International Journal of Molecular Sciences

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21 pages, 3846 KiB

Open AccessArticle

Epigenetic Modifications in Alternative Splicing of LDLR pre-mRNA on Hypercholesterolemia Following Aerobic Exercise Training

by Jinfeng Zhao, Peirun Yan, Yana Pang, Yuankun Dong and Xiangrong Shi

Int. J. Mol. Sci. 2025, 26(9), 4262; https://doi.org/10.3390/ijms26094262 - 30 Apr 2025

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Abstract

This study investigated whether exercise training improved cholesterol metabolism through modifying alternative splicing of the low-density lipoprotein receptor (LDLR). Blood lipids and expressions of LDLR splice variants were compared between exercise-trained and non-trained young adults with normal and high cholesterol. The expression of [...] Read more.

This study investigated whether exercise training improved cholesterol metabolism through modifying alternative splicing of the low-density lipoprotein receptor (LDLR). Blood lipids and expressions of LDLR splice variants were compared between exercise-trained and non-trained young adults with normal and high cholesterol. The expression of LDLR splice isoforms were examined using RT-PCR and the histone H3K36me3 by CHIP-assay in mouse liver following a 13-week normal or high-cholesterol-diet combined with or without 8 weeks of aerobic exercise-training. The influence of histone modifications on LDLR alternative splicing was examined in HepG2 cells (human liver cell-line). Expression levels of LDLR deletions in exons 4 and 12 (LDLR-∆Exon4 and LDLR-∆Exon12) were significantly higher in the obese adults with high-cholesterol. These LDLR splice variants were significantly lower in the exercise-trained than non-trained group with normal cholesterol. Thirteen weeks of high-cholesterol feeding increased LDLR-∆Exon14 expression in mice, which was diminished after 8 weeks of exercise training. When H3-K36me3 or the MORF-related gene on chromosomes 15 were overexpressed and interfered, the levels of LDLR-∆Exon4 and LDLR-∆Exon12 expression in HepG2 cells were significantly augmented and inhibited, respectively. Hypercholesterolemia was associated with augmented expressions of LDLR splice variants in obese adults and following high-cholesterol diet in mice. Aerobic exercise training prevented and reversed the dyslipidemia-related alternative splicing of LDLR pre-mRNA. The histone modifications contributed to the alternative splicing. Full article

(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)

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11 pages, 1061 KiB

Open AccessArticle

The Regulator of G Protein Signaling 14 Knockout Mouse, a Model of Healthful Longevity Protects Against Obesity and Glucose Intolerance Through a Brown Adipose Tissue Mechanism

by Stephen F. Vatner, Jie Zhang, Marko Oydanich and Dorothy E. Vatner

Int. J. Mol. Sci. 2025, 26(9), 4113; https://doi.org/10.3390/ijms26094113 - 26 Apr 2025

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Abstract

The Regulator of G Protein Signaling 14 (RGS14) knockout (KO) mouse is a model of healthful longevity, i.e., its lifespan is prolonged and demonstrates enhanced exercise performance and protection against heart disease and hypertension. In this investigation, we found the RGS14 [...] Read more.

The Regulator of G Protein Signaling 14 (RGS14) knockout (KO) mouse is a model of healthful longevity, i.e., its lifespan is prolonged and demonstrates enhanced exercise performance and protection against heart disease and hypertension. In this investigation, we found the RGS14 KO mouse is also protected against obesity and glucose intolerance by promoting a low white adipose tissue (WAT) phenotype with increased brown adipose tissue (BAT). This was confirmed by lower body weight, lower white adipocyte size, increased metabolism and improved glucose tolerance and insulin sensitivity. Upon examination of the white adipose tissue, RGS14 KO exhibited increased expression of “beiging” genes as well as significant increase in Uncoupling protein-1 (UCP-1) expression. The mechanism behind this protection was due to its unique brown adipose tissue. This was determined by BAT transplantation, which led to a reversal of phenotype, such that RGS14 BAT recipients developed protection similar to intact RGS14 KO mice, and the RGS14 KO BAT donors lost their protection. Thus, two novel mechanisms mediating obesity and glucose intolerance were found, i.e., inhibition of RGS14 and its BAT. Full article

