mitsugumin 53		⇑
⇓
⇓
?
⇓
?		[7,69]
[85,86]
[87]
[88]
[89]
[90]
OsteogenesisIGF-1
decorin
IL-6 		⇓
⇓
⇑		[91]
[92]
[93]
Browning of WATIrisin
IL-6
meteorin-like
FGF-21
BAIBA
follistatin
myonectin
BMP-7		⇓
⇑
?
⇓
⇓
⇓
?
⇓		[84]
[94]
[95]
[96]
[97,98]
[99]
[100]
[101]
LipolysisIL-6
FGF-21
ANGPTL-4		⇑
⇓
?		[7]
[102]
[103]
Muscle innervationBDNF
FGFBP-1		⇓
?		[104]
[105]
Muscle angiogenesisIL-8
VEGF-A		⇓
?		[76]
[106,107]
LIF: leukemia inhibitory factor; IL-6: interleukin-6; IL-7: interleukin-7; IL-15: interleukin-15; BDNF: brain-derived neurotrophic factor; IGF-1: insulin-like growth factor-1; SPARC, secreted protein acidic and rich in cysteine; BMP-7, bone morphogenetic protein-7; FGF-21: fibroblast growth factor 21; BAIBA: β-aminoisobutyric acid; CNTFR-A: ciliary neurotrophic factor receptor-A; ANGPTL-4, angiopoietin-like protein 4; FGFBP-1, fibroblast growth factor binding protein 1; VEGF-A: vascular endothelial growth factor-A.

5. Muscle Mass Changes across Aging

Aging-related decline in skeletal muscle structure (quantity and quality) and function, known as sarcopenia, occurs as a result of aging. This process takes place slowly but represents a critical and significant event during the aging process.
After the age of 50, muscle mass declines yearly in men and in women, with reduced muscle fiber number and size, mainly due to a progressive loss of motoneurons.
Muscle quality significantly changes with aging, and this process occurs earlier than the reduction in muscle mass. The muscle’s architecture is modified, type II fibers decline, and vasculature is reduced. Fat deposition inside muscles, called myosteatosis and characterized by both inter- and intra-muscular fat, rises significantly with aging together with fibrosis affecting insulin sensitivity as well as peak muscle force generation, leading to impaired mobility and metabolic dysfunction in older adults [108,109].
Modification of muscle proteins and loss of coordinated control between contractile, mitochondrial and sarcoplasmic reticulum protein occur, with mitochondria alterations. Finally, progressive motoneuron loss occurs, and this is not adequately compensated by reinnervation of muscle fibers by the remaining motoneurons [108].
Aging-related muscle changes are also due to the secretion of myokines. The contents of various myokines, such as interleukin IL-6, irisin, myostatin, brain-derived neurotrophic factor (BDNF) and apelin change correspondingly with increasing age [110]. During aging, an increase in the muscle cells’ expression of pro-inflammatory cytokines (IL-6, IL-1β and TNF-α) is observed, leading to skeletal muscle atrophy [108].
Absolute serum irisin concentrations are significantly higher in the young compared to older adults. With increasing age and the occurrence of muscle atrophy in aged mice and older humans, the level of circulating irisin decreases [111].
Serum levels of BDNF myokine, widely expressed in different cell types and essential in regulating cardiomyocyte contraction, also decrease with aging [112].
Apelin, through the activation of AMPK signaling, has been shown to be an important promoter of mitochondrial biogenesis and muscle cell regeneration. Apelin production is induced by muscle contraction and is reduced with aging [113].
Myostatin is the most famous myokine in the muscle field; besides its well-established role in muscle wasting, there are gaps in the evidence. For instance, the relationship between serum myostatin and skeletal muscle mass in humans remains controversial [114]. Some authors observed an inverse relationship between age-related muscle loss and serum myostatin levels in the frail elderly [115], while skeletal muscle atrophy associated with lower myostatin levels has also been observed [116].

6. Muscle–Adipose Tissue Crosstalk: Role of Myokines

There is strong evidence, from proteomics studies using in vitro and in vivo models, that many myokines are key endocrine mediators in glucose and lipid metabolism, especially in response to exercise, through crosstalk with other tissues, including WAT. IL-6 is known to increase lipolysis and fatty acid release from WAT [117]; it has been observed that exercise training leading to reduction in VAT was avoided by IL-6 receptor blockade with tocilizumab (IL-6 receptor antibody) [118].
Irisin is one of the myokines of greatest interest, produced in response to muscle contraction and secreted after cleavage of the intracellular form FNDC5 [84]; irisin influences energy homeostasis, and it is a key regulator in adipocyte metabolism, since it is thought to be a bridge between exercise and metabolic homeostasis. Irisin has been proposed as the main mediator in WAT browning and an activator of thermogenesis, which promotes an increase in energy expenditure, thus preventing fat gain [119]. Irisin also improves the structure and strength of cortical bone, as a key player in muscle–bone crosstalk [120,121].
Myonectin has also been shown to act on WAT; as with irisin, it is produced in response to muscle contraction and appears to be involved in the regulation of FFA uptake in adipocytes in vitro [81]. Interestingly, myonectin transcription in muscle cells can be up-regulated with the addition of FFA and glucose, which suggests a role in muscle–adipose tissue crosstalk that informs tissues of nutrient status and promotes nutrient uptake and storage [81,122].
Evidence suggests a unique picture for the action of FGF-21 in muscle and adipose tissue crosstalk [102]; FGF-21 has also been shown to be secreted by muscle cells, in addition to the liver and WAT, which contributes to reducing blood glucose and plasma TG levels as well as increasing insulin sensitivity [123]. In fact, FGF21 produced by muscle cells seems to have an interesting effect on adipocytes, modulating their gene expression, for example, by increasing the expression of adiponectin [124]. Kim et al. [125] demonstrated that FGF21 deficiency exacerbated obesity-induced inflammation and atrophic responses in the skeletal muscle of obese mice. Collectively, these data suggest that FGF21 could protect the body against obesity and insulin resistance [123].
Apelin was, until recently, described as an adipokine [126] whose expression and circulating levels were increased in obesity [127]; further evidence showed that apelin is also produced by myocytes during muscle contraction [128]. Available evidence indicates that it has beneficial effects on glucose and lipid metabolism both in WAT and skeletal muscle [129,130,131,132].
Alongside its role in promoting muscle trophism, improvement of glucose tolerance has also been described for decorin; decorin-knockout mice showed higher leptin levels and impaired glucose tolerance [133].
Recent evidence suggests that several myokines may induce browning of WAT, thus enhancing global energy expenditure [134]. In fact, exercise-induced circulating factors (“exerkines”) are able to modulate activation of brown adipose tissue (BAT) and browning of WAT by activating uncoupling protein 1 (UCP1) [135]. Exercise training as well as cold exposure and dietary components are associated with the enhanced accumulation of metabolically active beige adipocytes and BAT activation in adult humans [136,137]. The expression of UCP1 is modulated by PGC-1α, which is dependent on several myokines: irisin, βaminoisobutyric acid (BAIBA), myostatin, follistatin, decorin, meteorin-like (Mtrn-like), IL-6 and lactate [134]. The regulation of the PI3K-AKT pathway and the expression of UCP1 in BAT is upregulated by irisin [135]. A role of FGF-21 in the browning of WAT has also been hypothesized [94,96].
Other molecules potentially implicated in WAT browning and energy expenditure regulation include BAIBA and meteorin-like [95]. BAIBA is a small aminoacidic metabolite derived from valine and thyamine catabolism and is released by contracting myocytes [97]; its role in the beiging of WAT has been described by Roberts et al. [97], and it has also been hypothesized as an actor in suppressing inflammation in skeletal muscle and WAT, as well as in boosting insulin sensitivity [97,138,139]. Similar to many other myokines, its levels are reduced with aging [140,141]. BAIBA involves specific PPARα-dependent mechanisms and exhibits an increased BAT-specific gene expression (Pgc1a, Ucp1, Cidea and Cytc) in both mice and humans, as well as increased mitochondrial activity [134]. The Mtrn-like glial cell differentiation regulator is a novel protein secreted by muscle cells that increases after training and promotes mitochondrial gene programs in WAT and energy expenditure by increasing the brown/beige shift of adipose cells [95]. The browning effect of Mtrn-like shared with the better known irisin, however, seems to be mediated by an indirect mechanism, with the involvement of immune cells in the muscle and WAT crosstalk [95]. Moreover, the myogenic effects of Mtrn-like seem to be mediated by an anti-inflammatory response triggered by macrophage activation [142]. The release into circulation of Mtrn-like indirectly leads to an increased expression of UCP1, via an eosinophil-dependent mechanism and the eosinophil-specific chemokines IL-4 and IL-13, and promotes the activation of WAT macrophages, which produce catecholamines and ultimately activate a pro-thermogenic program [49,134].

7. Adipose Tissue Muscle Crosstalk: Role of Adipokines

The first evidence of a link between WAT and muscle mass arises from the fact that muscle alterations in terms of quantity and quality are observed in individuals with both WAT deficiency [143] and excess.
WAT excess or dysfunction may be related to muscle damage through the excessive FFA production by hypertrophic adipocytes that may accumulate in and between muscle fibers ectopically. This determines mitochondrial dysfunction, increased ROS production during FFA oxidation and accumulation of reactive lipids in skeletal muscle and leads to lipotoxicity, a process that contributes substantially to the pathophysiology of insulin resistance, sarcopenia and SO [144].
Furthermore, several adipokines have been shown to produce positive or negative effects on skeletal muscle [145,146].
Hypertrophic adipocytes increase the secretion of proinflammatory adipokines, determining insulin resistance and thus muscle protein catabolism and protein synthesis inhibition [8,147].
Leptin is one of the most abundant circulating adipokines released by SAT. It induces myocyte cell proliferation and some myogenic factors, since it can also suppress myostatin as a negative regulator of muscle growth and some atrophy markers such as MuRF1, which promotes muscle growth. Leptin activates the Akt/mechanistic target of the rapamycin (mTOR) signaling cascade [148,149]. C2C12 derived myotubes’ exposure to leptin has been shown to increase protein synthesis, decrease degradation and increase myoblast proliferation [150].
The role of leptin in muscle mass has been recently confirmed in a study conducted in fat-free lipodystrophic mice with decreased muscle mass and strength, in which a full rescue of muscle mass, in term of quantity and function, was observed after replacement of just ∼10% of normal WAT, and in which this effect was shown to be independently due to leptin and separable from the reversal of systemic metabolic derangement [151].
However, in the case of obesity, aging and chronic disease, hyperleptinemia induces leptin resistance, which limits muscle FFA oxidation and precludes any of the above-mentioned positive effects of leptin on muscle.
Leptin activates white adipose cell differentiation towards a BAT-like phenotype through the activation of sympathetic nerve activity. Furthermore, leptin and insulin act synergistically on distinct POMC neuronal subsets to promote WAT browning. Interestingly, leptin has different effects in skeletal muscle and in SAT. In the former, it increases Fndc5 gene expression levels and stimulates irisin-induced muscle growth, while in the latter, it downregulates the transcript levels of Fndc5 [134]. Adipocyte-derived FGF-21 activates the thermogenic gene expression, mediated by central (via sympathetic activation) and local (via induction of the PGC-1α protein) mechanisms. Anti-inflammatory M2 macrophages, whose proliferation is promoted by adiponectin, have recently been proposed as an important source of norepinephrine, a hormone involved in browning and thermogenesis in BAT [134].
Adiponectin is another peptide secreted by adipocytes with known anti-inflammatory and insulin sensitizer properties. Adiponectin has also been found to be expressed by skeletal muscle cells [152]. Adiponectin increases FFA oxidation and glucose uptake in skeletal muscle and inhibits hepatic gluconeogenesis. Furthermore, high intensity aerobic physical activity has been shown to increase plasma levels of adiponectin [110], and upregulation of adiponectin receptors in skeletal muscle of severely obese subjects in response to endurance training has been observed. Some evidence of the effect of resistin and chemerin on muscle cells has been observed in vitro: chronic incubation of resistin in skeletal muscle cells has been found to decrease fatty acid uptake and metabolism as well as to reduce basal and insulin-stimulated glucose uptake, oxidation, and glycogen synthesis, while incubation of skeletal muscle cells with chemerin promotes proliferation and suppresses differentiation of muscle cells through ERK1/2 and mTOR signaling pathways [145,153]. Chemerin, whose gene expression has been shown to be altered in WAT and skeletal muscle of obese/diabetic mice, worsens insulin sensitivity in myocytes and adipocytes [154].
BAT is also able to secrete different factors, called batokines, such as prostaglandin, endothelin, IL-6, fibroblast growth factor-21, myostatin and CXCL14, which contribute to fat browning [155]. Preadipocytes from myostatin-deficient mice have exhibited an increased propensity to differentiate into brown fat cells, which secrete CXCL14, leading to adaptive thermogenesis via M2 macrophage recruitment, enhancing BAT activation as well as the browning of WAT [134].

