International Journal of Molecular Sciences

Research

17 pages, 6006 KiB

Open AccessArticle

Kappa-Opioid Receptor Blockade Ameliorates Obesity Caused by Estrogen Withdrawal via Promotion of Energy Expenditure through mTOR Pathway

by Amparo Romero-Picó, Marta G. Novelle, Omar Al-Massadi, Daniel Beiroa, Marta Tojo, Violeta Heras, Francisco Ruiz-Pino, Ana Senra, Miguel López, Clemence Blouet, Manuel Tena-Sempere, Rubén Nogueiras and Carlos Diéguez

Int. J. Mol. Sci. 2022, 23(6), 3118; https://doi.org/10.3390/ijms23063118 - 14 Mar 2022

Cited by 9 | Viewed by 3174

Abstract

Weight gain is a hallmark of decreased estradiol (E2) levels because of menopause or following surgical ovariectomy (OVX) at younger ages. Of note, this weight gain tends to be around the abdomen, which is frequently associated with impaired metabolic homeostasis and greater cardiovascular [...] Read more.

Weight gain is a hallmark of decreased estradiol (E2) levels because of menopause or following surgical ovariectomy (OVX) at younger ages. Of note, this weight gain tends to be around the abdomen, which is frequently associated with impaired metabolic homeostasis and greater cardiovascular risk in both rodents and humans. However, the molecular underpinnings and the neuronal basis for these effects remain to be elucidated. The aim of this study is to elucidate whether the kappa-opioid receptor (k-OR) system is involved in mediating body weight changes associated with E2 withdrawal. Here, we document that body weight gain induced by OVX occurs, at least partially, in a k-OR dependent manner, by modulation of energy expenditure independently of food intake as assessed in Oprk1−/−global KO mice. These effects were also observed following central pharmacological blockade of the k-OR system using the k-OR-selective antagonist PF-04455242 in wild type mice, in which we also observed a decrease in OVX-induced weight gain associated with increased UCP1 positive immunostaining in brown adipose tissue (BAT) and browning of white adipose tissue (WAT). Remarkably, the hypothalamic mTOR pathway plays an important role in regulating weight gain and adiposity in OVX mice. These findings will help to define new therapies to manage metabolic disorders associated with low/null E2 levels based on the modulation of central k-OR signaling. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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18 pages, 3115 KiB

Open AccessArticle

Feeding Rhythm-Induced Hypothalamic Agouti-Related Protein Elevation via Glucocorticoids Leads to Insulin Resistance in Skeletal Muscle

by Tetsuya Shiuchi, Airi Otsuka, Noriyuki Shimizu, Sachiko Chikahisa and Hiroyoshi Séi

Int. J. Mol. Sci. 2021, 22(19), 10831; https://doi.org/10.3390/ijms221910831 - 7 Oct 2021

Cited by 4 | Viewed by 3196

Abstract

Circadian phase shifts in peripheral clocks induced by changes in feeding rhythm often result in insulin resistance. However, whether the hypothalamic control system for energy metabolism is involved in the feeding rhythm-related development of insulin resistance is unknown. Here, we show the physiological [...] Read more.

Circadian phase shifts in peripheral clocks induced by changes in feeding rhythm often result in insulin resistance. However, whether the hypothalamic control system for energy metabolism is involved in the feeding rhythm-related development of insulin resistance is unknown. Here, we show the physiological significance and mechanism of the involvement of the agouti-related protein (AgRP) in evening feeding-associated alterations in insulin sensitivity. Evening feeding during the active dark period increased hypothalamic AgRP expression and skeletal muscle insulin resistance in mice. Inhibiting AgRP expression by administering an antisense oligo or a glucocorticoid receptor antagonist mitigated these effects. AgRP-producing neuron-specific glucocorticoid receptor-knockout (AgRP-GR-KO) mice had normal skeletal muscle insulin sensitivity even under evening feeding schedules. Hepatic vagotomy enhanced AgRP expression in the hypothalamus even during ad-lib feeding in wild-type mice but not in AgRP-GR-KO mice. The findings of this study indicate that feeding in the late active period may affect hypothalamic AgRP expression via glucocorticoids and induce skeletal muscle insulin resistance. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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27 pages, 7565 KiB

Open AccessArticle

5-Hydroxytryptamine Modulates Maturation and Mitochondria Function of Human Oligodendrocyte Progenitor M03-13 Cells

by Simona Damiano, Giuliana La Rosa, Concetta Sozio, Gina Cavaliere, Giovanna Trinchese, Maddalena Raia, Roberto Paternò, Maria Pina Mollica, Vittorio Enrico Avvedimento and Mariarosaria Santillo

Int. J. Mol. Sci. 2021, 22(5), 2621; https://doi.org/10.3390/ijms22052621 - 5 Mar 2021

Cited by 12 | Viewed by 3881

Abstract

Inside the adult CNS, oligodendrocyte progenitor cells (OPC_S) are able to proliferate, migrate and differentiate into mature oligodendrocytes (OLs) which are responsible for the production of myelin sheet and energy supply for neurons. Moreover, in demyelinating diseases, OPCs are recruited to [...] Read more.