(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)

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17 pages, 10364 KiB

Open AccessArticle

Rno-miR-130b Attenuates Lipid Accumulation Through Promoting Apoptosis and Inhibiting Differentiation in Rat Intramuscular Adipocytes

by Yichen Yu, Yongfang Chen, Lijun Wang, Ji Cheng, Min Du and Shifeng Pan

Int. J. Mol. Sci. 2025, 26(4), 1399; https://doi.org/10.3390/ijms26041399 - 7 Feb 2025

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Abstract

Our previous studies have shown that miR-130b can significantly inhibit subcutaneous fat deposition in pigs. This study aims to further investigate its effect on lipid accumulation at early-stage (24 and 48 h) and late-stage (7 d) adipogenic differentiation and to clarify potential mechanisms [...] Read more.

Our previous studies have shown that miR-130b can significantly inhibit subcutaneous fat deposition in pigs. This study aims to further investigate its effect on lipid accumulation at early-stage (24 and 48 h) and late-stage (7 d) adipogenic differentiation and to clarify potential mechanisms using primary rat intramuscular preadipocytes (IMAs). Results showed that at 24 h and 48 h, miR-130b overexpression significantly reduced lipid deposition by inhibiting proliferation and inducing apoptosis. Furthermore, miR-130b overexpression significantly inhibited the expression of cell cycle and apoptosis marker genes. Specifically, the mRNA expression of Ccnd1 tended to decrease, while the BCL2 protein level was significantly decreased at 48 h. In contrast, miR-130b inhibition significantly increased the BCL2 protein level. At 7 d, the miR-130b mimic significantly decreased intracellular TG content and tended to decrease Hsd11b1 mRNA expression while significantly promoting Lpl mRNA expression. Additionally, the miR-130b mimic significantly increased the CASP3 protein level and tended to decrease the BCL2 protein level. In conclusion, our data indicated for the first time that miR-130b could reduce lipid deposition in rat IMAs through different mechanisms: at the early stage of differentiation by inhibiting proliferation and promoting apoptosis and at the late stage by inhibiting adipogenic differentiation, promoting lipid hydrolysis, and promoting apoptosis. Full article

(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)

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15 pages, 2311 KiB

Open AccessArticle

Diastolic Dysfunction with Normal Ejection Fraction and Reduced Heart Rate in Mice Expressing Human Growth Hormone and Displaying Signs of Growth Hormone Insufficiency

by Yan Jin, Bo Xiang, Vernon W. Dolinsky, Elissavet Kardami and Peter A. Cattini

Int. J. Mol. Sci. 2025, 26(1), 269; https://doi.org/10.3390/ijms26010269 - 31 Dec 2024

Viewed by 735

Abstract

Growth hormone (GH) signaling is essential for heart development. Both GH deficiency and excess raise cardiovascular risk. Human (h) and mouse (m) GH differ structurally and functionally: hGH binds both the GH receptor (GHR) and prolactin receptor (PRLR), whereas mGH binds only GHR; [...] Read more.

Growth hormone (GH) signaling is essential for heart development. Both GH deficiency and excess raise cardiovascular risk. Human (h) and mouse (m) GH differ structurally and functionally: hGH binds both the GH receptor (GHR) and prolactin receptor (PRLR), whereas mGH binds only GHR; thus, there is the potential for differential effects. We generated transgenic (hGH-TG) mice that produce pituitary hGH in response to hypothalamic signaling. These mice grow at the same rate as mGH-expressing wild-type (mGH-WT) mice but are smaller and have higher body fat. Echocardiography was used here to compare hGH-TG and mGH-WT mouse hearts. Male hGH-TG mice show a 48% lower left ventricular mass, 36% lower stroke volume, and 48% reduced cardiac output, resembling GH deficiency. Diastolic dysfunction, restrictive ventricular filling, and lower heart rate are suggested in hGH-TG mice. No significant differences in ejection fraction or fractional shortening were observed, even after high-fat diet (HFD) stress. HFD did not affect RNA markers of cardiac damage, although a possible association between B-type natriuretic peptide RNA levels and heart rate was detected. These observations suggest that diastolic dysfunction related to hGH and/or low GH might be offset by a lower heart rate, while structural changes precede functional effects. Full article