8. Adipomyokines and MicroRNA in the Crosstalk between AT and Muscle

Overlap between myokines and adipokines exists; in fact, several cytokines, called adipomyokines, secreted from skeletal muscle cells, are also secreted by adipocytes [110,156], confirming the existence of a strong interplay between muscle and WAT. Adipomyokines show a variety of actions; a general overview is summarized in Table 2. Myostatin, known as an inhibitor of myocyte differentiation and proliferation, is one of the best characterized adipomyokines.
Myostatin is upregulated in animal models of obesity, and elevated myostatin levels have been observed in obese subjects [157,158]. By collecting muscle biopsies in extremely obese women, a strong correlation has been found between the gene expression of myostatin and BMI and insulin-resistance [159]. Apart from its effects on muscle trophism and metabolism [160], myostatin has also shown to be a positive regulator of adipogenesis [161]. Across aging, augmented levels of myostatin may lead to the reduction of the age-related muscle mass [115]; this effect could also be accentuated by the possible role of myostatin in the inhibition of irisin synthesis, which contributes to decline in muscle mass as well as to rise of fat mass, and ultimately leads to SO [162]. Myostatin is negatively related to the expression of key brown (Pgc1a, Ucp1, Prdm16, Cidea and Dio2) and beige (Tmem26 and Cd137) WAT-specific genes [163]. Loss of myostatin leads to decreased miR-34a expression, which subsequently promotes Fndc5 expression, thereby increasing thermogenic gene expression and browning in WAT.
IL-15 is an exercise-modulated adipomyokine, with documented anabolic effects on muscle, for example, by reducing protein degradation [164] and regulatory effects on muscle oxidative metabolism, and in particular by increasing FFA oxidation and mitochondrial density [165,166] as well as reduction of lipogenesis and gluconeogenesis [167]. IL-15 can reduce VAT in mice and humans [164,168,169,170]; this effect could be mediated by IL-15 effects on adipocytes, which includes proliferation rate reduction and apoptosis [171]. Moreover, IL-15 inhibits the accumulation of lipids in preadipocytes and stimulates the secretion of adiponectin, which indirectly reduces WAT mass [170]. Evidence suggests that IL-15 is involved in reciprocal interplay between muscle and WAT, which provides beneficial effects in glucose and lipid metabolism.
Micro RNAs can be also involved in the crosstalk between WAT and muscle mass. MiRNAs expressed in skeletal muscles are defined as myomiRs; a role in myocyte differentiation and proliferation has been described for and includes miR-133b, miR-133a, miR-208a, miR-208b and miR-486 [172,173]. MiR27 mediates the communication between AT and skeletal muscle [174]. Administration of a miR-33a mimetic to primary duck myoblasts reduced proliferation while its inhibition led to its augmentation [175].
Table
Table 2. Selected adipomyokines in muscle and adipose tissue crosstalk.
Table 2. Selected adipomyokines in muscle and adipose tissue crosstalk.
AdipomyokineEffects–Skeletal MuscleEffects—Adipose TissueAgingReferences
IL-6 +muscle hypertrophy
+glucose uptake
+glycogenolysis, lipolysis		+lipolysis
+free fatty acid (FFA) oxidation
browning of WAT		⇑[7,69]
Irisin+glucose uptake
+muscle trophism 		+lipolysis
browning of WAT 		⇓[176,177]
IL-15+glucose uptake
+mitochondrial activity 		−lipid accumulation
+adiponectin secretion 		⇓[169,171,178]
BAIBA+mitochondrial FFA oxidation
+insulin sensitivity 		+mitochondrial FFA oxidation ⇓[97,139]
Meteorin-like +energy expenditure
+glucose tolerance		browning of WAT ?[95]
LIF+muscle hypertrophy
+satellite cell proliferation
regeneration after muscle damage		+adipocyte differentiation⇓[67]
Myostatin - muscle hypertrophy+adipogenesis⇑[60,161,179,180]
Apelin improves muscle metabolismglucose uptake
−lipid storage		⇓[129,130,131,132]
ANGPTL4+FFA oxidation+lipolysis?[103,181]
FGF-21+thermogenesis +glucose uptake ⇓[182,183]
Follistatin-like 1+endothelial cells function and survival ?[184,185]
IL-8+insulin resistance +insulin resistance ⇓[186,187]
MCP-1−glucose uptake ?[187]
PEDF+insulin resistance
+ectopic lipid deposition		+insulin resistance
+pro-inflammatory pathway 		?[188,189]
IL-6: nterleukin-6; IL-15: interleukin-15; BAIBA: β-aminoisobutyric acid; LIF: leukemia inhibitory factor; ANGPTL-4, angiopoietin-like protein 4; FGF-21: fibroblast growth factor-21; IL-8, interleukin-8; MCP-1, monocyte chemoattractant protein-1; PEDF, pigment epithelium-derived factor; "−": decreased; "+": increased.

9. Conclusions

With aging, loss of muscle mass and gain in fat occur and contribute, in the presence of a positive energy balance, to the development of SO [1], a condition frequently observed in the elderly. SO has been clearly recognized as a clinical condition linked to worse outcomes than obesity itself [1,2,190]. Hence, prevention and treatment of SO are mandatory. Crosstalk between muscle cells and adipose cells is one of many mechanisms that lead to SO. However, prevention strategies may help to reduce the occurrence of SO by correcting crosstalk between muscle and adipose cells.
There is some evidence that the release of some myokines by the skeletal muscle is increased by physical activity, across all age groups [191,192]. Yet the evidence currently available paints a complex picture, and there are still some gaps concerning the types and intensity of physical exercise required [193].
Some studies have already investigated the influence of nutrition on myokine production [194]. A role in the modulation of WAT and muscle cell function has been hypothesized for caloric restriction, dietary supplementation of polyphenols, prebiotics or probiotics, and 3-n PUFA [194]. Prevention of weight gain with aging as well as the promotion of an active lifestyle may be a strategy for preserving WAT function and muscle mass and to improve the interplay between muscle mass and WAT.

Author Contributions

Conceptualization: M.Z., F.F. and E.Z.; methodology: M.Z., A.B., S.U.; validation: M.Z. and F.F.; investigation: G.M., S.U., A.B., E.Z. and M.Z.; writing—original draft preparation: M.Z., F.F., S.U., A.B., T.S., E.Z., G.M. and A.P.R.; writing—review and editing: M.Z., F.F., S.U., A.B., T.S., E.Z., G.M., A.G. and A.P.R.; supervision: M.Z. and F.F. All authors have read and agreed to the published version of the manuscript.

Funding

This project was supported by grants from Fondazione Cariplo (2016-1006 to Mauro Zamboni).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Acknowledgments

