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15 pages, 10927 KiB

Open AccessArticle

Reactive Oxygen Species in the Aorta and Perivascular Adipose Tissue Precedes Endothelial Dysfunction in the Aorta of Mice with a High-Fat High-Sucrose Diet and Additional Factors

by Ayumu Osaki, Kazuki Kagami, Yuki Ishinoda, Atsushi Sato, Toyokazu Kimura, Shunpei Horii, Kei Ito, Takumi Toya, Yasuo Ido, Takayuki Namba, Nobuyuki Masaki, Yuji Nagatomo and Takeshi Adachi

Int. J. Mol. Sci. 2023, 24(7), 6486; https://doi.org/10.3390/ijms24076486 - 30 Mar 2023

Cited by 3 | Viewed by 1848

Abstract

Metabolic syndrome (Mets) is the major contributor to the onset of metabolic complications, such as hypertension, type 2 diabetes mellitus (DM), dyslipidemia, and non-alcoholic fatty liver disease, resulting in cardiovascular diseases. C57BL/6 mice on a high-fat and high-sucrose diet (HFHSD) are a well-established [...] Read more.

Metabolic syndrome (Mets) is the major contributor to the onset of metabolic complications, such as hypertension, type 2 diabetes mellitus (DM), dyslipidemia, and non-alcoholic fatty liver disease, resulting in cardiovascular diseases. C57BL/6 mice on a high-fat and high-sucrose diet (HFHSD) are a well-established model of Mets but have minor endothelial dysfunction in isolated aortas without perivascular adipose tissue (PVAT). The purpose of this study was to evaluate the effects of additional factors such as DM, dyslipidemia, and steatohepatitis on endothelial dysfunction in aortas without PVAT. Here, we employed eight-week-old male C57BL/6 mice fed with a normal diet (ND), HFHSD, steatohepatitis choline-deficient HFHSD (HFHSD-SH), and HFHSD containing 1% cholesterol and 0.1% deoxycholic acid (HFHSD-Chol) for 16 weeks. At week 20, some HFHSD-fed mice were treated with streptozocin to develop diabetes (HFHSD-DM). In PVAT-free aortas, the endothelial-dependent relaxation (EDR) did not differ between ND and HFHSD (p = 0.25), but in aortas with PVAT, the EDR of HFHSD-fed mice was impaired compared with ND-fed mice (p = 0.005). HFHSD-DM, HFHSD-SH, and HFHSD-Chol impaired the EDR in aortas without PVAT (p < 0.001, p = 0.019, and p = 0.009 vs. ND, respectively). Furthermore, tempol rescued the EDR in those models. In the Mets model, the EDR is compromised by PVAT, but with the addition of DM, dyslipidemia, and SH, the vessels themselves may result in impaired EDR. Full article

(This article belongs to the Special Issue Role of Dysfunctional Adipose Tissue in the Pathogenesis of Multiple Organ Injuries)

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12 pages, 1473 KiB

Open AccessArticle

Visceral Adipose Tissue Bioenergetics Varies According to Individuals’ Obesity Class

by Marcelo V. Topete, Sara Andrade, Raquel L. Bernardino, Marta Guimarães, Ana M. Pereira, Sofia B. Oliveira, Madalena M. Costa, Mário Nora, Mariana P. Monteiro and Sofia S. Pereira

Int. J. Mol. Sci. 2023, 24(2), 1679; https://doi.org/10.3390/ijms24021679 - 14 Jan 2023

Cited by 3 | Viewed by 2393

Abstract

Obesity is associated with complex adipose tissue energy metabolism remodeling. Whether AT metabolic reprogramming differs according to body mass index (BMI) and across different obesity classes is unknown. This study’s purpose was to evaluate and compare bioenergetics and energy substrate preference of visceral [...] Read more.

Obesity is associated with complex adipose tissue energy metabolism remodeling. Whether AT metabolic reprogramming differs according to body mass index (BMI) and across different obesity classes is unknown. This study’s purpose was to evaluate and compare bioenergetics and energy substrate preference of visceral adipose tissue (VAT) pertaining to individuals with obesity class 2 and class 3. VAT obtained from patients with obesity (n = 15) class 2 (n = 7; BMI 37.53 ± 0.58 kg/m²) or class 3 (n = 8; BMI 47.79 ± 1.52 kg/m²) was used to assess oxygen consumption rate (OCR) bioenergetics and mitochondrial substrate preferences. VAT of patients with obesity class 3 presented significantly higher non-mitochondrial oxygen consumption (p < 0.05). In VAT of patients with obesity class 2, inhibition of pyruvate and glutamine metabolism significantly decreased maximal respiration and spare respiratory capacity (p < 0.05), while pyruvate and fatty acid metabolism inhibition, which renders glutamine the only available substrate, increased the proton leak with a protective role against oxidative stress (p < 0.05). In conclusion, VAT bioenergetics of patients with obesity class 2 depicts a greater dependence on glucose/pyruvate and glutamine metabolism, suggesting that patients within this BMI range are more likely to be responsive to interventions based on energetic substrate modulation for obesity treatment. Full article