(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)

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20 pages, 4799 KiB

Open AccessArticle

Male Wistar Rats Chronically Fed with a High-Fat Diet Develop Inflammatory and Ionic Transport Angiotensin-(3–4)-Sensitive Myocardial Lesions but Preserve Echocardiographic Parameters

by Thuany Crisóstomo, Rafael Luzes, Matheus Leonardo Lima Gonçalves, Marco Antônio Estrela Pardal, Humberto Muzi-Filho, Glória Costa-Sarmento, Debora B. Mello and Adalberto Vieyra

Int. J. Mol. Sci. 2024, 25(22), 12474; https://doi.org/10.3390/ijms252212474 - 20 Nov 2024

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Abstract

The central aim of this study was to investigate whether male Wistar rats chronically fed a high-fat diet (HFD) over 106 days present high levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and Na⁺ and Ca²⁺ transport alterations in the [...] Read more.

The central aim of this study was to investigate whether male Wistar rats chronically fed a high-fat diet (HFD) over 106 days present high levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), and Na⁺ and Ca²⁺ transport alterations in the left ventricle, together with dyslipidemia and decreased glucose tolerance, and to investigate the influence of Ang-(3–4). The rats became moderately overweight with an expansion of visceral adiposity. Na⁺-transporting ATPases, sarco-endoplasmic reticulum Ca²⁺-ATPase (SERCA2a), and the abundance of Angiotensin II receptors were studied together with lipid and glycemic profiles from plasma and left-ventricle echocardiographic parameters fractional shortening (FS) and ejection fraction (EF). IL-6 and TNF-α increased (62% and 53%, respectively), but returned to normal levels with Angiotensin-(3–4) administration after 106 days. Significant lipidogram alterations accompanied a decrease in glucose tolerance. Angiotensin II receptors abundance did not change. (Na⁺ + K⁺)ATPase and ouabain-resistant Na⁺-ATPase were downregulated and upregulated, respectively, but returned to normal values upon Angiotensin-(3–4) administration. SERCA2a lost its ability to respond to excess ATP. Echocardiography showed no changes in FS or EF. We conclude that being overweight causes an increase in Ang-(3–4)-sensitive IL-6 and TNF-α levels, and ion transport alterations in the left ventricle that could evolve into future heart dysfunction. Full article

(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)

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15 pages, 3493 KiB

Open AccessArticle

Ascochlorin Attenuates the Early Stage of Adipogenesis via the Wnt/β-Catenin Pathway and Inhibits High-Fat-Diet-Induced Obesity in Mice

by Mi-Hee Yu, Yun-Jeong Jeong, Sung Wook Son, So Yoon Kwon, Kwon-Ho Song, Ho-Sang Son, Eon-Ju Jeon and Young-Chae Chang

Int. J. Mol. Sci. 2024, 25(18), 10226; https://doi.org/10.3390/ijms251810226 - 23 Sep 2024

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Abstract

This study investigated the effects of ascochlorin (ASC), a natural compound derived from the fungus Ascochyta viciae, on adipogenesis and obesity. We determined the effects of ASC on 3T3-L1 preadipocytes and whether it ameliorated to mitigate high-fat diet (HFD)-induced obesity in C57BL/6J mice. [...] Read more.