This article has been revised by a native English speaker, Mark Jeffrey Newman.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Donini, L.M.; Busetto, L.; Bischoff, S.C.; Cederholm, T.; Ballesteros-Pomar, M.D.; Batsis, J.A.; Bauer, J.M.; Boirie, Y.; Cruz-Jentoft, A.J.; Dicker, D.; et al. Definition and Diagnostic Criteria for Sarcopenic Obesity: ESPEN and EASO Consensus Statement. Obes. Facts 2022, 15, 321–335. [Google Scholar] [CrossRef] [PubMed]
  2. Zamboni, M.; Mazzali, G.; Fantin, F.; Rossi, A.; di Francesco, V. Sarcopenic Obesity: A New Category of Obesity in the Elderly. Nutr. Metab. Cardiovasc. Dis. 2008, 18, 388–395. [Google Scholar] [CrossRef] [PubMed]
  3. Batsis, J.A.; Villareal, D.T. Sarcopenic Obesity in Older Adults: Aetiology, Epidemiology and Treatment Strategies. Nat. Rev. Endocrinol. 2018, 14, 513–537. [Google Scholar] [CrossRef] [PubMed]
  4. Kim, Y.J.; Tamadon, A.; Park, H.T.; Kim, H.; Ku, S.-Y. The Role of Sex Steroid Hormones in the Pathophysiology and Treatment of Sarcopenia. Osteoporos. Sarcopenia 2016, 2, 140–155. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  5. Wawrzkiewicz-Jałowiecka, A.; Lalik, A.; Soveral, G. Recent Update on the Molecular Mechanisms of Gonadal Steroids Action in Adipose Tissue. Int. J. Mol. Sci. 2021, 22, 5226. [Google Scholar] [CrossRef]
  6. Funcke, J.-B.; Scherer, P.E. Beyond Adiponectin and Leptin: Adipose Tissue-Derived Mediators of Inter-Organ Communication. J. Lipid. Res. 2019, 60, 1648–1684. [Google Scholar] [CrossRef]
  7. Pedersen, B.K.; Febbraio, M.A. Muscle as an Endocrine Organ: Focus on Muscle-Derived Interleukin-6. Physiol. Rev. 2008, 88, 1379–1406. [Google Scholar] [CrossRef] [Green Version]
  8. Kershaw, E.E.; Flier, J.S. Adipose Tissue as an Endocrine Organ. J. Clin. Endocrinol. Metab. 2004, 89, 2548–2556. [Google Scholar] [CrossRef]
  9. Bosello, O.; Zamboni, M. Visceral Obesity and Metabolic Syndrome. Obes. Rev. 2000, 1, 47–56. [Google Scholar] [CrossRef]
  10. Kwon, H.; Kim, D.; Kim, J.S. Body Fat Distribution and the Risk of Incident Metabolic Syndrome: A Longitudinal Cohort Study. Sci. Rep. 2017, 7, 10955. [Google Scholar] [CrossRef]
  11. Hube, F.; Lietz, U.; Igel, M.; Jensen, P.; Tornqvist, H.; Joost, H.-G.; Hauner, H. Difference in Leptin MRNA Levels Between Omental and Subcutaneous Abdominal Adipose Tissue From Obese Humans. Horm. Metab. Res. 1996, 28, 690–693. [Google Scholar] [CrossRef]
  12. Lefebvre, A.-M.; Laville, M.; Vega, N.; Riou, J.P.; van Gaal, L.; Auwerx, J.; Vidal, H. Depot-Specific Differences in Adipose Tissue Gene Expression in Lean and Obese Subjects. Diabetes 1998, 47, 98–103. [Google Scholar] [CrossRef] [PubMed]
  13. Trayhurn, P.; Bing, C. Appetite and Energy Balance Signals from Adipocytes. Philos. Trans. R. Soc. B Biol. Sci. 2006, 361, 1237–1249. [Google Scholar] [CrossRef]
  14. Zhao, S.; Kusminski, C.M.; Scherer, P.E. Adiponectin, Leptin and Cardiovascular Disorders. Circ. Res. 2021, 128, 136–149. [Google Scholar] [CrossRef] [PubMed]
  15. Goldstein, B.J.; Scalia, R. Adiponectin: A Novel Adipokine Linking Adipocytes and Vascular Function. J. Clin. Endocrinol. Metab. 2004, 89, 2563–2568. [Google Scholar] [CrossRef] [Green Version]
  16. Guenther, M.; James, R.; Marks, J.; Zhao, S.; Szabo, A.; Kidambi, S. Adiposity Distribution Influences Circulating Adiponectin Levels. Transl. Res. 2014, 164, 270–277. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  17. Ryo, M.; Nakamura, T.; Kihara, S.; Kumada, M.; Shibazaki, S.; Takahashi, M.; Nagai, M.; Matsuzawa, Y.; Funahashi, T. Adiponectin as a Biomarker of the Metabolic Syndrome. Circ. J. 2004, 68, 975–981. [Google Scholar] [CrossRef] [Green Version]
  18. Weisberg, S.P.; McCann, D.; Desai, M.; Rosenbaum, M.; Leibel, R.L.; Ferrante, A.W. Obesity Is Associated with Macrophage Accumulation in Adipose Tissue. J. Clin. Investig. 2003, 112, 1796–1808. [Google Scholar] [CrossRef]
  19. Colleluori, G.; Villareal, D.T. Aging, Obesity, Sarcopenia and the Effect of Diet and Exercise Intervention. Exp. Gerontol. 2021, 155, 111561. [Google Scholar] [CrossRef]
  20. Hotamisligil, G.S. Inflammation, Metaflammation and Immunometabolic Disorders. Nature 2017, 542, 177–185. [Google Scholar] [CrossRef]
  21. Cinti, S.; Mitchell, G.; Barbatelli, G.; Murano, I.; Ceresi, E.; Faloia, E.; Wang, S.; Fortier, M.; Greenberg, A.S.; Obin, M.S. Adipocyte Death Defines Macrophage Localization and Function in Adipose Tissue of Obese Mice and Humans. J. Lipid. Res. 2005, 46, 2347–2355. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Zamboni, M.; Mazzali, G.; Zoico, E.; Harris, T.B.; Meigs, J.B.; di Francesco, V.; Fantin, F.; Bissoli, L.; Bosello, O. Health Consequences of Obesity in the Elderly: A Review of Four Unresolved Questions. Int. J. Obes. 2005, 29, 1011–1029. [Google Scholar] [CrossRef] [Green Version]
  23. Cruz-Jentoft, A.J.; Bahat, G.; Bauer, J.; Boirie, Y.; Bruyère, O.; Cederholm, T.; Cooper, C.; Landi, F.; Rolland, Y.; Sayer, A.A.; et al. Sarcopenia: Revised European Consensus on Definition and Diagnosis. Age Ageing 2019, 48, 16–31. [Google Scholar] [CrossRef] [Green Version]
  24. Zamboni, M.; Rossi, A.P.; Fantin, F.; Budui, S.L.; Zoico, E.; Zamboni, G.A.; Mazzali, G. Predictors of Ectopic Fat in Humans. Curr. Obes. Rep. 2014, 3, 404–413. [Google Scholar] [CrossRef] [PubMed]
  25. Zamboni, M.; Nori, N.; Brunelli, A.; Zoico, E. How Does Adipose Tissue Contribute to Inflammageing? Exp. Gerontol. 2021, 143, 111162. [Google Scholar] [CrossRef]
  26. Santoro, A.; Bientinesi, E.; Monti, D. Immunosenescence and Inflammaging in the Aging Process: Age-Related Diseases or Longevity? Ageing Res. Rev. 2021, 71, 101422. [Google Scholar] [CrossRef]
  27. Johnson, K.O.; Shannon, O.M.; Matu, J.; Holliday, A.; Ispoglou, T.; Deighton, K. Differences in Circulating Appetite-Related Hormone Concentrations between Younger and Older Adults: A Systematic Review and Meta-Analysis. Aging Clin. Exp. Res. 2020, 32, 1233–1244. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  28. Picard, F.; Carter, S.; Caron, A.; Richard, D. Role of Leptin Resistance in the Development of Obesity in Older Patients. Clin. Interv. Aging 2013, 8, 829. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Kizer, J.R.; Arnold, A.M.; Jenny, N.S.; Cushman, M.; Strotmeyer, E.S.; Ives, D.G.; Ding, J.; Kritchevsky, S.B.; Chaves, P.H.M.; Hirsch, C.H.; et al. Longitudinal Changes in Adiponectin and Inflammatory Markers and Relation to Survival in the Oldest Old: The Cardiovascular Health Study All Stars Study. J. Gerontol. A Biol. Sci. Med. Sci. 2011, 66, 1100–1107. [Google Scholar] [CrossRef]
  30. Arai, Y.; Kamide, K.; Hirose, N. Adipokines and Aging: Findings From Centenarians and the Very Old. Front. Endocrinol. 2019, 10, 142. [Google Scholar] [CrossRef]
  31. Mancuso, P.; Bouchard, B. The Impact of Aging on Adipose Function and Adipokine Synthesis. Front. Endocrinol. 2019, 10, 137. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Baker, J.F.; Newman, A.B.; Kanaya, A.; Leonard, M.B.; Zemel, B.; Miljkovic, I.; Long, J.; Weber, D.; Harris, T.B. The Adiponectin Paradox in the Elderly: Associations With Body Composition, Physical Functioning, and Mortality. J. Gerontol. Ser. A 2019, 74, 247–253. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Yu, Y.-H.; Zhu, H. Chronological Changes in Metabolism and Functions of Cultured Adipocytes: A Hypothesis for Cell Aging in Mature Adipocytes. Am. J. Physiol. Endocrinol. Metab. 2004, 286, E402–E410. [Google Scholar] [CrossRef]
  34. Zoico, E.; Rizzatti, V.; Policastro, G.; Tebon, M.; Darra, E.; Rossi, A.P.; Mazzali, G.; Fantin, F.; Zamboni, M. In Vitro Model of Chronological Aging of Adipocytes: Interrelationships with Hypoxia and Oxidation. Exp. Gerontol. 2019, 121, 81–90. [Google Scholar] [CrossRef]
  35. Zoico, E.; di Francesco, V.; Olioso, D.; Fratta Pasini, A.M.; Sepe, A.; Bosello, O.; Cinti, S.; Cominacini, L.; Zamboni, M. In Vitro Aging of 3T3-L1 Mouse Adipocytes Leads to Altered Metabolism and Response to Inflammation. Biogerontology 2010, 11, 111–122. [Google Scholar] [CrossRef]
  36. Palmer, A.K.; Kirkland, J.L. Aging and Adipose Tissue: Potential Interventions for Diabetes and Regenerative Medicine. Exp. Gerontol. 2016, 86, 97–105. [Google Scholar] [CrossRef] [Green Version]
  37. Lumeng, C.N.; Saltiel, A.R. Inflammatory Links between Obesity and Metabolic Disease. J. Clin. Investig. 2011, 121, 2111–2117. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Garg, S.K.; Delaney, C.; Shi, H.; Yung, R. Changes in Adipose Tissue Macrophages and T Cells during Aging. Crit. Rev. Immunol. 2014, 34, 1–14. [Google Scholar] [CrossRef]