Inside the adult CNS, oligodendrocyte progenitor cells (OPC_S) are able to proliferate, migrate and differentiate into mature oligodendrocytes (OLs) which are responsible for the production of myelin sheet and energy supply for neurons. Moreover, in demyelinating diseases, OPCs are recruited to the lesion areas where they undergo differentiation and myelin synthesis. Serotonin (5-hydroxytryptamine, 5-HT) is involved in OLs’ development and myelination, but so far the molecular mechanisms involved or the effects of 5-HT on mitochondria function have not yet been well documented. Our data show that 5-HT inhibits migration and proliferation committing cells toward differentiation in an immortalized human oligodendrocyte precursor cell line, M03-13. Migration blockage is mediated by reactive oxygen species (ROS) generation since antioxidants, such as Vit C and Cu-Zn superoxide dismutase, prevent the inhibitory effects of 5-HT on cell migration. 5-HT inhibits OPC migration and proliferation and increases OL phenotypic markers myelin basic protein (MBP) and Olig-2 via protein kinase C (PKC) activation since the inhibitor of PKC, bis-indolyl-maleimide (BIM), counteracts 5-HT effects. NOX inhibitors as well, reverse the effects of 5-HT, indicating that 5-HT influences the maturation process of OPCs by NOX-dependent ROS production. Finally, 5-HT increases mitochondria function and antioxidant activity. The identification of the molecular mechanisms underlying the effects of 5-HT on maturation and energy metabolism of OPCs could pave the way for the development of new treatments for autoimmune demyelinating diseases such as Multiple Sclerosis where oligodendrocytes are the primary target of immune attack. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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16 pages, 2821 KiB

Open AccessArticle

Adipokines and Metabolic Regulators in Human and Experimental Pulmonary Arterial Hypertension

by Aimilia Eirini Papathanasiou, Fotios Spyropoulos, Zoe Michael, Kyoung E. Joung, Despina D. Briana, Ariadne Malamitsi-Puchner, Christos S. Mantzoros and Helen Christou

Int. J. Mol. Sci. 2021, 22(3), 1435; https://doi.org/10.3390/ijms22031435 - 1 Feb 2021

Cited by 8 | Viewed by 3661

Abstract

Pulmonary hypertension (PH) is associated with meta-inflammation related to obesity but the role of adipose tissue in PH pathogenesis is unknown. We hypothesized that adipose tissue-derived metabolic regulators are altered in human and experimental PH. We measured circulating levels of fatty acid binding [...] Read more.

Pulmonary hypertension (PH) is associated with meta-inflammation related to obesity but the role of adipose tissue in PH pathogenesis is unknown. We hypothesized that adipose tissue-derived metabolic regulators are altered in human and experimental PH. We measured circulating levels of fatty acid binding protein 4 (FABP-4), fibroblast growth factor -21 (FGF-21), adiponectin, and the mRNA levels of FABP-4, FGF-21, and peroxisome proliferator-activated receptor γ (PPARγ) in lung tissue of patients with idiopathic PH and healthy controls. We also evaluated lung and adipose tissue expression of these mediators in the three most commonly used experimental rodent models of pulmonary hypertension. Circulating levels of FABP-4, FGF-21, and adiponectin were significantly elevated in PH patients compared to controls and the mRNA levels of these regulators and PPARγ were also significantly increased in human PH lungs and in the lungs of rats with experimental PH compared to controls. These findings were coupled with increased levels of adipose tissue mRNA of genes related to glucose uptake, glycolysis, tricarboxylic acid cycle, and fatty acid oxidation in experimental PH. Our results support that metabolic alterations in human PH are recapitulated in rodent models of the disease and suggest that adipose tissue may contribute to PH pathogenesis. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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19 pages, 5047 KiB

Open AccessArticle

Linagliptin Ameliorates Hepatic Steatosis via Non-Canonical Mechanisms in Mice Treated with a Dual Inhibitor of Insulin Receptor and IGF-1 Receptor

by Tomoko Okuyama, Jun Shirakawa, Kazuki Tajima, Yoko Ino, Heidrun Vethe, Yu Togashi, Mayu Kyohara, Ryota Inoue, Daisuke Miyashita, Jinghe Li, Nozomi Goto, Taiga Ichikawa, Shingo Yamasaki, Haruka Ohnuma, Rie Takayanagi, Yayoi Kimura, Hisashi Hirano and Yasuo Terauchi

Int. J. Mol. Sci. 2020, 21(21), 7815; https://doi.org/10.3390/ijms21217815 - 22 Oct 2020

Cited by 11 | Viewed by 4031

Abstract

Abnormal hepatic insulin signaling is a cause or consequence of hepatic steatosis. DPP-4 inhibitors might be protective against fatty liver. We previously reported that the systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by the administration of OSI-906 (linsitinib), a dual [...] Read more.

Abnormal hepatic insulin signaling is a cause or consequence of hepatic steatosis. DPP-4 inhibitors might be protective against fatty liver. We previously reported that the systemic inhibition of insulin receptor (IR) and IGF-1 receptor (IGF1R) by the administration of OSI-906 (linsitinib), a dual IR/IGF1R inhibitor, induced glucose intolerance, hepatic steatosis, and lipoatrophy in mice. In the present study, we investigated the effects of a DPP-4 inhibitor, linagliptin, on hepatic steatosis in OSI-906-treated mice. Unlike high-fat diet-induced hepatic steatosis, OSI-906-induced hepatic steatosis is not characterized by elevations in inflammatory responses or oxidative stress levels. Linagliptin improved OSI-906-induced hepatic steatosis via an insulin-signaling-independent pathway, without altering glucose levels, free fatty acid levels, gluconeogenic gene expressions in the liver, or visceral fat atrophy. Hepatic quantitative proteomic and phosphoproteomic analyses revealed that perilipin-2 (PLIN2), major urinary protein 20 (MUP20), cytochrome P450 2b10 (CYP2B10), and nicotinamide N-methyltransferase (NNMT) are possibly involved in the process of the amelioration of hepatic steatosis by linagliptin. Thus, linagliptin improved hepatic steatosis induced by IR and IGF1R inhibition via a previously unknown mechanism that did not involve gluconeogenesis, lipogenesis, or inflammation, suggesting the non-canonical actions of DPP-4 inhibitors in the treatment of hepatic steatosis under insulin-resistant conditions. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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12 pages, 2426 KiB