(This article belongs to the Special Issue Role of Dysfunctional Adipose Tissue in the Pathogenesis of Multiple Organ Injuries)

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16 pages, 2441 KiB

Open AccessArticle

Targeting ABCC6 in Mesenchymal Stem Cells: Impairment of Mature Adipocyte Lipid Homeostasis

by Ricarda Plümers, Michel R. Osterhage, Christopher Lindenkamp, Cornelius Knabbe and Doris Hendig

Int. J. Mol. Sci. 2022, 23(16), 9218; https://doi.org/10.3390/ijms23169218 - 16 Aug 2022

Cited by 1 | Viewed by 1980

Abstract

Mutations in ABCC6, an ATP-binding cassette transporter with a so far unknown substrate mainly expressed in the liver and kidney, cause pseudoxanthoma elasticum (PXE). Symptoms of PXE in patients originate from the calcification of elastic fibers in the skin, eye, and vessels. Previous [...] Read more.

Mutations in ABCC6, an ATP-binding cassette transporter with a so far unknown substrate mainly expressed in the liver and kidney, cause pseudoxanthoma elasticum (PXE). Symptoms of PXE in patients originate from the calcification of elastic fibers in the skin, eye, and vessels. Previous studies suggested an involvement of ABCC6 in cholesterol and lipid homeostasis. The intention of this study was to examine the influence of ABCC6 deficiency during adipogenic differentiation of human bone marrow-derived stem cells (hMSCs). Induction of adipogenic differentiation goes along with significantly elevated ABCC6 gene expression in mature adipocytes. We generated an ABCC6-deficient cell culture model using clustered regulatory interspaced short palindromic repeat Cas9 (CRISPR–Cas9) system to clarify the role of ABCC6 in lipid homeostasis. The lack of ABCC6 in hMSCs does not influence gene expression of differentiation markers in adipogenesis but results in a decreased triglyceride content in cell culture medium. Protein and gene expression analysis of mature ABCC6-deficient adipocytes showed diminished intra- and extra-cellular lipolysis, release of lipids, and fatty acid neogenesis. Therefore, our results demonstrate impaired lipid trafficking in adipocytes due to ABCC6 deficiency, highlighting adipose tissue and peripheral lipid metabolism as a relevant target for uncovering systemic PXE pathogenesis. Full article

(This article belongs to the Special Issue Role of Dysfunctional Adipose Tissue in the Pathogenesis of Multiple Organ Injuries)

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Review

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20 pages, 1218 KiB

Open AccessReview

Impact of Dysfunctional Adipose Tissue Depots on the Cardiovascular System

by Rossella D’Oria, Valentina Annamaria Genchi, Cristina Caccioppoli, Isabella Calderoni, Nicola Marrano, Giuseppina Biondi, Anna Borrelli, Ludovico Di Gioia, Francesco Giorgino and Luigi Laviola

Int. J. Mol. Sci. 2022, 23(22), 14296; https://doi.org/10.3390/ijms232214296 - 18 Nov 2022

Cited by 6 | Viewed by 2892

Abstract

Obesity with its associated complications represents a social, economic and health problem of utmost importance worldwide. Specifically, obese patients carry a significantly higher risk of developing cardiovascular disease compared to nonobese individuals. Multiple molecular mechanisms contribute to the impaired biological activity of the [...] Read more.