  39. Nakagami, H. Cellular Senescence and Senescence-Associated T Cells as a Potential Therapeutic Target. Geriatr. Gerontol. Int. 2020, 20, 97–100. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  40. Kalathookunnel Antony, A.; Lian, Z.; Wu, H. T Cells in Adipose Tissue in Aging. Front. Immunol. 2018, 9, 2945. [Google Scholar] [CrossRef]
  41. Kirkland, J.L.; Tchkonia, T.; Pirtskhalava, T.; Han, J.; Karagiannides, I. Adipogenesis and Aging: Does Aging Make Fat Go MAD? Exp. Gerontol. 2002, 37, 757–767. [Google Scholar] [CrossRef]
  42. Carobbio, S.; Pellegrinelli, V.; Vidal-Puig, A. Adipose Tissue Function and Expandability as Determinants of Lipotoxicity and the Metabolic Syndrome. Adv. Exp. Med. Biol. 2017, 960, 161–196. [Google Scholar] [CrossRef]
  43. Sepe, A.; Tchkonia, T.; Thomou, T.; Zamboni, M.; Kirkland, J.L. Aging and Regional Differences in Fat Cell Progenitors—A Mini-Review. Gerontology 2011, 57, 66–75. [Google Scholar] [CrossRef] [Green Version]
  44. Donato, A.J.; Henson, G.D.; Hart, C.R.; Layec, G.; Trinity, J.D.; Bramwell, R.C.; Enz, R.A.; Morgan, R.G.; Reihl, K.D.; Hazra, S.; et al. The Impact of Ageing on Adipose Structure, Function and Vasculature in the B6D2F1 Mouse: Evidence of Significant Multisystem Dysfunction. J. Physiol. 2014, 592, 4083–4096. [Google Scholar] [CrossRef]
  45. Tardif, N.; Salles, J.; Guillet, C.; Tordjman, J.; Reggio, S.; Landrier, J.-F.; Giraudet, C.; Patrac, V.; Bertrand-Michel, J.; Migne, C.; et al. Muscle Ectopic Fat Deposition Contributes to Anabolic Resistance in Obese Sarcopenic Old Rats through EIF2α Activation. Aging Cell 2014, 13, 1001–1011. [Google Scholar] [CrossRef]
  46. Khan, T.; Muise, E.S.; Iyengar, P.; Wang, Z.V.; Chandalia, M.; Abate, N.; Zhang, B.B.; Bonaldo, P.; Chua, S.; Scherer, P.E. Metabolic Dysregulation and Adipose Tissue Fibrosis: Role of Collagen VI. Mol. Cell. Biol. 2009, 29, 1575–1591. [Google Scholar] [CrossRef] [Green Version]
  47. Tchkonia, T.; Lenburg, M.; Thomou, T.; Giorgadze, N.; Frampton, G.; Pirtskhalava, T.; Cartwright, A.; Cartwright, M.; Flanagan, J.; Karagiannides, I.; et al. Identification of Depot-Specific Human Fat Cell Progenitors through Distinct Expression Profiles and Developmental Gene Patterns. Am. J. Physiol. Endocrinol. Metab. 2007, 292, E298–E307. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Tchkonia, T.; Kirkland, J.L. Aging, Cell Senescence, and Chronic Disease: Emerging Therapeutic Strategies. JAMA 2018, 320, 1319–1320. [Google Scholar] [CrossRef]
  49. Severinsen, M.C.K.; Pedersen, B.K. Muscle-Organ Crosstalk: The Emerging Roles of Myokines. Endocr. Rev. 2020, 41, 594–609. [Google Scholar] [CrossRef] [PubMed]
  50. Pedersen, B.K.; Febbraio, M.A. Muscles, Exercise and Obesity: Skeletal Muscle as a Secretory Organ. Nat. Rev. Endocrinol. 2012, 8, 457–465. [Google Scholar] [CrossRef]
  51. Henningsen, J.; Rigbolt, K.T.G.; Blagoev, B.; Pedersen, B.K.; Kratchmarova, I. Dynamics of the Skeletal Muscle Secretome during Myoblast Differentiation. Mol. Cell. Proteom. 2010, 9, 2482–2496. [Google Scholar] [CrossRef] [Green Version]
  52. Henningsen, J.; Pedersen, B.K.; Kratchmarova, I. Quantitative Analysis of the Secretion of the MCP Family of Chemokines by Muscle Cells. Mol. Biosyst. 2011, 7, 311–321. [Google Scholar] [CrossRef] [Green Version]
  53. Waldemer-Streyer, R.J.; Kim, D.; Chen, J. Muscle Cell-Derived Cytokines in Skeletal Muscle Regeneration. FEBS J. 2022, 24, 16372. [Google Scholar] [CrossRef] [PubMed]
  54. Florini, J.R.; Ewton, D.Z.; Coolican, S.A. Growth Hormone and the Insulin-Like Growth Factor System in Myogenesis*. Endocr. Rev. 1996, 17, 481–517. [Google Scholar] [CrossRef] [Green Version]
  55. Florini, J.R.; Magri, K.A.; Ewton, D.Z.; James, P.L.; Grindstaff, K.; Rotwein, P.S. “Spontaneous” Differentiation of Skeletal Myoblasts Is Dependent upon Autocrine Secretion of Insulin-like Growth Factor-II. J. Biol. Chem. 1991, 266, 15917–15923. [Google Scholar] [CrossRef]
  56. Yoshida, T.; Delafontaine, P. Mechanisms of IGF-1-Mediated Regulation of Skeletal Muscle Hypertrophy and Atrophy. Cells 2020, 9, 1970. [Google Scholar] [CrossRef] [PubMed]
  57. Ahmad, S.S.; Ahmad, K.; Lee, E.J.; Lee, Y.-H.; Choi, I. Implications of Insulin-Like Growth Factor-1 in Skeletal Muscle and Various Diseases. Cells 2020, 9, 1773. [Google Scholar] [CrossRef] [PubMed]
  58. Haugen, F.; Norheim, F.; Lian, H.; Wensaas, A.J.; Dueland, S.; Berg, O.; Funderud, A.; Skålhegg, B.S.; Raastad, T.; Drevon, C.A. IL-7 Is Expressed and Secreted by Human Skeletal Muscle Cells. Am. J. Physiol. Cell Physiol. 2010, 298, C807–C816. [Google Scholar] [CrossRef] [Green Version]
  59. Olson, E.N.; Sternberg, E.; Hu, J.S.; Spizz, G.; Wilcox, C. Regulation of Myogenic Differentiation by Type Beta Transforming Growth Factor. J. Cell. Biol. 1986, 103, 1799–1805. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  60. Joulia, D.; Bernardi, H.; Garandel, V.; Rabenoelina, F.; Vernus, B.; Cabello, G. Mechanisms Involved in the Inhibition of Myoblast Proliferation and Differentiation by Myostatin. Exp. Cell. Res. 2003, 286, 263–275. [Google Scholar] [CrossRef]
  61. McPherron, A.C.; Lawler, A.M.; Lee, S.J. Regulation of Skeletal Muscle Mass in Mice by a New TGF-Beta Superfamily Member. Nature 1997, 387, 83–90. [Google Scholar] [CrossRef]
  62. Grobet, L.; Martin, L.J.; Poncelet, D.; Pirottin, D.; Brouwers, B.; Riquet, J.; Schoeberlein, A.; Dunner, S.; Ménissier, F.; Massabanda, J.; et al. A Deletion in the Bovine Myostatin Gene Causes the Double-Muscled Phenotype in Cattle. Nat. Genet. 1997, 17, 71–74. [Google Scholar] [CrossRef] [PubMed]
  63. Mosher, D.S.; Quignon, P.; Bustamante, C.D.; Sutter, N.B.; Mellersh, C.S.; Parker, H.G.; Ostrander, E.A. A Mutation in the Myostatin Gene Increases Muscle Mass and Enhances Racing Performance in Heterozygote Dogs. PLoS Genet. 2007, 3, e79. [Google Scholar] [CrossRef] [PubMed]
  64. Gilson, H.; Schakman, O.; Kalista, S.; Lause, P.; Tsuchida, K.; Thissen, J.-P. Follistatin Induces Muscle Hypertrophy through Satellite Cell Proliferation and Inhibition of Both Myostatin and Activin. Am. J. Physiol. Endocrinol. Metab. 2009, 297, E157–E164. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. el Shafey, N.; Guesnon, M.; Simon, F.; Deprez, E.; Cosette, J.; Stockholm, D.; Scherman, D.; Bigey, P.; Kichler, A. Inhibition of the Myostatin/Smad Signaling Pathway by Short Decorin-Derived Peptides. Exp. Cell. Res. 2016, 341, 187–195. [Google Scholar] [CrossRef] [PubMed]
  66. Serrano, A.L.; Baeza-Raja, B.; Perdiguero, E.; Jardí, M.; Muñoz-Cánoves, P. Interleukin-6 Is an Essential Regulator of Satellite Cell-Mediated Skeletal Muscle Hypertrophy. Cell Metab. 2008, 7, 33–44. [Google Scholar] [CrossRef] [Green Version]
  67. Broholm, C.; Pedersen, B.K. Leukaemia Inhibitory Factor--an Exercise-Induced Myokine. Exerc. Immunol. Rev. 2010, 16, 77–85. [Google Scholar]
  68. Matthews, V.B.; Aström, M.-B.; Chan, M.H.S.; Bruce, C.R.; Krabbe, K.S.; Prelovsek, O.; Akerström, T.; Yfanti, C.; Broholm, C.; Mortensen, O.H.; et al. Brain-Derived Neurotrophic Factor Is Produced by Skeletal Muscle Cells in Response to Contraction and Enhances Fat Oxidation via Activation of AMP-Activated Protein Kinase. Diabetologia 2009, 52, 1409–1418. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Carey, A.L.; Steinberg, G.R.; Macaulay, S.L.; Thomas, W.G.; Holmes, A.G.; Ramm, G.; Prelovsek, O.; Hohnen-Behrens, C.; Watt, M.J.; James, D.E.; et al. Interleukin-6 Increases Insulin-Stimulated Glucose Disposal in Humans and Glucose Uptake and Fatty Acid Oxidation In Vitro via AMP-Activated Protein Kinase. Diabetes 2006, 55, 2688–2697. [Google Scholar] [CrossRef] [Green Version]
  70. Petersen, E.W.; Carey, A.L.; Sacchetti, M.; Steinberg, G.R.; Macaulay, S.L.; Febbraio, M.A.; Pedersen, B.K. Acute IL-6 Treatment Increases Fatty Acid Turnover in Elderly Humans in Vivo and in Tissue Culture in Vitro. Am. J. Physiol. Endocrinol. Metab. 2005, 288, E155–E162. [Google Scholar] [CrossRef]
  71. Colombo, E.; Bedogni, F.; Lorenzetti, I.; Landsberger, N.; Previtali, S.C.; Farina, C. Autocrine and Immune Cell-Derived BDNF in Human Skeletal Muscle: Implications for Myogenesis and Tissue Regeneration. J. Pathol. 2013, 231, 190–198. [Google Scholar] [CrossRef] [PubMed]
  72. Guo, A.; Li, K.; Xiao, Q. Sarcopenic Obesity: Myokines as Potential Diagnostic Biomarkers and Therapeutic Targets? Exp. Gerontol. 2020, 139, 111022. [Google Scholar] [CrossRef] [PubMed]
  73. Li, B.; Lang, N.; Cheng, Z.-F. Serum Levels of Brain-Derived Neurotrophic Factor Are Associated with Diabetes Risk, Complications, and Obesity: A Cohort Study from Chinese Patients with Type 2 Diabetes. Mol. Neurobiol. 2016, 53, 5492–5499. [Google Scholar] [CrossRef]
