Pathogenesis Of Sarcopenic Obesity Research Articles

GABA Prevents Age-Related Sarcopenic Obesity in Mice with High-Fat-Diet-Induced Obesity.

Sarcopenic obesity is characterized by concurrent obesity and muscle wasting (sarcopenia) and is common in the elderly. Sarcopenic obesity has steadily increased as the aging population has grown and is an increasing public health burden. Both obesity and sarcopenia independently increase health risks of the elderly, but sarcopenic obesity has a greater effect on metabolic disease than either obesity or sarcopenia alone. The metabolic mechanisms of obesity and sarcopenia are strongly interconnected, and obesity and sarcopenia form a vicious cycle, with each pathology exacerbating the other. The pathogenesis of sarcopenic obesity is more complex than either disease alone and remains incompletely understood, underscoring the significant unmet clinical need for effective sarcopenic obesity treatments. We aimed to determine the efficacy and underlying regulatory mechanisms of Gamma-aminobutyric acid (GABA) in sarcopenic obesity in high-fat-diet-fed obese aged mice and alterations in related mechanisms to determine the potential of GABA as a therapeutic modality for sarcopenic obesity. In this study, we used young (3 months) and aged (20 months) mice to evaluate age-related sarcopenic obesity. The daily administration of GABA for 8 weeks resulted in decreased fat mass and increased muscle mass and strength in aged mice. GABA also enhanced energy expenditure in both adipose tissue and skeletal muscle. In addition, GABA promoted muscle synthesis and decreased muscle degradation by activating the phosphatidylinositol-3-kinase (PI3K)/Akt pathway. These findings demonstrate that GABA has potential uses in preventing age-related sarcopenic obesity and related metabolic diseases.

Sarcopenic Obesity: Involvement of Oxidative Stress and Beneficial Role of Antioxidant Flavonoids.

Sarcopenic obesity, which refers to concurrent sarcopenia and obesity, is characterized by decreased muscle mass, strength, and performance along with abnormally excessive fat mass. Sarcopenic obesity has received considerable attention as a major health threat in older people. However, it has recently become a health problem in the general population. Sarcopenic obesity is a major risk factor for metabolic syndrome and other complications such as osteoarthritis, osteoporosis, liver disease, lung disease, renal disease, mental disease and functional disability. The pathogenesis of sarcopenic obesity is multifactorial and complicated, and it is caused by insulin resistance, inflammation, hormonal changes, decreased physical activity, poor diet and aging. Oxidative stress is a core mechanism underlying sarcopenic obesity. Some evidence indicates a protective role of antioxidant flavonoids in sarcopenic obesity, although the precise mechanisms remain unclear. This review summarizes the general characteristics and pathophysiology of sarcopenic obesity and focuses on the role of oxidative stress in sarcopenic obesity. The potential benefits of flavonoids in sarcopenic obesity have also been discussed.

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

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

Mitochondrial Uncoupling Decreases Sarcopenic Obesity By Activation of Skeletal Muscle Mitochondrial Quality Control and Attenuated ER Stress

BackgroundSarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified an orally available mitochondrial‐targeted furazano[3,4‐b]pyrazine named BAM15 that selectively lowers respiratory coupling efficiency and protects against diet‐induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity.Methods80‐week‐old male C57BL/6J mice with obesity were randomized to 10 weeks of high fat diet (CTRL) or BAM15 (BAM15; 0.1% w/w in high fat diet) treatment. Body composition, muscle function, energy expenditure, and locomotor activity were determined after treatment. Skeletal muscle was harvested and evaluated for histology, gene expression, protein signaling, and mitochondrial structure and function.ResultsBAM15 decreased body weight (~25% reduction, P<0.001) which was attributable to increased energy expenditure (~20% increment, P<0.001). BAM15 increased muscle mass (~13% increment, P<0.001), strength (~37% increment, P<0.0001), and locomotor activity (~25% increment, P<0.001). Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation (IL‐6 and gp130, both P<0.05), enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis and reduced inflammation. Specifically, BAM15 activated mitochondrial quality control through AMPK (PINK1‐ubiquitin binding and LC3II, P<0.01), increased electron transport chain activity (citrate synthase and complex II activity, all P<0.05), restricted endoplasmic reticulum (ER) misfolding (decreased oligomer A11 insoluble/soluble ratio, P<0.0001) while limiting ER stress (decreased PERK signaling, P<0.0001), apoptotic signaling (decreased cytochrome C release and Caspase‐3/9 activation, all P<0.001), and muscle protein degradation (decreased 14‐kDa actin fragment insoluble/soluble ratio, P<0.001).ConclusionsMitochondrial uncoupling agents such as BAM15 may mitigate age‐related decline in muscle mass and function by molecular and cellular bioenergetic adaptations that confer protection against sarcopenic obesity through activation of mitochondrial quality control and attenuation of ER stress.

Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control.

BackgroundSarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified that a mitochondrial‐targeted furazano[3,4‐b]pyrazine named BAM15 is orally available and selectively lowers respiratory coupling efficiency and protects against diet‐induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity.MethodsEighty‐week‐old male C57BL/6J mice with obesity were randomized to 10 weeks of high fat diet (CTRL) or BAM15 (BAM15; 0.1% w/w in high fat diet) treatment. Body weight and food intake were measured weekly. Body composition, muscle function, energy expenditure, locomotor activity, and glucose tolerance were determined after treatment. Skeletal muscle was harvested and evaluated for histology, gene expression, protein signalling, and mitochondrial structure and function.ResultsBAM15 decreased body weight (54.0 ± 2.0 vs. 42.3 ± 1.3 g, P < 0.001) which was attributable to increased energy expenditure (10.1 ± 0.1 vs. 11.3 ± 0.4 kcal/day, P < 0.001). BAM15 increased muscle mass (52.7 ± 0.4 vs. 59.4 ± 1.0%, P < 0.001), strength (91.1 ± 1.3 vs. 124.9 ± 1.2 g, P < 0.0001), and locomotor activity (347.0 ± 14.4 vs. 432.7 ± 32.0 m, P < 0.001). Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation (interleukin 6 and gp130, both P < 0.05), enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis. Specifically, BAM15 activated mitochondrial quality control (PINK1‐ubiquitin binding and LC3II, P < 0.01), increased mitochondrial activity (citrate synthase and complex II activity, all P < 0.05), restricted endoplasmic reticulum (ER) misfolding (decreased oligomer A11 insoluble/soluble ratio, P < 0.0001) while limiting ER stress (decreased PERK signalling, P < 0.0001), apoptotic signalling (decreased cytochrome C release and Caspase‐3/9 activation, all P < 0.001), and muscle protein degradation (decreased 14‐kDa actin fragment insoluble/soluble ratio, P < 0.001).ConclusionsMitochondrial uncoupling by agents such as BAM15 may mitigate age‐related decline in muscle mass and function by molecular and cellular bioenergetic adaptations that confer protection against sarcopenic obesity.

MicroRNAs in obesity, sarcopenia, and commonalities for sarcopenic obesity: a systematic review.