Open AccessArticle

Fasting Drives Nrf2-Related Antioxidant Response in Skeletal Muscle

by Daniele Lettieri-Barbato, Giuseppina Minopoli, Rocco Caggiano, Rossella Izzo, Mariarosaria Santillo, Katia Aquilano and Raffaella Faraonio

Int. J. Mol. Sci. 2020, 21(20), 7780; https://doi.org/10.3390/ijms21207780 - 21 Oct 2020

Cited by 15 | Viewed by 5162

Abstract

A common metabolic condition for living organisms is starvation/fasting, a state that could play systemic-beneficial roles. Complex adaptive responses are activated during fasting to help the organism to maintain energy homeostasis and avoid nutrient stress. Metabolic rearrangements during fasting cause mild oxidative stress [...] Read more.

A common metabolic condition for living organisms is starvation/fasting, a state that could play systemic-beneficial roles. Complex adaptive responses are activated during fasting to help the organism to maintain energy homeostasis and avoid nutrient stress. Metabolic rearrangements during fasting cause mild oxidative stress in skeletal muscle. The nuclear factor erythroid 2-related factor 2 (Nrf2) controls adaptive responses and remains the major regulator of quenching mechanisms underlying different types of stress. Here, we demonstrate a positive role of fasting as a protective mechanism against oxidative stress in skeletal muscle. In particular, by using in vivo and in vitro models of fasting, we found that typical Nrf2-dependent genes, including those controlling iron (e.g., Ho-1) and glutathione (GSH) metabolism (e.g., Gcl, Gsr) are induced along with increased levels of the glutathione peroxidase 4 (Gpx4), a GSH-dependent antioxidant enzyme. These events are associated with a significant reduction in malondialdehyde, a well-known by-product of lipid peroxidation. Our results suggest that fasting could be a valuable approach to boost the adaptive anti-oxidant responses in skeletal muscle. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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15 pages, 2434 KiB

Open AccessArticle

PPARδ and FOXO1 Mediate Palmitate-Induced Inhibition of Muscle Pyruvate Dehydrogenase Complex and CHO Oxidation, Events Reversed by Electrical Pulse Stimulation

by Hung-Che Chien, Paul L. Greenhaff and Dumitru Constantin-Teodosiu

Int. J. Mol. Sci. 2020, 21(16), 5942; https://doi.org/10.3390/ijms21165942 - 18 Aug 2020

Cited by 7 | Viewed by 4133

Abstract

The mechanisms behind the reduction in muscle pyruvate dehydrogenase complex (PDC)-controlled carbohydrate (CHO) oxidation during chronic high-fat dietary intake are poorly understood, as is the basis of CHO oxidation restoration during muscle contraction. C2C12 myotubes were treated with (300 μM) palmitate or without [...] Read more.

The mechanisms behind the reduction in muscle pyruvate dehydrogenase complex (PDC)-controlled carbohydrate (CHO) oxidation during chronic high-fat dietary intake are poorly understood, as is the basis of CHO oxidation restoration during muscle contraction. C2C12 myotubes were treated with (300 μM) palmitate or without (control) for 16 h in the presence and absence of electrical pulse stimulation (EPS, 11.5 V, 1 Hz, 2 ms). Compared to control, palmitate reduced cell glucose uptake (p < 0.05), PDC activity (p < 0.01), acetylcarnitine accumulation (p < 0.05) and glucose-derived mitochondrial ATP production (p < 0.01) and increased pyruvate dehydrogenase kinase isoform 4 (PDK4) (p < 0.01), peroxisome proliferator-activated receptor alpha (PPARα) (p < 0.01) and peroxisome proliferator-activated receptor delta (PPARδ) (p < 0.01) proteins, and reduced the whole-cell p-FOXO1/t-FOXO1 (Forkhead Box O1) ratio (p < 0.01). EPS rescued palmitate-induced inhibition of CHO oxidation, reflected by increased glucose uptake (p < 0.01), PDC activity (p < 0.01) and glucose-derived mitochondrial ATP production (p < 0.01) compared to palmitate alone. EPS was also associated with less PDK4 (p < 0.01) and PPARδ (p < 0.01) proteins, and lower nuclear p-FOXO1/t-FOXO1 ratio normalised to the cytoplasmic ratio, but with no changes in PPARα protein. Collectively, these data suggest PPARδ, and FOXO1 transcription factors increased PDK4 protein in the presence of palmitate, which limited PDC activity and flux, and blunted CHO oxidation and glucose uptake. Conversely, EPS rescued these metabolic events by modulating the same transcription factors. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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19 pages, 3142 KiB

Open AccessArticle

Interleukin-4 Improves Metabolic Abnormalities in Leptin-Deficient and High-Fat Diet Mice

by Shih-Yi Lin, Ching-Ping Yang, Ya-Yu Wang, Chiao-Wan Hsiao, Wen-Ying Chen, Su-Lan Liao, Yu-Li Lo, Yih-Hsin Chang, Chen-Jee Hong and Chun-Jung Chen

Int. J. Mol. Sci. 2020, 21(12), 4451; https://doi.org/10.3390/ijms21124451 - 23 Jun 2020

Cited by 12 | Viewed by 4242

Abstract

Obesity is a metabolic disorder that results from complex interactions between genetic predisposition and dietary factors. Interleukin-4 (IL-4), besides its role in immunity, has metabolic effects on insulin efficacy. We studied the effects of IL-4 on metabolic abnormalities in a mice model of [...] Read more.