This study investigated the effects of ascochlorin (ASC), a natural compound derived from the fungus Ascochyta viciae, on adipogenesis and obesity. We determined the effects of ASC on 3T3-L1 preadipocytes and whether it ameliorated to mitigate high-fat diet (HFD)-induced obesity in C57BL/6J mice. We found that ASC significantly inhibited the differentiation of preadipocytes by modulating the Wnt/β-catenin signaling pathway, a key regulator of adipogenic processes. Treatment with ASC not only reduced the mRNA and protein expression of key adipogenic transcription factors such as C/EBPα and PPARγ, but also reduced lipid accumulation both in vitro and in vivo. In addition, treatment HFD-fed mice with ASC significantly reduced their weight gain and adiposity vs. control mice. These results suggest that ASC has considerable potential as a therapeutic agent for obesity, owing to its dual action of inhibiting adipocyte differentiation and reducing lipid accumulation. Thus, ASC represents a promising candidate as a natural anti-obesity agent. Full article

(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)

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12 pages, 1572 KiB

Open AccessCommunication

The Expression of Genes Related to Reverse Cholesterol Transport and Leptin Receptor Pathways in Peripheral Blood Mononuclear Cells Are Decreased in Morbid Obesity and Related to Liver Function

by Carlos Jiménez-Cortegana, Soledad López-Enríquez, Gonzalo Alba, Consuelo Santa-María, Gracia M. Martín-Núñez, Francisco J. Moreno-Ruiz, Sergio Valdés, Sara García-Serrano, Cristina Rodríguez-Díaz, Ailec Ho-Plágaro, María I. Fontalba-Romero, Eduardo García-Fuentes, Lourdes Garrido-Sánchez and Víctor Sánchez-Margalet

Int. J. Mol. Sci. 2024, 25(14), 7549; https://doi.org/10.3390/ijms25147549 - 9 Jul 2024

Viewed by 1755

Abstract

Obesity is frequently accompanied by non-alcoholic fatty liver disease (NAFLD). These two diseases are associated with altered lipid metabolism, in which reverse cholesterol transport (LXRα/ABCA1/ABCG1) and leptin response (leptin receptor (Ob-Rb)/Sam68) are involved. The two pathways were evaluated in peripheral blood mononuclear cells [...] Read more.

Obesity is frequently accompanied by non-alcoholic fatty liver disease (NAFLD). These two diseases are associated with altered lipid metabolism, in which reverse cholesterol transport (LXRα/ABCA1/ABCG1) and leptin response (leptin receptor (Ob-Rb)/Sam68) are involved. The two pathways were evaluated in peripheral blood mononuclear cells (PBMCs) from 86 patients with morbid obesity (MO) before and six months after Roux-en-Y gastric bypass (RYGB) and 38 non-obese subjects. In the LXRα pathway, LXRα, ABCA1, and ABCG1 mRNA expressions were decreased in MO compared to non-obese subjects (p < 0.001, respectively). Ob-Rb was decreased (p < 0.001), whereas Sam68 was increased (p < 0.001) in MO. RYGB did not change mRNA gene expressions. In the MO group, the LXRα pathway (LXRα/ABCA1/ABCG1) negatively correlated with obesity-related variables (weight, body mass index, and hip), inflammation (C-reactive protein), and liver function (alanine-aminotransferase, alkaline phosphatase, and fatty liver index), and positively with serum albumin. In the Ob-R pathway, Ob-Rb and Sam68 negatively correlated with alanine-aminotransferase and positively with albumin. The alteration of LXRα and Ob-R pathways may play an important role in NAFLD development in MO. It is possible that MO patients may require more than 6 months following RYBGB to normalize gene expression related to reverse cholesterol transport or leptin responsiveness. Full article

(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)

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12 pages, 848 KiB

Open AccessArticle

Association between Visceral Adipose Tissue Metabolism and Cerebral Glucose Metabolism in Patients with Cognitive Impairment

by Mi-Hee Yu, Ji Sun Lim, Hyon-Ah Yi, Kyoung Sook Won and Hae Won Kim

Int. J. Mol. Sci. 2024, 25(13), 7479; https://doi.org/10.3390/ijms25137479 - 8 Jul 2024

Cited by 1 | Viewed by 1448

Abstract

Visceral adipose tissue (VAT) dysfunction has been recently recognized as a potential contributor to the development of Alzheimer’s disease (AD). This study aimed to explore the relationship between VAT metabolism and cerebral glucose metabolism in patients with cognitive impairment. This cross-sectional prospective study [...] Read more.