  74. Allen, D.L.; Hittel, D.S.; McPherron, A.C. Expression and Function of Myostatin in Obesity, Diabetes, and Exercise Adaptation. Med. Sci. Sports Exerc. 2011, 43, 1828–1835. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  75. Gao, S.; Durstine, J.L.; Koh, H.-J.; Carver, W.E.; Frizzell, N.; Carson, J.A. Acute Myotube Protein Synthesis Regulation by IL-6-Related Cytokines. Am. J. Physiol. Cell Physiol. 2017, 313, C487–C500. [Google Scholar] [CrossRef] [Green Version]
  76. Nielsen, A.R.; Pedersen, B.K. The Biological Roles of Exercise-Induced Cytokines: IL-6, IL-8, and IL-15. Appl. Physiol. Nutr. Metab. 2007, 32, 833–839. [Google Scholar] [CrossRef]
  77. Re Cecconi, A.D.; Forti, M.; Chiappa, M.; Zhu, Z.; Zingman, L.V.; Cervo, L.; Beltrame, L.; Marchini, S.; Piccirillo, R. Musclin, A Myokine Induced by Aerobic Exercise, Retards Muscle Atrophy During Cancer Cachexia in Mice. Cancers 2019, 11, 1541. [Google Scholar] [CrossRef] [Green Version]
  78. Kota, J.; Handy, C.R.; Haidet, A.M.; Montgomery, C.L.; Eagle, A.; Rodino-Klapac, L.R.; Tucker, D.; Shilling, C.J.; Therlfall, W.R.; Walker, C.M.; et al. Follistatin Gene Delivery Enhances Muscle Growth and Strength in Nonhuman Primates. Sci. Transl. Med. 2009, 1, 6ra15. [Google Scholar] [CrossRef] [Green Version]
  79. Miura, T.; Kishioka, Y.; Wakamatsu, J.; Hattori, A.; Hennebry, A.; Berry, C.J.; Sharma, M.; Kambadur, R.; Nishimura, T. Decorin Binds Myostatin and Modulates Its Activity to Muscle Cells. Biochem. Biophys. Res. Commun. 2006, 340, 675–680. [Google Scholar] [CrossRef]
  80. Kanzleiter, T.; Rath, M.; Görgens, S.W.; Jensen, J.; Tangen, D.S.; Kolnes, A.J.; Kolnes, K.J.; Lee, S.; Eckel, J.; Schürmann, A.; et al. The Myokine Decorin Is Regulated by Contraction and Involved in Muscle Hypertrophy. Biochem. Biophys. Res. Commun. 2014, 450, 1089–1094. [Google Scholar] [CrossRef]
  81. Seldin, M.M.; Peterson, J.M.; Byerly, M.S.; Wei, Z.; Wong, G.W. Myonectin (CTRP15), a Novel Myokine That Links Skeletal Muscle to Systemic Lipid Homeostasis. J. Biol. Chem. 2012, 287, 11968–11980. [Google Scholar] [CrossRef] [PubMed]
  82. Subbotina, E.; Sierra, A.; Zhu, Z.; Gao, Z.; Koganti, S.R.K.; Reyes, S.; Stepniak, E.; Walsh, S.A.; Acevedo, M.R.; Perez-Terzic, C.M.; et al. Musclin Is an Activity-Stimulated Myokine That Enhances Physical Endurance. Proc. Natl. Acad. Sci. USA 2015, 112, 16042–16047. [Google Scholar] [CrossRef] [Green Version]
  83. Bruce, C.R.; Dyck, D.J. Cytokine Regulation of Skeletal Muscle Fatty Acid Metabolism: Effect of Interleukin-6 and Tumor Necrosis Factor-α. Am. J. Physiol. Endocrinol. Metab. 2004, 287, E616–E621. [Google Scholar] [CrossRef] [PubMed]
  84. Boström, P.; Wu, J.; Jedrychowski, M.P.; Korde, A.; Ye, L.; Lo, J.C.; Rasbach, K.A.; Boström, E.A.; Choi, J.H.; Long, J.Z.; et al. A PGC1-α-Dependent Myokine That Drives Brown-Fat-like Development of White Fat and Thermogenesis. Nature 2012, 481, 463–468. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Quinn, L.; Straitbodey, L.; Anderson, B.; Argiles, J.; Havel, P. Interleukin-15 Stimulates Adiponectin Secretion by 3T3-L1 Adipocytes: Evidence for a Skeletal Muscle-to-Fat Signaling Pathway. Cell. Biol. Int. 2005, 29, 449–457. [Google Scholar] [CrossRef] [Green Version]
  86. Krolopp, J.E.; Thornton, S.M.; Abbott, M.J. IL-15 Activates the Jak3/STAT3 Signaling Pathway to Mediate Glucose Uptake in Skeletal Muscle Cells. Front. Physiol. 2016, 7, 626. [Google Scholar] [CrossRef] [Green Version]
  87. Aoi, W.; Hirano, N.; Lassiter, D.G.; Björnholm, M.; Chibalin, A.V.; Sakuma, K.; Tanimura, Y.; Mizushima, K.; Takagi, T.; Naito, Y.; et al. Secreted Protein Acidic and Rich in Cysteine (SPARC) Improves Glucose Tolerance via AMP-activated Protein Kinase Activation. FASEB J. 2019, 33, 10551–10562. [Google Scholar] [CrossRef] [Green Version]
  88. Brandt, N.; O’Neill, H.M.; Kleinert, M.; Schjerling, P.; Vernet, E.; Steinberg, G.R.; Richter, E.A.; Jørgensen, S.B. Leukemia Inhibitory Factor Increases Glucose Uptake in Mouse Skeletal Muscle. Am. J. Physiol. -Endocrinol. Metab. 2015, 309, E142–E153. [Google Scholar] [CrossRef] [Green Version]
  89. Chattopadhyay, T.; Singh, R.R.; Gupta, S.; Surolia, A. Bone Morphogenetic Protein-7 (BMP-7) Augments Insulin Sensitivity in Mice with Type II Diabetes Mellitus by Potentiating PI3K/AKT Pathway. BioFactors 2017, 43, 195–209. [Google Scholar] [CrossRef]
  90. Wu, H.-K.; Zhang, Y.; Cao, C.-M.; Hu, X.; Fang, M.; Yao, Y.; Jin, L.; Chen, G.; Jiang, P.; Zhang, S.; et al. Glucose-Sensitive Myokine/Cardiokine MG53 Regulates Systemic Insulin Response and Metabolic Homeostasis. Circulation 2019, 139, 901–914. [Google Scholar] [CrossRef]
  91. Perrini, S.; Laviola, L.; Carreira, M.C.; Cignarelli, A.; Natalicchio, A.; Giorgino, F. The GH/IGF1 Axis and Signaling Pathways in the Muscle and Bone: Mechanisms Underlying Age-Related Skeletal Muscle Wasting and Osteoporosis. J. Endocrinol. 2010, 205, 201–210. [Google Scholar] [CrossRef] [PubMed]
  92. Kaji, H. Effects of Myokines on Bone. Bonekey Rep. 2016, 5, 826. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Axmann, R.; Böhm, C.; Krönke, G.; Zwerina, J.; Smolen, J.; Schett, G. Inhibition of Interleukin-6 Receptor Directly Blocks Osteoclast Formation In Vitro and In Vivo. Arthritis Rheum. 2009, 60, 2747–2756. [Google Scholar] [CrossRef] [PubMed]
  94. Kharitonenkov, A.; Shiyanova, T.L.; Koester, A.; Ford, A.M.; Micanovic, R.; Galbreath, E.J.; Sandusky, G.E.; Hammond, L.J.; Moyers, J.S.; Owens, R.A.; et al. FGF-21 as a Novel Metabolic Regulator. J. Clin. Investig. 2005, 115, 1627–1635. [Google Scholar] [CrossRef] [Green Version]
  95. Rao, R.R.; Long, J.Z.; White, J.P.; Svensson, K.J.; Lou, J.; Lokurkar, I.; Jedrychowski, M.P.; Ruas, J.L.; Wrann, C.D.; Lo, J.C.; et al. Meteorin-like Is a Hormone That Regulates Immune-Adipose Interactions to Increase Beige Fat Thermogenesis. Cell 2014, 157, 1279–1291. [Google Scholar] [CrossRef] [Green Version]
  96. Véniant, M.M.; Sivits, G.; Helmering, J.; Komorowski, R.; Lee, J.; Fan, W.; Moyer, C.; Lloyd, D.J. Pharmacologic Effects of FGF21 Are Independent of the “Browning” of White Adipose Tissue. Cell Metab. 2015, 21, 731–738. [Google Scholar] [CrossRef] [Green Version]
  97. Roberts, L.D.; Boström, P.; O’Sullivan, J.F.; Schinzel, R.T.; Lewis, G.D.; Dejam, A.; Lee, Y.-K.; Palma, M.J.; Calhoun, S.; Georgiadi, A.; et al. β-Aminoisobutyric Acid Induces Browning of White Fat and Hepatic β-Oxidation and Is Inversely Correlated with Cardiometabolic Risk Factors. Cell Metab. 2014, 19, 96–108. [Google Scholar] [CrossRef] [Green Version]
  98. Tanianskii, D.A.; Jarzebska, N.; Birkenfeld, A.L.; O’Sullivan, J.F.; Rodionov, R.N. Beta-Aminoisobutyric Acid as a Novel Regulator of Carbohydrate and Lipid Metabolism. Nutrients 2019, 11, 524. [Google Scholar] [CrossRef] [Green Version]
  99. Singh, R.; Braga, M.; Pervin, S. Regulation of Brown Adipocyte Metabolism by Myostatin/Follistatin Signaling. Front. Cell Dev. Biol. 2014, 2, 60. [Google Scholar] [CrossRef] [Green Version]
  100. Peterson, J.M.; Mart, R.; Bond, C.E. Effect of Obesity and Exercise on the Expression of the Novel Myokines, Myonectin and Fibronectin Type III Domain Containing 5. PeerJ 2014, 2, e605. [Google Scholar] [CrossRef] [Green Version]
  101. Tseng, Y.-H.; Kokkotou, E.; Schulz, T.J.; Huang, T.L.; Winnay, J.N.; Taniguchi, C.M.; Tran, T.T.; Suzuki, R.; Espinoza, D.O.; Yamamoto, Y.; et al. New Role of Bone Morphogenetic Protein 7 in Brown Adipogenesis and Energy Expenditure. Nature 2008, 454, 1000–1004. [Google Scholar] [CrossRef] [PubMed]
  102. Cuevas-Ramos, D.; Aguilar-Salinas, C.A. Modulation of Energy Balance by Fibroblast Growth Factor 21. Horm. Mol. Biol. Clin. Investig 2016, 30. [Google Scholar] [CrossRef] [PubMed]
  103. Staiger, H.; Haas, C.; Machann, J.; Werner, R.; Weisser, M.; Schick, F.; Machicao, F.; Stefan, N.; Fritsche, A.; Häring, H.-U. Muscle-Derived Angiopoietin-Like Protein 4 Is Induced by Fatty Acids via Peroxisome Proliferator–Activated Receptor (PPAR)-δ and Is of Metabolic Relevance in Humans. Diabetes 2009, 58, 579–589. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Sakuma, K.; Yamaguchi, A. The Recent Understanding of the Neurotrophin’s Role in Skeletal Muscle Adaptation. J. Biomed. Biotechnol. 2011, 2011, 201696. [Google Scholar] [CrossRef] [Green Version]
  105. Taetzsch, T.; Tenga, M.J.; Valdez, G. Muscle Fibers Secrete FGFBP1 to Slow Degeneration of Neuromuscular Synapses during Aging and Progression of ALS. J. Neurosci. 2017, 37, 70–82. [Google Scholar] [CrossRef] [Green Version]
  106. Hoier, B.; Hellsten, Y. Exercise-Induced Capillary Growth in Human Skeletal Muscle and the Dynamics of VEGF. Microcirculation 2014, 21, 301–314. [Google Scholar] [CrossRef]
  107. Jensen, L.; Schjerling, P.; Hellsten, Y. Regulation of VEGF and BFGF MRNA Expression and Other Proliferative Compounds in Skeletal Muscle Cells. Angiogenesis 2004, 7, 255–267. [Google Scholar] [CrossRef]