Obesity with its associated complications represents a social, economic and health problem of utmost importance worldwide. Specifically, obese patients carry a significantly higher risk of developing cardiovascular disease compared to nonobese individuals. Multiple molecular mechanisms contribute to the impaired biological activity of the distinct adipose tissue depots in obesity, including secretion of proinflammatory mediators and reactive oxygen species, ultimately leading to an unfavorable impact on the cardiovascular system. This review summarizes data relating to the contribution of the main adipose tissue depots, including both remote (i.e., intra-abdominal, hepatic, skeletal, pancreatic, renal, and mesenteric adipose fat), and cardiac (i.e., the epicardial fat) adipose locations, on the cardiovascular system. Finally, we discuss both pharmacological and non-pharmacological strategies aimed at reducing cardiovascular risk through acting on adipose tissues, with particular attention to the epicardial fat. Full article

(This article belongs to the Special Issue Role of Dysfunctional Adipose Tissue in the Pathogenesis of Multiple Organ Injuries)

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15 pages, 4043 KiB

Open AccessReview

Adipose Tissue Dysfunction and Obesity-Related Male Hypogonadism

by Valentina Annamaria Genchi, Erica Rossi, Celeste Lauriola, Rossella D’Oria, Giuseppe Palma, Anna Borrelli, Cristina Caccioppoli, Francesco Giorgino and Angelo Cignarelli

Int. J. Mol. Sci. 2022, 23(15), 8194; https://doi.org/10.3390/ijms23158194 - 25 Jul 2022

Cited by 42 | Viewed by 6074

Abstract

Obesity is a chronic illness associated with several metabolic derangements and comorbidities (i.e., insulin resistance, leptin resistance, diabetes, etc.) and often leads to impaired testicular function and male subfertility. Several mechanisms may indeed negatively affect the hypothalamic–pituitary–gonadal health, such as higher testosterone conversion [...] Read more.

Obesity is a chronic illness associated with several metabolic derangements and comorbidities (i.e., insulin resistance, leptin resistance, diabetes, etc.) and often leads to impaired testicular function and male subfertility. Several mechanisms may indeed negatively affect the hypothalamic–pituitary–gonadal health, such as higher testosterone conversion to estradiol by aromatase activity in the adipose tissue, increased ROS production, and the release of several endocrine molecules affecting the hypothalamus–pituitary–testis axis by both direct and indirect mechanisms. In addition, androgen deficiency could further accelerate adipose tissue expansion and therefore exacerbate obesity, which in turn enhances hypogonadism, thus inducing a vicious cycle. Based on these considerations, we propose an overview on the relationship of adipose tissue dysfunction and male hypogonadism, highlighting the main biological pathways involved and the current therapeutic options to counteract this condition. Full article

(This article belongs to the Special Issue Role of Dysfunctional Adipose Tissue in the Pathogenesis of Multiple Organ Injuries)

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23 pages, 1044 KiB

Open AccessReview

Adipose Tissue Inflammation and Pulmonary Dysfunction in Obesity

by Giuseppe Palma, Gian Pio Sorice, Valentina Annamaria Genchi, Fiorella Giordano, Cristina Caccioppoli, Rossella D’Oria, Nicola Marrano, Giuseppina Biondi, Francesco Giorgino and Sebastio Perrini

Int. J. Mol. Sci. 2022, 23(13), 7349; https://doi.org/10.3390/ijms23137349 - 1 Jul 2022

Cited by 40 | Viewed by 6575

Abstract

Obesity is a chronic disease caused by an excess of adipose tissue that may impair health by altering the functionality of various organs, including the lungs. Excessive deposition of fat in the abdominal area can lead to abnormal positioning of the diaphragm and [...] Read more.

Obesity is a chronic disease caused by an excess of adipose tissue that may impair health by altering the functionality of various organs, including the lungs. Excessive deposition of fat in the abdominal area can lead to abnormal positioning of the diaphragm and consequent reduction in lung volume, leading to a heightened demand for ventilation and increased exposure to respiratory diseases, such as chronic obstructive pulmonary disease, asthma, and obstructive sleep apnoea. In addition to mechanical ventilatory constraints, excess fat and ectopic deposition in visceral depots can lead to adipose tissue dysfunction, which promotes metabolic disorders. An altered adipokine-secretion profile from dysfunctional adipose tissue in morbid obesity fosters systemic, low-grade inflammation, impairing pulmonary immune response and promoting airway hyperresponsiveness. A potential target of these adipokines could be the NLRP3 inflammasome, a critical component of the innate immune system, the harmful pro-inflammatory effect of which affects both adipose and lung tissue in obesity. In this review, we will investigate the crosstalk between adipose tissue and the lung in obesity, highlighting the main inflammatory mediators and novel therapeutic targets in preventing pulmonary dysfunction. Full article

(This article belongs to the Special Issue Role of Dysfunctional Adipose Tissue in the Pathogenesis of Multiple Organ Injuries)