Visceral adipose tissue (VAT) dysfunction has been recently recognized as a potential contributor to the development of Alzheimer’s disease (AD). This study aimed to explore the relationship between VAT metabolism and cerebral glucose metabolism in patients with cognitive impairment. This cross-sectional prospective study included 54 patients who underwent ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) brain and torso positron emission tomography/computed tomography (PET/CT), and neuropsychological evaluations. VAT metabolism was measured by ¹⁸F-FDG torso PET/CT, and cerebral glucose metabolism was measured using ¹⁸F-FDG brain PET/CT. A voxel-based analysis revealed that the high-VAT-metabolism group exhibited a significantly lower cerebral glucose metabolism in AD-signature regions such as the parietal and temporal cortices. In the volume-of-interest analysis, multiple linear regression analyses with adjustment for age, sex, and white matter hyperintensity volume revealed that VAT metabolism was negatively associated with cerebral glucose metabolism in AD-signature regions. In addition, higher VAT metabolism was correlated with poorer outcomes on cognitive assessments, including the Korean Boston Naming Test, Rey Complex Figure Test immediate recall, and the Controlled Oral Word Association Test. In conclusion, our study revealed significant relationships among VAT metabolism, cerebral glucose metabolism, and cognitive function. This suggests that VAT dysfunction actively contributes to the neurodegenerative processes characteristic of AD, making VAT dysfunction targeting a novel AD therapy approach. Full article

(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)

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Review

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33 pages, 2520 KiB

Open AccessReview

Relationship Between Obesity and Depression Considering the Inflammatory Theory

by Aleksandra Julia Oracz, Mateusz Zwierz, Maciej Naumowicz, Maria Suprunowicz and Napoleon Waszkiewicz

Int. J. Mol. Sci. 2025, 26(11), 4966; https://doi.org/10.3390/ijms26114966 - 22 May 2025

Viewed by 142

Abstract

Numerous scientific findings indicate that excess adipose tissue, particularly visceral fat, is associated with a chronic inflammatory state manifested by elevated levels of proinflammatory cytokines and an imbalance in the T helper type 1/type 2 (Th1/Th2) response, which carries numerous metabolic consequences. Obesity [...] Read more.

Numerous scientific findings indicate that excess adipose tissue, particularly visceral fat, is associated with a chronic inflammatory state manifested by elevated levels of proinflammatory cytokines and an imbalance in the T helper type 1/type 2 (Th1/Th2) response, which carries numerous metabolic consequences. Obesity induces, among other effects, the activation of the kynurenine pathway and a reduction in serotonin synthesis, alterations in adipokine profiles, modifications of the hypothalamic–pituitary–adrenal (HPA) axis, disturbances in fatty acid ratios, oxidative stress, and dysfunction of the gamma-aminobutyric acid (GABA)ergic system. These neuroimmunological and metabolic disturbances, along with obesity-induced neurotransmission abnormalities that may represent a common underlying model of depression, could provide valuable insights into the pathomechanisms of depression, allowing for prediction of disease progression and individualized therapeutic strategies in overweight patients. Furthermore, the analysis of inflammation-associated biomarkers opens up new therapeutic perspectives, suggesting that interventions aimed at reducing inflammation might lead to potential advances in the treatment of depression. Full article

(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)

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28 pages, 1426 KiB

Open AccessReview

Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review

by Nikolaos Theodorakis, Magdalini Kreouzi, Andreas Pappas and Maria Nikolaou

Int. J. Mol. Sci. 2024, 25(24), 13438; https://doi.org/10.3390/ijms252413438 - 15 Dec 2024

Cited by 7 | Viewed by 6220

Abstract

The global rise in obesity underscores the need for effective weight management strategies that address individual metabolic and hormonal variability, moving beyond the simplistic “calories in, calories out” model. Body types—ectomorph, mesomorph, and endomorph—provide a framework for understanding the differences in fat storage, [...] Read more.