  108. Larsson, L.; Degens, H.; Li, M.; Salviati, L.; Lee, Y.I.; Thompson, W.; Kirkland, J.L.; Sandri, M. Sarcopenia: Aging-Related Loss of Muscle Mass and Function. Physiol. Rev. 2019, 99, 427–511. [Google Scholar] [CrossRef]
  109. Correa-De-Araujo, R.; Rossi, A.P.; Zamboni, M.; Addison, O.; Miljkovic, I.; Goodpaster, B. Editorial: Muscle Quality in Skeletal Muscle Function Deficit: Recent Advances and Potential Clinical and Therapeutic Implications. Front. Physiol. 2022, 13, 847883. [Google Scholar] [CrossRef]
  110. Li, J.; Wang, Z.; Li, C.; Song, Y.; Wang, Y.; Bo, H.; Zhang, Y. Impact of Exercise and Aging on Mitochondrial Homeostasis in Skeletal Muscle: Roles of ROS and Epigenetics. Cells 2022, 11, 2086. [Google Scholar] [CrossRef]
  111. Huh, J.Y.; Mougios, V.; Kabasakalis, A.; Fatouros, I.; Siopi, A.; Douroudos, I.I.; Filippaios, A.; Panagiotou, G.; Park, K.H.; Mantzoros, C.S. Exercise-Induced Irisin Secretion Is Independent of Age or Fitness Level and Increased Irisin May Directly Modulate Muscle Metabolism Through AMPK Activation. J. Clin. Endocrinol. Metab. 2014, 99, E2154–E2161. [Google Scholar] [CrossRef] [PubMed]
  112. Elia, A.; Cannavo, A.; Gambino, G.; Cimini, M.; Ferrara, N.; Kishore, R.; Paolocci, N.; Rengo, G. Aging Is Associated with Cardiac Autonomic Nerve Fiber Depletion and Reduced Cardiac and Circulating BDNF Levels. J. Geriatr. Cardiol. 2021, 18, 549–559. [Google Scholar] [CrossRef] [PubMed]
  113. Dray, C.; Knauf, C.; Daviaud, D.; Waget, A.; Boucher, J.; Buléon, M.; Cani, P.D.; Attané, C.; Guigné, C.; Carpéné, C.; et al. Apelin Stimulates Glucose Utilization in Normal and Obese Insulin-Resistant Mice. Cell Metab. 2008, 8, 437–445. [Google Scholar] [CrossRef] [PubMed]
  114. Peng, L.-N.; Lee, W.-J.; Liu, L.-K.; Lin, M.-H.; Chen, L.-K. Healthy Community-Living Older Men Differ from Women in Associations between Myostatin Levels and Skeletal Muscle Mass. J. Cachexia Sarcopenia Muscle 2018, 9, 635–642. [Google Scholar] [CrossRef]
  115. Yarasheski, K.E.; Bhasin, S.; Sinha-Hikim, I.; Pak-Loduca, J.; Gonzalez-Cadavid, N.F. Serum Myostatin-Immunoreactive Protein Is Increased in 60-92 Year Old Women and Men with Muscle Wasting. J. Nutr. Health Aging 2002, 6, 343–348. [Google Scholar]
  116. Jeanplong, F.; Osepchook, C.C.; Falconer, S.J.; Smith, H.K.; Bass, J.J.; McMahon, C.D.; Oldham, J.M. Undernutrition Regulates the Expression of a Novel Splice Variant of Myostatin and Insulin-like Growth Factor 1 in Ovine Skeletal Muscle. Domest. Anim. Endocrinol. 2015, 52, 17–24. [Google Scholar] [CrossRef]
  117. Wueest, S.; Item, F.; Boyle, C.N.; Jirkof, P.; Cesarovic, N.; Ellingsgaard, H.; Böni-Schnetzler, M.; Timper, K.; Arras, M.; Donath, M.Y.; et al. Interleukin-6 Contributes to Early Fasting-Induced Free Fatty Acid Mobilization in Mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2014, 306, R861–R867. [Google Scholar] [CrossRef]
  118. Wedell-Neergaard, A.-S.; Lang Lehrskov, L.; Christensen, R.H.; Legaard, G.E.; Dorph, E.; Larsen, M.K.; Launbo, N.; Fagerlind, S.R.; Seide, S.K.; Nymand, S.; et al. Exercise-Induced Changes in Visceral Adipose Tissue Mass Are Regulated by IL-6 Signaling: A Randomized Controlled Trial. Cell Metab. 2019, 29, 844–855.e3. [Google Scholar] [CrossRef]
  119. Graf, C.; Ferrari, N. Metabolic Health—The Role of Adipo-Myokines. Int. J. Mol. Sci. 2019, 20, 6159. [Google Scholar] [CrossRef] [Green Version]
  120. Colaianni, G.; Mongelli, T.; Cuscito, C.; Pignataro, P.; Lippo, L.; Spiro, G.; Notarnicola, A.; Severi, I.; Passeri, G.; Mori, G.; et al. Irisin Prevents and Restores Bone Loss and Muscle Atrophy in Hind-Limb Suspended Mice. Sci. Rep. 2017, 7, 2811. [Google Scholar] [CrossRef] [Green Version]
  121. Gomarasca, M.; Banfi, G.; Lombardi, G. Myokines: The Endocrine Coupling of Skeletal Muscle and Bone. Adv. Clin. Chem. 2020, 94, 155–218. [Google Scholar] [CrossRef] [PubMed]
  122. Seldin, M.M.; Wong, G.W. Regulation of Tissue Crosstalk by Skeletal Muscle-Derived Myonectin and Other Myokines. Adipocyte 2012, 1, 200–202. [Google Scholar] [CrossRef] [PubMed]
  123. Katsu-Jiménez, Y.; Giménez-Cassina, A. Fibroblast Growth Factor-21 Promotes Ketone Body Utilization in Neurons through Activation of AMP-Dependent Kinase. Mol. Cell. Neurosci. 2019, 101, 103415. [Google Scholar] [CrossRef] [PubMed]
  124. Lin, Z.; Tian, H.; Lam, K.S.L.; Lin, S.; Hoo, R.C.L.; Konishi, M.; Itoh, N.; Wang, Y.; Bornstein, S.R.; Xu, A.; et al. Adiponectin Mediates the Metabolic Effects of FGF21 on Glucose Homeostasis and Insulin Sensitivity in Mice. Cell Metab. 2013, 17, 779–789. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  125. Kim, C.-S.; Joe, Y.; Choi, H.-S.; Back, S.H.; Park, J.W.; Chung, H.T.; Roh, E.; Kim, M.-S.; Ha, T.Y.; Yu, R. Deficiency of Fibroblast Growth Factor 21 Aggravates Obesity-Induced Atrophic Responses in Skeletal Muscle. J. Inflamm. 2019, 16, 17. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  126. Castan-Laurell, I.; Boucher, J.; Dray, C.; Daviaud, D.; Guigné, C.; Valet, P. Apelin, a Novel Adipokine over-Produced in Obesity: Friend or Foe? Mol. Cell. Endocrinol. 2005, 245, 7–9. [Google Scholar] [CrossRef]
  127. Boucher, J.; Masri, B.; Daviaud, D.; Gesta, S.; Guigné, C.; Mazzucotelli, A.; Castan-Laurell, I.; Tack, I.; Knibiehler, B.; Carpéné, C.; et al. Apelin, a Newly Identified Adipokine Up-Regulated by Insulin and Obesity. Endocrinology 2005, 146, 1764–1771. [Google Scholar] [CrossRef]
  128. Besse-Patin, A.; Montastier, E.; Vinel, C.; Castan-Laurell, I.; Louche, K.; Dray, C.; Daviaud, D.; Mir, L.; Marques, M.-A.; Thalamas, C.; et al. Effect of Endurance Training on Skeletal Muscle Myokine Expression in Obese Men: Identification of Apelin as a Novel Myokine. Int. J. Obes. 2014, 38, 707–713. [Google Scholar] [CrossRef]
  129. Higuchi, K.; Masaki, T.; Gotoh, K.; Chiba, S.; Katsuragi, I.; Tanaka, K.; Kakuma, T.; Yoshimatsu, H. Apelin, an APJ Receptor Ligand, Regulates Body Adiposity and Favors the Messenger Ribonucleic Acid Expression of Uncoupling Proteins in Mice. Endocrinology 2007, 148, 2690–2697. [Google Scholar] [CrossRef]
  130. Son, J.S.; Kim, H.J.; Son, Y.; Lee, H.; Chae, S.A.; Seong, J.K.; Song, W. Effects of exercise-induced apelin levels on skeletal muscle and their capillarization in type 2 diabetic rats. Muscle Nerve. 2017, 56, 1155–1163. [Google Scholar] [CrossRef]
  131. Yue, P.; Jin, H.; Aillaud, M.; Deng, A.C.; Azuma, J.; Asagami, T.; Kundu, R.K.; Reaven, G.M.; Quertermous, T.; Tsao, P.S. Apelin Is Necessary for the Maintenance of Insulin Sensitivity. Am. J. Physiol. Endocrinol. Metab. 2010, 298, E59–E67. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  132. Attané, C.; Foussal, C.; le Gonidec, S.; Benani, A.; Daviaud, D.; Wanecq, E.; Guzmán-Ruiz, R.; Dray, C.; Bezaire, V.; Rancoule, C.; et al. Apelin Treatment Increases Complete Fatty Acid Oxidation, Mitochondrial Oxidative Capacity, and Biogenesis in Muscle of Insulin-Resistant Mice. Diabetes 2012, 61, 310–320. [Google Scholar] [CrossRef] [PubMed]
  133. Svärd, J.; Røst, T.H.; Sommervoll, C.E.N.; Haugen, C.; Gudbrandsen, O.A.; Mellgren, A.E.; Rødahl, E.; Fernø, J.; Dankel, S.N.; Sagen, J.V.; et al. Absence of the Proteoglycan Decorin Reduces Glucose Tolerance in Overfed Male Mice. Sci. Rep. 2019, 9, 4614. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Rodríguez, A.; Catalán, V.; Ramírez, B.; Unamuno, X.; Portincasa, P.; Gómez-Ambrosi, J.; Frühbeck, G.; Becerril, S. Impact of Adipokines and Myokines on Fat Browning. J. Physiol. Biochem. 2020, 76, 227–240. [Google Scholar] [CrossRef] [PubMed]
  135. Kim, H.J.; Kim, Y.J.; Seong, J.K. AMP-Activated Protein Kinase Activation in Skeletal Muscle Modulates Exercise-Induced Uncoupled Protein 1 Expression in Brown Adipocyte in Mouse Model. J. Physiol. 2022, 600, 2359–2376. [Google Scholar] [CrossRef]
  136. Severinsen, M.C.K.; Schéele, C.; Pedersen, B.K. Exercise and Browning of White Adipose Tissue—A Translational Perspective. Curr. Opin. Pharmacol. 2020, 52, 18–24. [Google Scholar] [CrossRef]
  137. Scheel, A.K.; Espelage, L.; Chadt, A. Many Ways to Rome: Exercise, Cold Exposure and Diet-Do They All Affect BAT Activation and WAT Browning in the Same Manner? Int. J. Mol. Sci. 2022, 23, 4759. [Google Scholar] [CrossRef]
  138. Kamei, Y.; Hatazawa, Y.; Uchitomi, R.; Yoshimura, R.; Miura, S. Regulation of Skeletal Muscle Function by Amino Acids. Nutrients 2020, 12, 261. [Google Scholar] [CrossRef] [Green Version]
  139. Jung, T.W.; Park, H.S.; Choi, G.H.; Kim, D.; Lee, T. β-Aminoisobutyric Acid Attenuates LPS-Induced Inflammation and Insulin Resistance in Adipocytes through AMPK-Mediated Pathway. J. Biomed. Sci. 2018, 25, 27. [Google Scholar] [CrossRef] [Green Version]