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30 pages, 993 KiB

Open AccessReview

Adipose Tissue Secretion Pattern Influences β-Cell Wellness in the Transition from Obesity to Type 2 Diabetes

by Giuseppina Biondi, Nicola Marrano, Anna Borrelli, Martina Rella, Giuseppe Palma, Isabella Calderoni, Edoardo Siciliano, Pasquale Lops, Francesco Giorgino and Annalisa Natalicchio

Int. J. Mol. Sci. 2022, 23(10), 5522; https://doi.org/10.3390/ijms23105522 - 15 May 2022

Cited by 27 | Viewed by 6192

Abstract

The dysregulation of the β-cell functional mass, which is a reduction in the number of β-cells and their ability to secure adequate insulin secretion, represents a key mechanistic factor leading to the onset of type 2 diabetes (T2D). Obesity is recognised as a [...] Read more.

The dysregulation of the β-cell functional mass, which is a reduction in the number of β-cells and their ability to secure adequate insulin secretion, represents a key mechanistic factor leading to the onset of type 2 diabetes (T2D). Obesity is recognised as a leading cause of β-cell loss and dysfunction and a risk factor for T2D. The natural history of β-cell failure in obesity-induced T2D can be divided into three steps: (1) β-cell compensatory hyperplasia and insulin hypersecretion, (2) insulin secretory dysfunction, and (3) loss of β-cell mass. Adipose tissue (AT) secretes many hormones/cytokines (adipokines) and fatty acids that can directly influence β-cell function and viability. As this secretory pattern is altered in obese and diabetic patients, it is expected that the cross-talk between AT and pancreatic β-cells could drive the maintenance of the β-cell integrity under physiological conditions and contribute to the reduction in the β-cell functional mass in a dysmetabolic state. In the current review, we summarise the evidence of the ability of the AT secretome to influence each step of β-cell failure, and attempt to draw a timeline of the alterations in the adipokine secretion pattern in the transition from obesity to T2D that reflects the progressive deterioration of the β-cell functional mass. Full article

(This article belongs to the Special Issue Role of Dysfunctional Adipose Tissue in the Pathogenesis of Multiple Organ Injuries)

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16 pages, 1233 KiB

Open AccessReview

Adipose Tissue Plasticity in Response to Pathophysiological Cues: A Connecting Link between Obesity and Its Associated Comorbidities

by Michelatonio De Fano, Desirèe Bartolini, Cristina Tortoioli, Cristiana Vermigli, Massimo Malara, Francesco Galli and Giuseppe Murdolo

Int. J. Mol. Sci. 2022, 23(10), 5511; https://doi.org/10.3390/ijms23105511 - 14 May 2022

Cited by 21 | Viewed by 5385

Abstract

Adipose tissue (AT) is a remarkably plastic and active organ with functional pleiotropism and high remodeling capacity. Although the expansion of fat mass, by definition, represents the hallmark of obesity, the dysregulation of the adipose organ emerges as the forefront of the link [...] Read more.

Adipose tissue (AT) is a remarkably plastic and active organ with functional pleiotropism and high remodeling capacity. Although the expansion of fat mass, by definition, represents the hallmark of obesity, the dysregulation of the adipose organ emerges as the forefront of the link between adiposity and its associated metabolic and cardiovascular complications. The dysfunctional fat displays distinct biological signatures, which include enlarged fat cells, low-grade inflammation, impaired redox homeostasis, and cellular senescence. While these events are orchestrated in a cell-type, context-dependent and temporal manner, the failure of the adipose precursor cells to form new adipocytes appears to be the main instigator of the adipose dysregulation, which, ultimately, poses a deleterious milieu either by promoting ectopic lipid overspill in non-adipose targets (i.e., lipotoxicity) or by inducing an altered secretion of different adipose-derived hormones (i.e., adipokines and lipokines). This “adipocentric view” extends the previous “expandability hypothesis”, which implies a reduced plasticity of the adipose organ at the nexus between unhealthy fat expansion and the development of obesity-associated comorbidities. In this review, we will briefly summarize the potential mechanisms by which adaptive changes to variations of energy balance may impair adipose plasticity and promote fat organ dysfunction. We will also highlight the conundrum with the perturbation of the adipose microenvironment and the development of cardio-metabolic complications by focusing on adipose lipoxidation, inflammation and cellular senescence as a novel triad orchestrating the conspiracy to adipose dysfunction. Finally, we discuss the scientific rationale for proposing adipose organ plasticity as a target to curb/prevent adiposity-linked cardio-metabolic complications. Full article

(This article belongs to the Special Issue Role of Dysfunctional Adipose Tissue in the Pathogenesis of Multiple Organ Injuries)

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