The global rise in obesity underscores the need for effective weight management strategies that address individual metabolic and hormonal variability, moving beyond the simplistic “calories in, calories out” model. Body types—ectomorph, mesomorph, and endomorph—provide a framework for understanding the differences in fat storage, muscle development, and energy expenditure, as each type responds uniquely to caloric intake and exercise. Variability in weight outcomes is influenced by factors such as genetic polymorphisms and epigenetic changes in hormonal signaling pathways and metabolic processes, as well as lifestyle factors, including nutrition, exercise, sleep, and stress. These factors impact the magnitude of lipogenesis and myofibrillar protein synthesis during overfeeding, as well as the extent of lipolysis and muscle proteolysis during caloric restriction, through complex mechanisms that involve changes in the resting metabolic rate, metabolic pathways, and hormonal profiles. Precision approaches, such as nutrigenomics, indirect calorimetry, and artificial-intelligence-based strategies, can potentially leverage these insights to create individualized weight management strategies aligned with each person’s unique metabolic profile. By addressing these personalized factors, precision nutrition offers a promising pathway to sustainable and effective weight management outcomes. The main objective of this review is to examine the metabolic and hormonal adaptations driving variability in weight management outcomes and explore how precision nutrition can address these challenges through individualized strategies. Full article

(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)

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18 pages, 798 KiB

Open AccessReview

Childhood Cardiovascular Health, Obesity, and Some Related Disorders: Insights into Chronic Inflammation and Oxidative Stress

by Tjaša Hertiš Petek and Nataša Marčun Varda

Int. J. Mol. Sci. 2024, 25(17), 9706; https://doi.org/10.3390/ijms25179706 - 7 Sep 2024

Cited by 6 | Viewed by 3006

Abstract

Childhood obesity and associated metabolic abnormalities have become pressing public health concerns worldwide, significantly impacting cardiovascular health. Metabolic syndrome, characterized by a cluster of metabolic abnormalities including central obesity, altered glucose metabolism, dyslipidemia, and arterial hypertension, has emerged as a critical precursor to [...] Read more.

Childhood obesity and associated metabolic abnormalities have become pressing public health concerns worldwide, significantly impacting cardiovascular health. Metabolic syndrome, characterized by a cluster of metabolic abnormalities including central obesity, altered glucose metabolism, dyslipidemia, and arterial hypertension, has emerged as a critical precursor to cardiovascular disease. Chronic systemic inflammation and oxidative stress seem to play pivotal roles in the pathogenesis of childhood obesity-related disorders such as early atherosclerosis. A significant distinction between the objective components of cardiovascular health metrics, including body mass index, blood pressure, cholesterol, and fasting glucose levels, and the definition of metabolic syndrome is evident in the identification of obesity. Whereas cardiovascular health metrics predominantly rely on body mass index percentiles to assess obesity, metabolic syndrome criteria prioritize waist circumference, specifically targeting individuals with a measurement ≥90th percentile. This discrepancy emphasizes the need for a nuanced approach in assessing the risks associated with obesity and underscores the importance of considering multiple factors when evaluating cardiovascular risk in children. By recognizing the complex interplay between various health metrics, obesity and metabolic syndrome criteria, clinicians can more accurately identify individuals at risk and tailor interventions accordingly to mitigate cardiovascular disease in children with obesity. Full article

(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)

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23 pages, 754 KiB

Open AccessReview

The Impact of the Endocrine and Immunological Function of Adipose Tissue on Reproduction in Women with Obesity

by Katarzyna Mączka, Olga Stasiak, Paulina Przybysz, Monika Grymowicz and Roman Smolarczyk

Int. J. Mol. Sci. 2024, 25(17), 9391; https://doi.org/10.3390/ijms25179391 - 29 Aug 2024

Cited by 7 | Viewed by 2242

Abstract

Obesity, which leads to metabolic dysregulation and body function impairment, emerges as one of the pressing health challenges worldwide. Excessive body fat deposits comprise a dynamic and biologically active organ possessing its own endocrine function. One of the mechanisms underlying the pathophysiology of [...] Read more.