  140. Ginter, E.; Simko, V. Recent Data on Obesity Research: β-Aminoisobutyric Acid. Bratisl. Med. J. 2014, 115, 492–493. [Google Scholar] [CrossRef]
  141. Hangelbroek, R.W.J.; Fazelzadeh, P.; Tieland, M.; Boekschoten, M.V.; Hooiveld, G.J.E.J.; van Duynhoven, J.P.M.; Timmons, J.A.; Verdijk, L.B.; de Groot, L.C.P.G.M.; van Loon, L.J.C.; et al. Expression of Protocadherin Gamma in Skeletal Muscle Tissue Is Associated with Age and Muscle Weakness. J. Cachexia Sarcopenia Muscle 2016, 7, 604–614. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  142. Baht, G.S.; Bareja, A.; Lee, D.E.; Rao, R.R.; Huang, R.; Huebner, J.L.; Bartlett, D.B.; Hart, C.R.; Gibson, J.R.; Lanza, I.R.; et al. Meteorin-like Facilitates Skeletal Muscle Repair through a Stat3/IGF-1 Mechanism. Nat. Metab. 2020, 2, 278–289. [Google Scholar] [CrossRef]
  143. Akinci, G.; Topaloglu, H.; Demir, T.; Danyeli, A.E.; Talim, B.; Keskin, F.E.; Kadioglu, P.; Talip, E.; Altay, C.; Yaylali, G.F.; et al. Clinical Spectra of Neuromuscular Manifestations in Patients with Lipodystrophy: A Multicenter Study. Neuromuscul. Disord. 2017, 27, 923–930. [Google Scholar] [CrossRef] [PubMed]
  144. Unger, R.H. Longevity, Lipotoxicity and Leptin: The Adipocyte Defense against Feasting and Famine. Biochimie 2005, 87, 57–64. [Google Scholar] [CrossRef] [PubMed]
  145. Li, F.; Li, Y.; Duan, Y.; Hu, C.-A.A.; Tang, Y.; Yin, Y. Myokines and Adipokines: Involvement in the Crosstalk between Skeletal Muscle and Adipose Tissue. Cytokine Growth Factor Rev. 2017, 33, 73–82. [Google Scholar] [CrossRef]
  146. Nicholson, T.; Church, C.; Baker, D.J.; Jones, S.W. The Role of Adipokines in Skeletal Muscle Inflammation and Insulin Sensitivity. J. Inflamm. 2018, 15, 9. [Google Scholar] [CrossRef] [Green Version]
  147. Lynch, G.M.; Murphy, C.H.; de Castro, E.M.; Roche, H.M. Inflammation and Metabolism: The Role of Adiposity in Sarcopenic Obesity. Proc. Nutr. Soc. 2020, 79, 435–447. [Google Scholar] [CrossRef]
  148. Minard, A.Y.; Tan, S.-X.; Yang, P.; Fazakerley, D.J.; Domanova, W.; Parker, B.L.; Humphrey, S.J.; Jothi, R.; Stöckli, J.; James, D.E. MTORC1 Is a Major Regulatory Node in the FGF21 Signaling Network in Adipocytes. Cell Rep. 2016, 17, 29–36. [Google Scholar] [CrossRef] [Green Version]
  149. Rodríguez, A.; Catalán, V.; Gómez-Ambrosi, J.; García-Navarro, S.; Rotellar, F.; Valentí, V.; Silva, C.; Gil, M.J.; Salvador, J.; Burrell, M.A.; et al. Insulin- and Leptin-Mediated Control of Aquaglyceroporins in Human Adipocytes and Hepatocytes Is Mediated via the PI3K/Akt/MTOR Signaling Cascade. J. Clin. Endocrinol. Metab. 2011, 96, E586–E597. [Google Scholar] [CrossRef] [Green Version]
  150. Arounleut, P.; Bowser, M.; Upadhyay, S.; Shi, X.-M.; Fulzele, S.; Johnson, M.H.; Stranahan, A.M.; Hill, W.D.; Isales, C.M.; Hamrick, M.W. Absence of Functional Leptin Receptor Isoforms in the POUND (Lepr(Db/Lb)) Mouse Is Associated with Muscle Atrophy and Altered Myoblast Proliferation and Differentiation. PLoS ONE 2013, 8, e72330. [Google Scholar] [CrossRef]
  151. Collins, K.H.; Gui, C.; Ely, E.V.; Lenz, K.L.; Harris, C.A.; Guilak, F.; Meyer, G.A. Leptin Mediates the Regulation of Muscle Mass and Strength by Adipose Tissue. J. Physiol. 2022, 600, 3795–3817. [Google Scholar] [CrossRef] [PubMed]
  152. Krause, M.P.; Liu, Y.; Vu, V.; Chan, L.; Xu, A.; Riddell, M.C.; Sweeney, G.; Hawke, T.J. Adiponectin Is Expressed by Skeletal Muscle Fibers and Influences Muscle Phenotype and Function. Am. J. Physiol. Cell Physiol. 2008, 295, C203–C212. [Google Scholar] [CrossRef] [PubMed]
  153. Yang, H.; Li, F.; Kong, X.; Yuan, X.; Wang, W.; Huang, R.; Li, T.; Geng, M.; Wu, G.; Yin, Y. Chemerin Regulates Proliferation and Differentiation of Myoblast Cells via ERK1/2 and MTOR Signaling Pathways. Cytokine 2012, 60, 646–652. [Google Scholar] [CrossRef] [PubMed]
  154. Becker, M.; Rabe, K.; Lebherz, C.; Zugwurst, J.; Göke, B.; Parhofer, K.G.; Lehrke, M.; Broedl, U.C. Expression of Human Chemerin Induces Insulin Resistance in the Skeletal Muscle but Does Not Affect Weight, Lipid Levels, and Atherosclerosis in LDL Receptor Knockout Mice on High-Fat Diet. Diabetes 2010, 59, 2898–2903. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  155. da Silva, G.N.; Amato, A.A. Thermogenic Adipose Tissue Aging: Mechanisms and Implications. Front. Cell. Dev. Biol. 2022, 10, 955612. [Google Scholar] [CrossRef]
  156. de Oliveira dos Santos, A.R.; de Oliveira Zanuso, B.; Miola, V.F.B.; Barbalho, S.M.; Santos Bueno, P.C.; Flato, U.A.P.; Detregiachi, C.R.P.; Buchaim, D.V.; Buchaim, R.L.; Tofano, R.J.; et al. Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions. Int. J. Mol. Sci. 2021, 22, 2639. [Google Scholar] [CrossRef]
  157. Haines, M.S.; Dichtel, L.E.; Kimball, A.; Bollinger, B.; Gerweck, A.V.; Bredella, M.A.; Miller, K.K. OR26-03 Lower Serum Myostatin Levels Are Associated with Higher Insulin Sensitivity in Adults with Overweight/Obesity. J. Endocr. Soc. 2020, 4, OR26-03. [Google Scholar] [CrossRef]
  158. Amor, M.; Itariu, B.K.; Moreno-Viedma, V.; Keindl, M.; Jürets, A.; Prager, G.; Langer, F.; Grablowitz, V.; Zeyda, M.; Stulnig, T.M. Serum Myostatin Is Upregulated in Obesity and Correlates with Insulin Resistance in Humans. Exp. Clin. Endocrinol. Diabetes 2019, 127, 550–556. [Google Scholar] [CrossRef]
  159. Hittel, D.S.; Berggren, J.R.; Shearer, J.; Boyle, K.; Houmard, J.A. Increased Secretion and Expression of Myostatin in Skeletal Muscle From Extremely Obese Women. Diabetes 2009, 58, 30–38. [Google Scholar] [CrossRef] [Green Version]
  160. Hjorth, M.; Pourteymour, S.; Görgens, S.W.; Langleite, T.M.; Lee, S.; Holen, T.; Gulseth, H.L.; Birkeland, K.I.; Jensen, J.; Drevon, C.A.; et al. Myostatin in Relation to Physical Activity and Dysglycaemia and Its Effect on Energy Metabolism in Human Skeletal Muscle Cells. Acta Physiol. 2016, 217, 45–60. [Google Scholar] [CrossRef]
  161. Lin, J.; Arnold, H.B.; Della-Fera, M.A.; Azain, M.J.; Hartzell, D.L.; Baile, C.A. Myostatin Knockout in Mice Increases Myogenesis and Decreases Adipogenesis. Biochem. Biophys. Res. Commun. 2002, 291, 701–706. [Google Scholar] [CrossRef] [PubMed]
  162. CONSITT, L.A.; CLARK, B.C. The vicious cycle of myostatin signaling in sarcopenic obesity: Myostatin role in skeletal muscle growth, insulin signaling and implications for clinical trials. J. Frailty Aging 2017, 7, 21–27. [Google Scholar] [CrossRef] [PubMed]
  163. Shan, T.; Liang, X.; Bi, P.; Kuang, S. Myostatin Knockout Drives Browning of White Adipose Tissue through Activating the AMPK-PGC1α-Fndc5 Pathway in Muscle. FASEB J. 2013, 27, 1981–1989. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  164. Nielsen, A.R.; Mounier, R.; Plomgaard, P.; Mortensen, O.H.; Penkowa, M.; Speerschneider, T.; Pilegaard, H.; Pedersen, B.K. Expression of Interleukin-15 in Human Skeletal Muscle Effect of Exercise and Muscle Fibre Type Composition. J. Physiol. 2007, 584, 305–312. [Google Scholar] [CrossRef] [PubMed]
  165. Quinn, L.S.; Anderson, B.G.; Conner, J.D.; Wolden-Hanson, T. IL-15 Overexpression Promotes Endurance, Oxidative Energy Metabolism, and Muscle PPARδ, SIRT1, PGC-1α, and PGC-1β Expression in Male Mice. Endocrinology 2013, 154, 232–245. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  166. O’Connell, G.C.; Pistilli, E.E. Interleukin-15 Directly Stimulates pro-Oxidative Gene Expression in Skeletal Muscle in-Vitro via a Mechanism That Requires Interleukin-15 Receptor Alpha. Biochem. Biophys. Res. Commun. 2015, 458, 614–619. [Google Scholar] [CrossRef]
  167. Sun, H.; Liu, D. Hydrodynamic Delivery of Interleukin 15 Gene Promotes Resistance to High Fat Diet-Induced Obesity, Fatty Liver and Improves Glucose Homeostasis. Gene. Ther. 2015, 22, 341–347. [Google Scholar] [CrossRef] [Green Version]
  168. Carbó, N.; López-Soriano, J.; Costelli, P.; Alvarez, B.; Busquets, S.; Baccino, F.M.; Quinn, L.S.; López-Soriano, F.J.; Argilés, J.M. Interleukin-15 Mediates Reciprocal Regulation of Adipose and Muscle Mass: A Potential Role in Body Weight Control. Biochim. Biophys. Acta 2001, 1526, 17–24. [Google Scholar] [CrossRef]
  169. Nielsen, A.R.; Hojman, P.; Erikstrup, C.; Fischer, C.P.; Plomgaard, P.; Mounier, R.; Mortensen, O.H.; Broholm, C.; Taudorf, S.; Krogh-Madsen, R.; et al. Association between Interleukin-15 and Obesity: Interleukin-15 as a Potential Regulator of Fat Mass. J. Clin. Endocrinol. Metab. 2008, 93, 4486–4493. [Google Scholar] [CrossRef] [Green Version]
  170. Quinn, L.S.; Anderson, B.G.; Strait-Bodey, L.; Stroud, A.M.; Argilés, J.M. Oversecretion of Interleukin-15 from Skeletal Muscle Reduces Adiposity. Am. J. Physiol. Endocrinol. Metab. 2009, 296, E191–E202. [Google Scholar] [CrossRef] [Green Version]