Obesity is a metabolic disorder that results from complex interactions between genetic predisposition and dietary factors. Interleukin-4 (IL-4), besides its role in immunity, has metabolic effects on insulin efficacy. We studied the effects of IL-4 on metabolic abnormalities in a mice model of obesity involving leptin deficiency and leptin resistance. Leptin-deficient 145E and leptin-resistant high-fat diet (HFD) mice showed lower levels of circulating IL-4. 145E and HFD mice showed a number of abnormalities: Obesity, hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, liver injury, and adiposity with concurrent inflammation, decreases in Akt, signal transducer and activator of transcription 3 (STAT3), and STAT6 phosphorylation in the hypothalamus, liver, and epididymal fat. Independent of leptin-deficient obesity and dietary obesity, a course of 8-week IL-4 supplementation improved obesity and impairment in Akt, STAT3, and STAT6 signaling. Amelioration of cytokine expression, despite variable extents, was closely linked with the actions of IL-4. Additionally, the browning of white adipocytes by IL-4 was found in epididymal white adipose tissues and 3T3-L1 preadipocytes. Chronic exercise, weight management, and probiotics are recommended to overweight patients and IL-4 signaling is associated with clinical improvement. Thus, IL-4 could be a metabolic regulator and antiobesity candidate for the treatment of obesity and its complications. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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18 pages, 1104 KiB

Open AccessArticle

Evaluation of Prognostic Factors of Severity in Acute Biliary Pancreatitis

by Pedro Silva-Vaz, Ana Margarida Abrantes, Sara Morgado-Nunes, Miguel Castelo-Branco, António Gouveia, Maria Filomena Botelho and José Guilherme Tralhão

Int. J. Mol. Sci. 2020, 21(12), 4300; https://doi.org/10.3390/ijms21124300 - 16 Jun 2020

Cited by 37 | Viewed by 4331

Abstract

Acute pancreatitis (AP) is an inflammatory disorder of the pancreas that, when classified as severe, is associated with high morbidity and mortality. Promptly identifying the severity of AP is of extreme importance for improving clinical outcomes. The aim of this study was to [...] Read more.

Acute pancreatitis (AP) is an inflammatory disorder of the pancreas that, when classified as severe, is associated with high morbidity and mortality. Promptly identifying the severity of AP is of extreme importance for improving clinical outcomes. The aim of this study was to compare the prognostic value of serological biomarkers, ratios, and multifactorial scores in patients with acute biliary pancreatitis and to identify the best predictors. In this observational and prospective study, the biomarkers, ratios and multifactorial scores were evaluated on admission and at 48 h of the symptom onset. On admission, regarding the AP severity, the white blood count (WBC) and neutrophil–lymphocyte ratio (NLR), and regarding the mortality, the WBC and the modified Marshall score (MMS) showed the best predictive values. At 48 h, regarding the AP severity, the hepcidin, NLR, systemic inflammatory response index (SIRI) and MMS and regarding the mortality, the NLR, hepcidin and the bedside index for severity in AP (BISAP) score, showed the best predictive values. The present study enabled the identification, for the first time, of SIRI as a new prognostic tool for AP severity, and validated hepcidin and the NLR as better prognostic markers than C-reactive protein (CRP) at 48 h of symptom onset. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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12 pages, 1804 KiB

Open AccessArticle

Short-Term Physiological Effects of a Very Low-Calorie Ketogenic Diet: Effects on Adiponectin Levels and Inflammatory States

by Vincenzo Monda, Rita Polito, Annarita Lovino, Antonio Finaldi, Anna Valenzano, Ersilia Nigro, Gaetano Corso, Francesco Sessa, Alessio Asmundo, Nunzio Di Nunno, Giuseppe Cibelli and Giovanni Messina

Int. J. Mol. Sci. 2020, 21(9), 3228; https://doi.org/10.3390/ijms21093228 - 2 May 2020

Cited by 54 | Viewed by 7043

Abstract

Adipose tissue is a multifunctional organ involved in many physiological and metabolic processes through the production of adipokines and, in particular, adiponectin. Caloric restriction is one of the most important strategies against obesity today. The very low-calorie ketogenic diet (VLCKD) represents a type [...] Read more.