Obesity, which leads to metabolic dysregulation and body function impairment, emerges as one of the pressing health challenges worldwide. Excessive body fat deposits comprise a dynamic and biologically active organ possessing its own endocrine function. One of the mechanisms underlying the pathophysiology of obesity is low-grade systemic inflammation mediated by pro-inflammatory factors such as free fatty acids, lipopolysaccharides, adipokines (including leptin, resistin and visfatin) and cytokines (TNF-α, IL-1β, Il-6), which are secreted by adipose tissue. Together with obesity-induced insulin resistance and hyperandrogenism, the exacerbated immune response has a negative impact on the hypothalamic–pituitary–gonadal axis at all levels and directly affects reproduction. In women, it results in disrupted ovarian function, irregular menstrual cycles and anovulation, contributing to infertility. This review focuses on the abnormal intracellular communication, altered gene expression and signaling pathways activated in obesity, underscoring its multifactorial character and consequences at a molecular level. Extensive presentation of the complex interplay between adipokines, cytokines, immune cells and neurons may serve as a foundation for future studies in search of potential sites for more targeted treatment of reproductive disorders related to obesity. Full article

(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)

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20 pages, 1055 KiB

Open AccessReview

Impact of Resistance and Endurance Training on Ghrelin and Plasma Leptin Levels in Overweight and Obese Subjects

by Brindusa Ilinca Mitoiu, Roxana Nartea and Roxana Steliana Miclaus

Int. J. Mol. Sci. 2024, 25(15), 8067; https://doi.org/10.3390/ijms25158067 - 24 Jul 2024

Cited by 3 | Viewed by 4329

Abstract

Exercise training is a valuable tool for improving body weight and composition in overweight or obese adults, which leads to a negative energy balance. It is relevant to consider whether exercise can help people lose weight or prevent weight gain because any energy [...] Read more.

Exercise training is a valuable tool for improving body weight and composition in overweight or obese adults, which leads to a negative energy balance. It is relevant to consider whether exercise can help people lose weight or prevent weight gain because any energy expended in exercise increases the severity of hunger and promotes food consumption. Over the past decade, the identification of the circulating peptide ghrelin, which alerts the brain to the body’s nutritional state, has significantly expanded our understanding of this homeostatic mechanism that controls appetite and body weight. To shed more light on this issue, we decided to investigate the effects of resistance and endurance training on plasma ghrelin and leptin levels. In addition, we sought to understand the mechanisms by which acute and chronic exercise can regulate hunger. This review analyzes studies published in the last fifteen years that focused on changes suffered by ghrelin, leptin, or both after physical exercise in overweight or obese individuals. Most studies have shown a decrease in leptin levels and an increase in ghrelin levels in these cases. Exercise regimens that support weight maintenance need further investigation. Full article

(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)

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61 pages, 7498 KiB

Open AccessReview

Cellular Senescence and Extracellular Vesicles in the Pathogenesis and Treatment of Obesity—A Narrative Review

by Yicong Liang, Devesh Kaushal and Robert Beaumont Wilson

Int. J. Mol. Sci. 2024, 25(14), 7943; https://doi.org/10.3390/ijms25147943 - 20 Jul 2024

Cited by 4 | Viewed by 5435

Abstract

This narrative review explores the pathophysiology of obesity, cellular senescence, and exosome release. When exposed to excessive nutrients, adipocytes develop mitochondrial dysfunction and generate reactive oxygen species with DNA damage. This triggers adipocyte hypertrophy and hypoxia, inhibition of adiponectin secretion and adipogenesis, increased [...] Read more.