Sarcopenic obesity is a distinct condition of sarcopenia in the context of obesity, with the cumulative health risks of both phenotypes. Differential expression of microRNAs (miRNAs) has been reported separately in people with obesity and sarcopenia and may play a role in the pathogenesis of sarcopenic obesity. However, this has not been explored to date. This study aimed to identify differentially expressed miRNAs reported in serum, plasma, and skeletal muscle of people with obesity and sarcopenia and whether there are any commonalities between these conditions. We performed a systematic review on Embase and MEDLINE (PROSPERO, CRD42020224486) for differentially expressed miRNAs (fold change >1.5 or P‐value <0.05) in (i) sarcopenia or frailty and (ii) obesity or metabolic syndrome. The functions and targets of miRNAs commonly changed in both conditions, in the same direction, were searched using PubMed. Following deduplication, 247 obesity and 42 sarcopenia studies were identified for full‐text screening. Screening identified 36 obesity and 6 sarcopenia studies for final inclusion. A total of 351 miRNAs were identified in obesity and 157 in sarcopenia. Fifty‐five miRNAs were identified in both obesity and sarcopenia—by sample type, 48 were found in plasma and one each in serum and skeletal muscle. Twenty‐four miRNAs were identified from 10 of the included studies as commonly changed in the same direction (22 in plasma and one each in serum and skeletal muscle) in obesity and sarcopenia. The majority of miRNA‐validated targets identified in the literature search were members of the phosphoinositide 3‐kinase/protein kinase B and transforming growth factor‐β signalling pathways. The most common targets identified were insulin‐like growth factor 1 (miR‐424‐5p, miR‐483‐3p, and miR‐18b‐5p) and members of the SMAD family (miR‐483‐3p, miR‐92a‐3p, and miR‐424‐5p). The majority of commonly changed miRNAs were involved in protein homeostasis, mitochondrial dynamics, determination of muscle fibre type, insulin resistance, and adipogenesis. Twenty‐four miRNAs were identified as commonly dysregulated in obesity and sarcopenia with functions and targets implicated in the pathogenesis of sarcopenic obesity. Given the adverse health outcomes associated with sarcopenic obesity, understanding the pathogenesis underlying this phenotype has the potential to lead to effective screening, monitoring, or treatment strategies. Further research is now required to confirm whether these miRNAs are differentially expressed in older adults with sarcopenic obesity.

Sarcopenic Obesity in Liver Cirrhosis: Possible Mechanism and Clinical Impact.

The picture of chronic liver diseases (CLDs) has changed considerably in recent years. One of them is the increase of non-alcoholic fatty liver disease. More and more CLD patients, even those with liver cirrhosis (LC), tend to be presenting with obesity these days. The annual rate of muscle loss increases with worsening liver reserve, and thus LC patients are more likely to complicate with sarcopenia. LC is also characterized by protein-energy malnutrition (PEM). Since the PEM in LC can be invariable, the patients probably present with sarcopenic obesity (Sa-O), which involves both sarcopenia and obesity. Currently, there is no mention of Sa-O in the guidelines; however, the rapidly increasing prevalence and poorer clinical consequences of Sa-O are recognized as an important public health problem, and the diagnostic value of Sa-O is expected to increase in the future. Sa-O involves a complex interplay of physiological mechanisms, including increased inflammatory cytokines, oxidative stress, insulin resistance, hormonal disorders, and decline of physical activity. The pathogenesis of Sa-O in LC is diverse, with a lot of perturbations in the muscle–liver–adipose tissue axis. Here, we overview the current knowledge of Sa-O, especially focusing on LC.

Sarcopenic obesity: research advances in pathogenesis and diagnostic criteria.

Sarcopenic obesity (SO) refers to an obesity disease accompanied by low skeletal muscle quality, strength and/or function, which is more common in the elderly and seriously affects their quality of life and can lead to falls, unstable walking, balance disorders and fractures in the elderly. The increase in aging populations and the various health problems and medical costs associated with SO have aroused widespread concern in society. However, the pathogenesis of SO has not been fully clarified and the diagnostic criteria are not uniform, meaning that there are inconsistent data on the prevalence of SO and the potential correlation between SO and health outcomes. Therefore, we review the research progress on delineating the pathogenesis and diagnostic criteria of SO, to assist in the early diagnosis and evaluation of SO and subsequent interventions.

Sarcopenic obesity.