Adipose tissue is a multifunctional organ involved in many physiological and metabolic processes through the production of adipokines and, in particular, adiponectin. Caloric restriction is one of the most important strategies against obesity today. The very low-calorie ketogenic diet (VLCKD) represents a type of caloric restriction with very or extremely low daily food energy consumption. This study aimed to investigate the physiological effects of a VLCKD on anthropometric and biochemical parameters such as adiponectin levels, as well as analyzing oligomeric profiles and cytokine serum levels in obese subjects before and after a VLCKD. Twenty obese subjects were enrolled. At baseline and after eight weeks of intervention, anthropometric and biochemical parameters, such as adiponectin levels, were recorded. Our findings showed a significant change in the anthropometric and biochemical parameters of these obese subjects before and after a VLCKD. We found a negative correlation between adiponectin and lipid profile, visceral adipose tissue (VAT), C-reactive protein (CRP), and pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), which confirmed the important involvement of adiponectin in metabolic and inflammatory diseases. We demonstrated the beneficial short-term effects of a VLCKD not only in the treatment of obesity but also in the establishment of obesity-correlated diseases. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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16 pages, 4305 KiB

Open AccessArticle

Probing Hexaminolevulinate Mediated PpIX Fluorescence in Cancer Cell Suspensions in the Presence of Chemical Adjuvants

by Kit Man Chan, Jonathan Gleadle, Krasimir Vasilev and Melanie MacGregor

Int. J. Mol. Sci. 2020, 21(8), 2963; https://doi.org/10.3390/ijms21082963 - 22 Apr 2020

Cited by 8 | Viewed by 3315

Abstract

Exogenous administration of hexaminolevulinate (HAL) induces fluorescent protoporphyrin IX (PpIX) accumulation preferentially in cancer cells. However, the PpIX fluorescence intensities between noncancer and cancer cells are highly variable. The contrast between cancer and noncancer cells may be insufficient to reliably discriminate, especially at [...] Read more.

Exogenous administration of hexaminolevulinate (HAL) induces fluorescent protoporphyrin IX (PpIX) accumulation preferentially in cancer cells. However, the PpIX fluorescence intensities between noncancer and cancer cells are highly variable. The contrast between cancer and noncancer cells may be insufficient to reliably discriminate, especially at the single cell level in cancer diagnostics. This study examines the use of the chemical adjuvants dimethylsulphoxide (DMSO) or deferoxamine (DFO) to enhance the HAL induced PpIX accumulation in cancer cells. Our results showed that in some of the incubation conditions tested, the addition of DFO with HAL significantly increased PpIX 21 fluorescence of adherent monolayer cancer cells, but this was never the case for cells in suspension. Permeabilisation with DMSO did not increase PpIX fluorescence. Cell-to-cell interaction may well play an important role in the PpIX accumulation when suspended cells are treated in HAL and adjuvant chemicals. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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13 pages, 2133 KiB

Open AccessArticle

BST Stimulation Induces Atrophy and Changes in Aerobic Energy Metabolism in Rat Skeletal Muscles—The Biphasic Action of Endogenous Glucocorticoids

by Mateusz Jakub Karnia, Dorota Myślińska, Katarzyna Patrycja Dzik, Damian Józef Flis, Magdalena Podlacha and Jan Jacek Kaczor

Int. J. Mol. Sci. 2020, 21(8), 2787; https://doi.org/10.3390/ijms21082787 - 17 Apr 2020

Cited by 7 | Viewed by 3340

Abstract

(1) The primary involvement in stress-induced disturbances in skeletal muscles is assigned to the release of glucocorticoids (GCs). The current study aims to investigate the impact of the biphasic action of the chronic stress response (CSR) induced by the electrical stimulation of the [...] Read more.

(1) The primary involvement in stress-induced disturbances in skeletal muscles is assigned to the release of glucocorticoids (GCs). The current study aims to investigate the impact of the biphasic action of the chronic stress response (CSR) induced by the electrical stimulation of the bed nucleus of the stria terminalis (BST) effects on muscle atrophy and aerobic energy metabolism in soleus (SOL) and extensor digitorum longus (EDL) muscles. (2) Male Wistar rats (n = 17) were used. The rats were divided randomly into three groups: the BST two weeks (ST2), four weeks (ST4), and the sham (SHM) electrically stimulated group. The plasma corticosterone (CORT) and irisin concentration were measured. Glucocorticoid and mineralocorticoid receptors (GR and MR), 11β-hydroxysteroid dehydrogenase type 1 and 2 (HSD11B1 and HSD11B2), atrogin-1, and insulin-like growth factor-1 (IGF-1) level were determined in SOL and EDL muscles. Citrate synthase (CS) activity was measured in both muscles. (3) We found elevated plasma concentration of CORT and irisin, raised the level of GR in SOL muscle, and the higher level of MR in both muscles in the ST4 group. The level of HSD11B1 was also higher in the ST4 group compared to the SHM group. Moreover, we observed increased activity of CS in SOL. (4) We suggest that biphasic action of the glucocorticoid induced by the CSR occurs and causes dysregulation of proteins involved in muscle atrophy and aerobic energy metabolism. Our findings potentially contribute to a better understanding of the mechanisms by which GCs and the CSR may regulate muscle atrophy and energy preservation of the red muscle. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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12 pages, 1215 KiB

Open AccessCommunication

A Molecular Basis for Reciprocal Regulation between Pheromones and Hormones in Response to Dietary Cues in C. elegans

by Saeram Park, Jun Young Park and Young-Ki Paik

Int. J. Mol. Sci. 2020, 21(7), 2366; https://doi.org/10.3390/ijms21072366 - 29 Mar 2020

Cited by 3 | Viewed by 2951

Abstract

Under stressful conditions, the early larvae of C. elegans enter dauer diapause, a non-aging period, driven by the seemingly opposite influence of ascaroside pheromones (ASCRs) and steroid hormone dafachronic acids (DAs). However, the molecular basis of how these small molecules engage in competitive [...] Read more.