This narrative review explores the pathophysiology of obesity, cellular senescence, and exosome release. When exposed to excessive nutrients, adipocytes develop mitochondrial dysfunction and generate reactive oxygen species with DNA damage. This triggers adipocyte hypertrophy and hypoxia, inhibition of adiponectin secretion and adipogenesis, increased endoplasmic reticulum stress and maladaptive unfolded protein response, metaflammation, and polarization of macrophages. Such feed-forward cycles are not resolved by antioxidant systems, heat shock response pathways, or DNA repair mechanisms, resulting in transmissible cellular senescence via autocrine, paracrine, and endocrine signaling. Senescence can thus affect preadipocytes, mature adipocytes, tissue macrophages and lymphocytes, hepatocytes, vascular endothelium, pancreatic β cells, myocytes, hypothalamic nuclei, and renal podocytes. The senescence-associated secretory phenotype is closely related to visceral adipose tissue expansion and metaflammation; inhibition of SIRT-1, adiponectin, and autophagy; and increased release of exosomes, exosomal micro-RNAs, pro-inflammatory adipokines, and saturated free fatty acids. The resulting hypernefemia, insulin resistance, and diminished fatty acid β-oxidation lead to lipotoxicity and progressive obesity, metabolic syndrome, and physical and cognitive functional decline. Weight cycling is related to continuing immunosenescence and exposure to palmitate. Cellular senescence, exosome release, and the transmissible senescence-associated secretory phenotype contribute to obesity and metabolic syndrome. Targeted therapies have interrelated and synergistic effects on cellular senescence, obesity, and premature aging. Full article

(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)

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20 pages, 2397 KiB

Open AccessReview

Adipocyte Mitochondria: Deciphering Energetic Functions across Fat Depots in Obesity and Type 2 Diabetes

by Snehasis Das, Alpana Mukhuty, Gregory P. Mullen and Michael C. Rudolph

Int. J. Mol. Sci. 2024, 25(12), 6681; https://doi.org/10.3390/ijms25126681 - 18 Jun 2024

Cited by 5 | Viewed by 4632

Abstract

Adipose tissue, a central player in energy balance, exhibits significant metabolic flexibility that is often compromised in obesity and type 2 diabetes (T2D). Mitochondrial dysfunction within adipocytes leads to inefficient lipid handling and increased oxidative stress, which together promote systemic metabolic disruptions central [...] Read more.

Adipose tissue, a central player in energy balance, exhibits significant metabolic flexibility that is often compromised in obesity and type 2 diabetes (T2D). Mitochondrial dysfunction within adipocytes leads to inefficient lipid handling and increased oxidative stress, which together promote systemic metabolic disruptions central to obesity and its complications. This review explores the pivotal role that mitochondria play in altering the metabolic functions of the primary adipocyte types, white, brown, and beige, within the context of obesity and T2D. Specifically, in white adipocytes, these dysfunctions contribute to impaired lipid processing and an increased burden of oxidative stress, worsening metabolic disturbances. Conversely, compromised mitochondrial function undermines their thermogenic capabilities, reducing the capacity for optimal energy expenditure in brown adipocytes. Beige adipocytes uniquely combine the functional properties of white and brown adipocytes, maintaining morphological similarities to white adipocytes while possessing the capability to transform into mitochondria-rich, energy-burning cells under appropriate stimuli. Each type of adipocyte displays unique metabolic characteristics, governed by the mitochondrial dynamics specific to each cell type. These distinct mitochondrial metabolic phenotypes are regulated by specialized networks comprising transcription factors, co-activators, and enzymes, which together ensure the precise control of cellular energy processes. Strong evidence has shown impaired adipocyte mitochondrial metabolism and faulty upstream regulators in a causal relationship with obesity-induced T2D. Targeted interventions aimed at improving mitochondrial function in adipocytes offer a promising therapeutic avenue for enhancing systemic macronutrient oxidation, thereby potentially mitigating obesity. Advances in understanding mitochondrial function within adipocytes underscore a pivotal shift in approach to combating obesity and associated comorbidities. Reigniting the burning of calories in adipose tissues, and other important metabolic organs such as the muscle and liver, is crucial given the extensive role of adipose tissue in energy storage and release. Full article

(This article belongs to the Special Issue Molecular Research in Obesity and Obesity Related Disorders: 2nd Edition)

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