Sarcopenic obesity, a chronic condition, is today a major public health problem with increasing prevalence worldwide, which is due to progressively aging populations, the increasing prevalence of obesity, and the changes in lifestyle during the last several decades. Patients usually present to healthcare facilities for obesity and related comorbidities (type 2 diabetes mellitus, non-alcoholic fatty liver disease, dyslipidemia, hypertension, and cardiovascular disease) or for non-specific symptoms related to sarcopenia per se (e.g., fatigue, weakness, and frailty). Because of the non-specificity of the symptoms, sarcopenic obesity remains largely unsuspected and undiagnosed. The pathogenesis of sarcopenic obesity is multifactorial. There is interplay between aging, sedentary lifestyle, and unhealthy dietary habits, and insulin resistance, inflammation, and oxidative stress, resulting in a quantitative and qualitative decline in muscle mass and an increase in fat mass. Myokines, including myostatin and irisin, and adipokines play a prominent role in the pathogenesis of sarcopenic obesity. It has been suggested that a number of disorders affecting metabolism, physical capacity, and quality of life may be attributed to sarcopenic obesity, although it is not as yet established whether sarcopenia and obesity act synergistically. There is to date no approved pharmacological treatment for sarcopenic obesity. The cornerstones of its management are weight loss and adequate protein intake combined with exercise, the latter in order to reduce the loss of muscle mass observed during weight loss following diet unpaired with exercise. A consensus on the definition of sarcopenic obesity is considered essential to facilitate the performance of mechanistic studies and clinical trials aimed at deepening our knowledge, thus enabling improved management of affected individuals in the near future.

Serum adipocyte fatty acid-binding protein levels are independently associated with sarcopenic obesity

AimsAdipocyte fatty acid-binding protein (A-FABP) plays a key role in obesity-related insulin resistance and inflammation which may be involved in the pathogenesis of sarcopenic obesity (SO). This study examined the association of SO with serum A-FABP levels in Korean adults. MethodsTwo hundred ninety eight adults aged 20–70 years were examined using dual X-ray absorptiometry and computed tomography and measuring serum A-FABP levels. Sarcopenia was defined as the appendicular skeletal muscle mass (ASM) divided by weight (%) of <1 SD below the mean values of young adults in both sexes. Obesity was defined as visceral fat area (VFA)≥100cm2. ResultsSerum A-FABP levels were higher in groups with SO compared to non-SO groups in both men and women. In the unadjusted model, serum A-FABP levels were positively associated with VFA and negatively associated with ASM/weight. Even after adjusting for possible confounding factors, ASM/weight was found to be independently and negatively associated with serum A-FABP levels. In addition, multiple logistic regression analysis showed that increased serum levels of A-FABP were independently associated with the presence of SO. ConclusionsThe present findings indicate that serum A-FABP levels may be valuable markers of the presence of SO.

Leptin in Sarcopenic Visceral Obesity: Possible Link between Adipocytes and Myocytes

The combination of sarcopenia, age-related loss of muscle strength and mass, and obesity has been recognized as a new category of obesity among the elderly. Given that leptin has been hypothesized to be involved in the pathogenesis of sarcopenic obesity, we investigated the relationship between plasma leptin levels and thigh muscle sarcopenia and visceral obesity. Thigh muscle cross-sectional area (CSA) and visceral fat area were measured using computed tomography as indices for muscle mass and visceral fat, respectively, in 782 middle-aged to elderly subjects (303 men and 479 women), participating in a medical check-up program. Visceral obesity was defined as visceral fat area >100 cm2, and sarcopenia was defined as < (one standard deviation − mean of thigh muscle CSA/body weight of young subjects [aged <50 years]).Thigh muscle CSA was significantly and negatively associated with plasma levels of leptin in both men (β = -0.28, p<0.0001) and women (β = -0.20, p<0.0001), even after correcting for other confounding parameters, including age, body weight, body height, visceral fat area, blood pressure, homeostatic model assessment index, and high sensitive C reactive protein. Subjects were divided into four groups based on presence or absence of sarcopenia or visceral obesity. Plasma levels of leptin were higher in subjects with sarcopenic visceral obesity than in those with either sarcopenia or visceral obesity alone. These findings indicate that sarcopenic visceral obesity is a more advanced, and suggest that leptin may link visceral obesity and sarcopenia.