Under stressful conditions, the early larvae of C. elegans enter dauer diapause, a non-aging period, driven by the seemingly opposite influence of ascaroside pheromones (ASCRs) and steroid hormone dafachronic acids (DAs). However, the molecular basis of how these small molecules engage in competitive crosstalk in coordination with insulin/IGF-1 signaling (IIS) remains elusive. Here we report a novel transcriptional regulatory pathway that seems to operate between the ASCR and DA biosynthesis under ad libitum (AL) feeding conditions or bacterial deprivation (BD). Although expression of the ASCR and DA biosynthetic genes reciprocally inhibit each other, ironically and interestingly, such dietary cue-mediated modulation requires the presence of the competitors. Under BD, induction of ASCR biosynthetic gene expression required DA, while ASCR suppresses the expression of the DA biosynthetic gene daf-36. The negative regulation of DA by ASCR was IIS-dependent, whereas daf-36 regulation appeared to be independent of IIS. These observations suggest that the presence of ASCR determines the IIS-dependency of DA gene expression regardless of dietary conditions. Thus, our work defines a molecular basis for a novel reciprocal gene regulation of pheromones and hormones to cope with stressful conditions during development and aging. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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13 pages, 3199 KiB

Open AccessArticle

Antidiabetic Effects of Bisamide Derivative of Dicarboxylic Acid in Metabolic Disorders

by Angelina Vladimirovna Pakhomova, Vladimir Evgenievich Nebolsin, Olga Victorovna Pershina, Vyacheslav Andreevich Krupin, Lubov Alexandrovna Sandrikina, Edgar Sergeevich Pan, Natalia Nicolaevna Ermakova, Olga Evgenevna Vaizova, Darius Widera, Wolf-Dieter Grimm, Viacheslav Yur’evich Kravtsov, Sergey Alexandrovich Afanasiev, Sergey Georgievich Morozov, Aslan Amirkhanovich Kubatiev, Alexander Mikhaylovich Dygai and Evgenii Germanovich Skurikhin

Int. J. Mol. Sci. 2020, 21(3), 991; https://doi.org/10.3390/ijms21030991 - 3 Feb 2020

Cited by 6 | Viewed by 3841

Abstract

In clinical practice, the metabolic syndrome can lead to multiple complications, including diabetes. It remains unclear which component of the metabolic syndrome (obesity, inflammation, hyperglycemia, or insulin resistance) has the strongest inhibitory effect on stem cells involved in beta cell regeneration. This makes [...] Read more.

In clinical practice, the metabolic syndrome can lead to multiple complications, including diabetes. It remains unclear which component of the metabolic syndrome (obesity, inflammation, hyperglycemia, or insulin resistance) has the strongest inhibitory effect on stem cells involved in beta cell regeneration. This makes it challenging to develop effective treatment options for complications such as diabetes. In our study, experiments were performed on male C57BL/6 mice where metabolic disorders have been introduced experimentally by a combination of streptozotocin-treatment and a high-fat diet. We evaluated the biological effects of Bisamide Derivative of Dicarboxylic Acid (BDDA) and its impact on pancreatic stem cells in vivo. To assess the impact of BDDA, we applied a combination of histological and biochemical methods along with a cytometric analysis of stem cell and progenitor cell markers. We show that in mice with metabolic disorders, BDDA has a positive effect on lipid and glucose metabolism. The pancreatic restoration was associated with a decrease of the inhibitory effects of inflammation and obesity factors on pancreatic stem cells. Our data shows that BDDA increases the number of pancreatic stem cells. Thus, BDDA could be used as a new compound for treating complication of the metabolic syndrome such as diabetes. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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Review

Jump to: Research, Other

30 pages, 1905 KiB

Open AccessReview

Like Brothers in Arms: How Hormonal Stimuli and Changes in the Metabolism Signaling Cooperate, Leading HPV Infection to Drive the Onset of Cervical Cancer

by Matthias Läsche, Julia Gallwas and Carsten Gründker

Int. J. Mol. Sci. 2022, 23(9), 5050; https://doi.org/10.3390/ijms23095050 - 2 May 2022

Cited by 8 | Viewed by 3874

Abstract

Despite all precautionary actions and the possibility of using vaccinations to counteract infections caused by human papillomaviruses (HPVs), HPV-related cancers still account for approximately 5% of all carcinomas. Worldwide, many women are still excluded from adequate health care due to their social position [...] Read more.

Despite all precautionary actions and the possibility of using vaccinations to counteract infections caused by human papillomaviruses (HPVs), HPV-related cancers still account for approximately 5% of all carcinomas. Worldwide, many women are still excluded from adequate health care due to their social position and origin. Therefore, immense efforts in research and therapy are still required to counteract the challenges that this disease entails. The special thing about an HPV infection is that it is not only able to trick the immune system in a sophisticated way, but also, through genetic integration into the host genome, to use all the resources available to the host cells to complete the replication cycle of the virus without activating the alarm mechanisms of immune recognition and elimination. The mechanisms utilized by the virus are the metabolic, immune, and hormonal signaling pathways that it manipulates. Since the virus is dependent on replication enzymes of the host cells, it also intervenes in the cell cycle of the differentiating keratinocytes and shifts their terminal differentiation to the uppermost layers of the squamocolumnar transformation zone (TZ) of the cervix. The individual signaling pathways are closely related and equally important not only for the successful replication of the virus but also for the onset of cervical cancer. We will therefore analyze the effects of HPV infection on metabolic signaling, as well as changes in hormonal and immune signaling in the tumor and its microenvironment to understand how each level of signaling interacts to promote tumorigenesis of cervical cancer. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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13 pages, 680 KiB

Open AccessReview

Impact of Genetic Variations and Epigenetic Mechanisms on the Risk of Obesity

by Martina Chiurazzi, Mauro Cozzolino, Roberta Clara Orsini, Martina Di Maro, Matteo Nicola Dario Di Minno and Antonio Colantuoni

Int. J. Mol. Sci. 2020, 21(23), 9035; https://doi.org/10.3390/ijms21239035 - 27 Nov 2020

Cited by 23 | Viewed by 7415

Abstract

Rare genetic obesity disorders are characterized by mutations of genes strongly involved in the central or peripheral regulation of energy balance. These mutations are effective in causing the early onset of severe obesity and insatiable hunger (hyperphagia), suggesting that the genetic component can [...] Read more.