  171. Alvarez, B.; Carbó, N.; López-Soriano, J.; Drivdahl, R.H.; Busquets, S.; López-Soriano, F.J.; Argilés, J.M.; Quinn, L.S. Effects of Interleukin-15 (IL-15) on Adipose Tissue Mass in Rodent Obesity Models: Evidence for Direct IL-15 Action on Adipose Tissue. Biochim. Et Biophys. Acta (BBA) Gen. Subj. 2002, 1570, 33–37. [Google Scholar] [CrossRef]
  172. Iannone, F.; Montesanto, A.; Cione, E.; Crocco, P.; Caroleo, M.C.; Dato, S.; Rose, G.; Passarino, G. Expression Patterns of Muscle-Specific MiR-133b and MiR-206 Correlate with Nutritional Status and Sarcopenia. Nutrients 2020, 12, 297. [Google Scholar] [CrossRef] [PubMed]
  173. Nachtigall, P.G.; Dias, M.C.; Carvalho, R.F.; Martins, C.; Pinhal, D. MicroRNA-499 Expression Distinctively Correlates to Target Genes Sox6 and Rod1 Profiles to Resolve the Skeletal Muscle Phenotype in Nile Tilapia. PLoS ONE 2015, 10, e0119804. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  174. Chen, T.; Zhang, Y.; Liu, Y.; Zhu, D.; Yu, J.; Li, G.; Sun, Z.; Wang, W.; Jiang, H.; Hong, Z. MiR-27a Promotes Insulin Resistance and Mediates Glucose Metabolism by Targeting PPAR-γ-Mediated PI3K/AKT Signaling. Aging 2019, 11, 7510–7524. [Google Scholar] [CrossRef] [PubMed]
  175. Li, X.; Qiu, J.; Liu, H.; Deng, Y.; Hu, S.; Hu, J.; Wang, Y.; Wang, J. MicroRNA-33a Negatively Regulates Myoblast Proliferation by Targeting IGF1, Follistatin and Cyclin D1. Biosci. Rep. 2020, 40, BSR20191327. [Google Scholar] [CrossRef] [PubMed]
  176. Chen, N.; Li, Q.; Liu, J.; Jia, S. Irisin, an Exercise-Induced Myokine as a Metabolic Regulator: An Updated Narrative Review. Diabetes Metab. Res. Rev. 2016, 32, 51–59. [Google Scholar] [CrossRef] [PubMed]
  177. Huh, J.Y.; Dincer, F.; Mesfum, E.; Mantzoros, C.S. Irisin Stimulates Muscle Growth-Related Genes and Regulates Adipocyte Differentiation and Metabolism in Humans. Int. J. Obes. 2014, 38, 1538–1544. [Google Scholar] [CrossRef]
  178. Barra, N.G.; Palanivel, R.; Denou, E.; Chew, M.V.; Gillgrass, A.; Walker, T.D.; Kong, J.; Richards, C.D.; Jordana, M.; Collins, S.M.; et al. Interleukin-15 Modulates Adipose Tissue by Altering Mitochondrial Mass and Activity. PLoS ONE 2014, 9, e114799. [Google Scholar] [CrossRef]
  179. Wang, M.; Yu, H.; Kim, Y.S.; Bidwell, C.A.; Kuang, S. Myostatin Facilitates Slow and Inhibits Fast Myosin Heavy Chain Expression during Myogenic Differentiation. Biochem. Biophys. Res. Commun. 2012, 426, 83–88. [Google Scholar] [CrossRef] [Green Version]
  180. Cleasby, M.E.; Jarmin, S.; Eilers, W.; Elashry, M.; Andersen, D.K.; Dickson, G.; Foster, K. Local Overexpression of the Myostatin Propeptide Increases Glucose Transporter Expression and Enhances Skeletal Muscle Glucose Disposal. Am. J. Physiol. Endocrinol. Metab. 2014, 306, E814–E823. [Google Scholar] [CrossRef]
  181. Kersten, S.; Lichtenstein, L.; Steenbergen, E.; Mudde, K.; Hendriks, H.F.J.; Hesselink, M.K.; Schrauwen, P.; Müller, M. Caloric Restriction and Exercise Increase Plasma ANGPTL4 Levels in Humans via Elevated Free Fatty Acids. Arterioscler. Thromb. Vasc. Biol. 2009, 29, 969–974. [Google Scholar] [CrossRef] [PubMed]
  182. Hojman, P.; Pedersen, M.; Nielsen, A.R.; Krogh-Madsen, R.; Yfanti, C.; Akerstrom, T.; Nielsen, S.; Pedersen, B.K. Fibroblast Growth Factor-21 Is Induced in Human Skeletal Muscles by Hyperinsulinemia. Diabetes 2009, 58, 2797–2801. [Google Scholar] [CrossRef] [PubMed]
  183. Lee, P.; Linderman, J.D.; Smith, S.; Brychta, R.J.; Wang, J.; Idelson, C.; Perron, R.M.; Werner, C.D.; Phan, G.Q.; Kammula, U.S.; et al. Irisin and FGF21 Are Cold-Induced Endocrine Activators of Brown Fat Function in Humans. Cell Metab. 2014, 19, 302–309. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  184. Ouchi, N.; Oshima, Y.; Ohashi, K.; Higuchi, A.; Ikegami, C.; Izumiya, Y.; Walsh, K. Follistatin-like 1, a Secreted Muscle Protein, Promotes Endothelial Cell Function and Revascularization in Ischemic Tissue through a Nitric-Oxide Synthase-Dependent Mechanism. J. Biol. Chem. 2008, 283, 32802–32811. [Google Scholar] [CrossRef] [Green Version]
  185. Görgens, S.W.; Raschke, S.; Holven, K.B.; Jensen, J.; Eckardt, K.; Eckel, J. Regulation of Follistatin-like Protein 1 Expression and Secretion in Primary Human Skeletal Muscle Cells. Arch. Physiol. Biochem. 2013, 119, 75–80. [Google Scholar] [CrossRef]
  186. Kim, C.-S.; Park, H.-S.; Kawada, T.; Kim, J.-H.; Lim, D.; Hubbard, N.E.; Kwon, B.-S.; Erickson, K.L.; Yu, R. Circulating Levels of MCP-1 and IL-8 Are Elevated in Human Obese Subjects and Associated with Obesity-Related Parameters. Int. J. Obes. 2006, 30, 1347–1355. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  187. Sell, H.; Dietze-Schroeder, D.; Kaiser, U.; Eckel, J. Monocyte Chemotactic Protein-1 Is a Potential Player in the Negative Cross-Talk between Adipose Tissue and Skeletal Muscle. Endocrinology 2006, 147, 2458–2467. [Google Scholar] [CrossRef] [Green Version]
  188. Sabater, M.; Moreno-Navarrete, J.M.; José Ortega, F.; Pardo, G.; Salvador, J.; Ricart, W.; Frühbeck, G.; Fernández-Real, J.M. Circulating Pigment Epithelium-Derived Factor Levels Are Associated with Insulin Resistance and Decrease after Weight Loss. J. Clin. Endocrinol. Metab. 2010, 95, 4720–4728. [Google Scholar] [CrossRef]
  189. Famulla, S.; Lamers, D.; Hartwig, S.; Passlack, W.; Horrighs, A.; Cramer, A.; Lehr, S.; Sell, H.; Eckel, J. Pigment Epithelium-Derived Factor (PEDF) Is One of the Most Abundant Proteins Secreted by Human Adipocytes and Induces Insulin Resistance and Inflammatory Signaling in Muscle and Fat Cells. Int. J. Obes. 2011, 35, 762–772. [Google Scholar] [CrossRef] [Green Version]
  190. Atkins, J.L.; Wannamathee, S.G. Sarcopenic Obesity in Ageing: Cardiovascular Outcomes and Mortality. Br. J. Nutr. 2020, 124, 1102–1113. [Google Scholar] [CrossRef]
  191. Chow, L.S.; Gerszten, R.E.; Taylor, J.M.; Pedersen, B.K.; van Praag, H.; Trappe, S.; Febbraio, M.A.; Galis, Z.S.; Gao, Y.; Haus, J.M.; et al. Exerkines in Health, Resilience and Disease. Nat. Rev. Endocrinol. 2022, 18, 273–289. [Google Scholar] [CrossRef] [PubMed]
  192. Laurens, C.; Bergouignan, A.; Moro, C. Exercise-Released Myokines in the Control of Energy Metabolism. Front. Physiol. 2020, 11, 91. [Google Scholar] [CrossRef] [PubMed]
  193. Zunner, B.E.M.; Wachsmuth, N.B.; Eckstein, M.L.; Scherl, L.; Schierbauer, J.R.; Haupt, S.; Stumpf, C.; Reusch, L.; Moser, O. Myokines and Resistance Training: A Narrative Review. Int. J. Mol. Sci. 2022, 23, 3501. [Google Scholar] [CrossRef] [PubMed]
  194. Senesi, P.; Luzi, L.; Terruzzi, I. Adipokines, Myokines, and Cardiokines: The Role of Nutritional Interventions. Int. J. Mol. Sci. 2020, 21, 8372. [Google Scholar] [CrossRef]
Cells 11 03361 g001 550
Figure 1. Main consequences of sarcopenic obesity in the elderly. CVD, cardiovascular disease.
Figure 1. Main consequences of sarcopenic obesity in the elderly. CVD, cardiovascular disease.
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Figure 2. Pathogenesis of sarcopenic obesity in the elderly, with a focus on muscle and adipose tissue crosstalk. More relevant links in bold. FFA, free fatty acids; TNF-alpha, tumor necrosis factor-alpha; IL-6, Interleukin-6; MCP-1, monocyte chemoattractant protein-1; UCP-1, uncoupling protein 1.
Figure 2. Pathogenesis of sarcopenic obesity in the elderly, with a focus on muscle and adipose tissue crosstalk. More relevant links in bold. FFA, free fatty acids; TNF-alpha, tumor necrosis factor-alpha; IL-6, Interleukin-6; MCP-1, monocyte chemoattractant protein-1; UCP-1, uncoupling protein 1.
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Zamboni, M.; Mazzali, G.; Brunelli, A.; Saatchi, T.; Urbani, S.; Giani, A.; Rossi, A.P.; Zoico, E.; Fantin, F. The Role of Crosstalk between Adipose Cells and Myocytes in the Pathogenesis of Sarcopenic Obesity in the Elderly. Cells 2022, 11, 3361. https://doi.org/10.3390/cells11213361

AMA Style

Zamboni M, Mazzali G, Brunelli A, Saatchi T, Urbani S, Giani A, Rossi AP, Zoico E, Fantin F. The Role of Crosstalk between Adipose Cells and Myocytes in the Pathogenesis of Sarcopenic Obesity in the Elderly. Cells. 2022; 11(21):3361. https://doi.org/10.3390/cells11213361

Chicago/Turabian Style

Zamboni, Mauro, Gloria Mazzali, Anna Brunelli, Tanaz Saatchi, Silvia Urbani, Anna Giani, Andrea P. Rossi, Elena Zoico, and Francesco Fantin. 2022. "The Role of Crosstalk between Adipose Cells and Myocytes in the Pathogenesis of Sarcopenic Obesity in the Elderly" Cells 11, no. 21: 3361. https://doi.org/10.3390/cells11213361

APA Style

Zamboni, M., Mazzali, G., Brunelli, A., Saatchi, T., Urbani, S., Giani, A., Rossi, A. P., Zoico, E., & Fantin, F. (2022). The Role of Crosstalk between Adipose Cells and Myocytes in the Pathogenesis of Sarcopenic Obesity in the Elderly. Cells, 11(21), 3361. https://doi.org/10.3390/cells11213361

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