Rare genetic obesity disorders are characterized by mutations of genes strongly involved in the central or peripheral regulation of energy balance. These mutations are effective in causing the early onset of severe obesity and insatiable hunger (hyperphagia), suggesting that the genetic component can contribute to 40–70% of obesity. However, genes’ roles in the processes leading to obesity are still unclear. This review is aimed to summarize the current knowledge of the genetic causes of obesity, especially monogenic obesity, describing the role of epigenetic mechanisms in obesity and metabolic diseases. A comprehensive understanding of the underlying genetic and epigenetic mechanisms, with the metabolic processes they control, will permit adequate management and prevention of obesity. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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22 pages, 1242 KiB

Open AccessReview

Metabolism Regulation and Redox State: Insight into the Role of Superoxide Dismutase 1

by Simona Damiano, Concetta Sozio, Giuliana La Rosa, Bruna Guida, Raffaella Faraonio, Mariarosaria Santillo and Paolo Mondola

Int. J. Mol. Sci. 2020, 21(18), 6606; https://doi.org/10.3390/ijms21186606 - 10 Sep 2020

Cited by 31 | Viewed by 4799

Abstract

Energy metabolism and redox state are strictly linked; energy metabolism is a source of reactive oxygen species (ROS) that, in turn, regulate the flux of metabolic pathways. Moreover, to assure redox homeostasis, metabolic pathways and antioxidant systems are often coordinately regulated. Several findings [...] Read more.

Energy metabolism and redox state are strictly linked; energy metabolism is a source of reactive oxygen species (ROS) that, in turn, regulate the flux of metabolic pathways. Moreover, to assure redox homeostasis, metabolic pathways and antioxidant systems are often coordinately regulated. Several findings show that superoxide dismutase 1 (SOD1) enzyme has effects that go beyond its superoxide dismutase activity and that its functions are not limited to the intracellular compartment. Indeed, SOD1 is secreted through unconventional secretory pathways, carries out paracrine functions and circulates in the blood bound to lipoproteins. Striking experimental evidence links SOD1 to the redox regulation of metabolism. Important clues are provided by the systemic effects on energy metabolism observed in mutant SOD1-mediated amyotrophic lateral sclerosis (ALS). The purpose of this review is to analyze in detail the involvement of SOD1 in redox regulation of metabolism, nutrient sensing, cholesterol metabolism and regulation of mitochondrial respiration. The scientific literature on the relationship between ALS, mutated SOD1 and metabolism will also be explored, in order to highlight the metabolic functions of SOD1 whose biological role still presents numerous unexplored aspects that deserve further investigation. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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22 pages, 1788 KiB

Open AccessReview

Interplay between Peripheral and Central Inflammation in Obesity-Promoted Disorders: The Impact on Synaptic Mitochondrial Functions

by Marianna Crispino, Giovanna Trinchese, Eduardo Penna, Fabiano Cimmino, Angela Catapano, Ines Villano, Carla Perrone-Capano and Maria Pina Mollica

Int. J. Mol. Sci. 2020, 21(17), 5964; https://doi.org/10.3390/ijms21175964 - 19 Aug 2020

Cited by 54 | Viewed by 6074

Abstract

The metabolic dysfunctions induced by high fat diet (HFD) consumption are not limited to organs involved in energy metabolism but cause also a chronic low-grade systemic inflammation that affects the whole body including the central nervous system. The brain has been considered for [...] Read more.

The metabolic dysfunctions induced by high fat diet (HFD) consumption are not limited to organs involved in energy metabolism but cause also a chronic low-grade systemic inflammation that affects the whole body including the central nervous system. The brain has been considered for a long time to be protected from systemic inflammation by the blood–brain barrier, but more recent data indicated an association between obesity and neurodegeneration. Moreover, obesity-related consequences, such as insulin and leptin resistance, mitochondrial dysfunction and reactive oxygen species (ROS) production, may anticipate and accelerate the physiological aging processes characterized by systemic inflammation and higher susceptibility to neurological disorders. Here, we discussed the link between obesity-related metabolic dysfunctions and neuroinflammation, with particular attention to molecules regulating the interplay between energetic impairment and altered synaptic plasticity, for instance AMP-activated protein kinase (AMPK) and Brain-derived neurotrophic factor (BDNF). The effects of HFD-induced neuroinflammation on neuronal plasticity may be mediated by altered brain mitochondrial functions. Since mitochondria play a key role in synaptic areas, providing energy to support synaptic plasticity and controlling ROS production, the negative effects of HFD may be more pronounced in synapses. In conclusion, it will be emphasized how HFD-induced metabolic alterations, systemic inflammation, oxidative stress, neuroinflammation and impaired brain plasticity are tightly interconnected processes, implicated in the pathogenesis of neurological diseases. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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15 pages, 1600 KiB

Open AccessReview

Regulatory Mechanisms of Somatostatin Expression

by Emmanuel Ampofo, Lisa Nalbach, Michael D. Menger and Matthias W. Laschke

Int. J. Mol. Sci. 2020, 21(11), 4170; https://doi.org/10.3390/ijms21114170 - 11 Jun 2020

Cited by 47 | Viewed by 8452

Abstract

Somatostatin is a peptide hormone, which most commonly is produced by endocrine cells and the central nervous system. In mammals, somatostatin originates from pre-prosomatostatin and is processed to a shorter form, i.e., somatostatin-14, and a longer form, i.e., somatostatin-28. The two peptides repress [...] Read more.

Somatostatin is a peptide hormone, which most commonly is produced by endocrine cells and the central nervous system. In mammals, somatostatin originates from pre-prosomatostatin and is processed to a shorter form, i.e., somatostatin-14, and a longer form, i.e., somatostatin-28. The two peptides repress growth hormone secretion and are involved in the regulation of glucagon and insulin synthesis in the pancreas. In recent years, the processing and secretion of somatostatin have been studied intensively. However, little attention has been paid to the regulatory mechanisms that control its expression. This review provides an up-to-date overview of these mechanisms. In particular, it focuses on the role of enhancers and silencers within the promoter region as well as on the binding of modulatory transcription factors to these elements. Moreover, it addresses extracellular factors, which trigger key signaling pathways, leading to an enhanced somatostatin expression in health and disease. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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14 pages, 1192 KiB

Open AccessReview

Mitochondrial Dynamics and Microglia as New Targets in Metabolism Regulation

by Martina Chiurazzi, Martina Di Maro, Mauro Cozzolino and Antonio Colantuoni

Int. J. Mol. Sci. 2020, 21(10), 3450; https://doi.org/10.3390/ijms21103450 - 13 May 2020

Cited by 21 | Viewed by 6291

Abstract

Energy homeostasis regulation is essential for the maintenance of life. Neuronal hypothalamic populations are involved in the regulation of energy balance. In order play this role, they require energy: mitochondria, indeed, have a key role in ensuring a constant energy supply to neurons. [...] Read more.

Energy homeostasis regulation is essential for the maintenance of life. Neuronal hypothalamic populations are involved in the regulation of energy balance. In order play this role, they require energy: mitochondria, indeed, have a key role in ensuring a constant energy supply to neurons. Mitochondria are cellular organelles that are involved in dynamic processes; their dysfunction has been associated with many diseases, such as obesity and type 2 diabetes, indicating their importance in cellular metabolism and bioenergetics. Food intake excess can induce mitochondrial dysfunction with consequent production of reactive oxygen species (ROS) and oxidative stress. Several studies have shown the involvement of mitochondrial dynamics in the modulation of releasing agouti-related protein (AgRP) and proopiomelanocortin (POMC) neuronal activity, although the mechanisms are still unclear. However, recent studies have shown that changes in mitochondrial metabolism, such as in inflammation, can contribute also to the activation of the microglial system in several diseases, especially degenerative diseases. This review is aimed to summarize the link between mitochondrial dynamics and hypothalamic neurons in the regulation of glucose and energy homeostasis. Furthermore, we focus on the importance of microglia activation in the pathogenesis of many diseases, such as obesity, and on the relationship with mitochondrial dynamics, although this process is still largely unknown. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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14 pages, 1605 KiB

Open AccessHypothesis

Functional Role of Dietary Intervention to Improve the Outcome of COVID-19: A Hypothesis of Work

by Giovanni Messina, Rita Polito, Vincenzo Monda, Luigi Cipolloni, Nunzio Di Nunno, Giulio Di Mizio, Paolo Murabito, Marco Carotenuto, Antonietta Messina, Daniela Pisanelli, Anna Valenzano, Giuseppe Cibelli, Alessia Scarinci, Marcellino Monda and Francesco Sessa

Int. J. Mol. Sci. 2020, 21(9), 3104; https://doi.org/10.3390/ijms21093104 - 28 Apr 2020

Cited by 135 | Viewed by 23139

Abstract

Background: On the 31 December 2019, the World Health Organization (WHO) was informed of a cluster of cases of pneumonia of unknown origin detected in Wuhan City, Hubei Province, China. The infection spread first in China and then in the rest of the [...] Read more.

Background: On the 31 December 2019, the World Health Organization (WHO) was informed of a cluster of cases of pneumonia of unknown origin detected in Wuhan City, Hubei Province, China. The infection spread first in China and then in the rest of the world, and on the 11th of March, the WHO declared that COVID-19 was a pandemic. Taking into consideration the mortality rate of COVID-19, about 5–7%, and the percentage of positive patients admitted to intensive care units being 9–11%, it should be mandatory to consider and take all necessary measures to contain the COVID-19 infection. Moreover, given the recent evidence in different hospitals suggesting IL-6 and TNF-α inhibitor drugs as a possible therapy for COVID-19, we aimed to highlight that a dietary intervention could be useful to prevent the infection and/or to ameliorate the outcomes during therapy. Considering that the COVID-19 infection can generate a mild or highly acute respiratory syndrome with a consequent release of pro-inflammatory cytokines, including IL-6 and TNF-α, a dietary regimen modification in order to improve the levels of adiponectin could be very useful both to prevent the infection and to take care of patients, improving their outcomes. Full article

(This article belongs to the Special Issue Central and Peripheral Molecular Mechanisms of Metabolism Regulation)

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