Obesity alters the muscle protein synthetic response to nutrition and exercise

Improving the health of skeletal muscle is an important component of obesity treatment. Apart from allowing for physical activity, skeletal muscle tissue is fundamental for the regulation of postprandial macronutrient metabolism, a time period that represents when metabolic derangements are most often observed in adults with obesity. In order for skeletal muscle to retain its capacity for physical activity and macronutrient metabolism, its protein quantity and composition must be maintained through the efficient degradation and resynthesis for proper tissue homeostasis. Life-style behaviors such as increasing physical activity and higher protein diets are front-line treatment strategies to enhance muscle protein remodeling by primarily stimulating protein synthesis rates. However, the muscle of individuals with obesity appears to be resistant to the anabolic action of targeted exercise regimes and protein ingestion when compared to normal-weight adults. This indicates impaired muscle protein remodeling in response to the main anabolic stimuli to human skeletal muscle tissue is contributing to poor muscle health with obesity. Deranged anabolic signaling related to insulin resistance, lipid accumulation, and/or systemic/muscle inflammation are likely at the root of the anabolic resistance of muscle protein synthesis rates with obesity. The purpose of this review is to discuss the impact of protein ingestion and exercise on muscle protein remodeling in people with obesity, and the potential mechanisms underlining anabolic resistance of their muscle

Anabolic resistance of muscle protein turnover comes in various shapes and sizes

Anabolic resistance is defined by a blunted stimulation of muscle protein synthesis rates (MPS) to common anabolic stimuli in skeletal muscle tissue such as dietary protein and exercise. Generally, MPS is the target of most exercise and feeding interventions as muscle protein breakdown rates seem to be less responsive to these stimuli. Ultimately, the blunted responsiveness of MPS to dietary protein and exercise underpins the loss of the amount and quality of skeletal muscle mass leading to decrements in physical performance in these populations. The increase of both habitual physical activity (including structured exercise that targets general fitness characteristics) and protein dense food ingestion are frontline strategies utilized to support muscle mass, performance, and health. In this paper, we discuss anabolic resistance as a common denominator underpinning muscle mass loss with aging, obesity, and other disease states. Namely, we discuss the fact that anabolic resistance exists as a dimmer switch, capable of varying from higher to lower levels of resistance, to the main anabolic stimuli of feeding and exercise depending on the population. Moreover, we review the evidence on whether increased physical activity and targeted exercise can be leveraged to restore the sensitivity of skeletal muscle tissue to dietary amino acids regardless of the population

Small molecule SWELL1 complex induction improves glycemic control and nonalcoholic fatty liver disease in murine Type 2 diabetes

Type 2 diabetes is associated with insulin resistance, impaired pancreatic β-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in adipose, skeletal muscle, and endothelium, and impairs β-cell insulin secretion and glycemic control. Here, we show that

Dynamic shifts in the composition of resident and recruited macrophages influence tissue remodeling in NASH

Macrophage-mediated inflammation is critical in the pathogenesis of non-alcoholic steatohepatitis (NASH). Here, we describe that, with high-fat, high-sucrose-diet feeding, mature TIM

Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease

BACKGROUNDAn increase in intrahepatic triglyceride (IHTG) is the hallmark feature of nonalcoholic fatty liver disease (NAFLD) and is decreased by weight loss. Hepatic de novo lipogenesis (DNL) contributes to steatosis in individuals with NAFLD. The physiological factors that stimulate hepatic DNL and the effect of weight loss on hepatic DNL are not clear.METHODSHepatic DNL, 24-hour integrated plasma insulin and glucose concentrations, and both liver and whole-body insulin sensitivity were determined in individuals who were lean (n = 14), obese with normal IHTG content (n = 26), or obese with NAFLD (n = 27). Hepatic DNL was assessed using the deuterated water method corrected for the potential confounding contribution of adipose tissue DNL. Liver and whole-body insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp procedure in conjunction with glucose tracer infusion. Six subjects in the obese-NAFLD group were also evaluated before and after a diet-induced weight loss of 10%.RESULTSThe contribution of hepatic DNL to IHTG-palmitate was 11%, 19%, and 38% in the lean, obese, and obese-NAFLD groups, respectively. Hepatic DNL was inversely correlated with hepatic and whole-body insulin sensitivity, but directly correlated with 24-hour plasma glucose and insulin concentrations. Weight loss decreased IHTG content, in conjunction with a decrease in hepatic DNL and 24-hour plasma glucose and insulin concentrations.CONCLUSIONSThese data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK52574 (Digestive Disease Research Center), and RR024992 (Clinical and Translational Science Award), and by grants from the Academy of Nutrition and Dietetics Foundation, the College of Natural Resources of UCB, and the Pershing Square Foundation

Steatosis drives monocyte-derived macrophage accumulation in human metabolic dysfunction-associated fatty liver disease

BACKGROUND & AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common complication of obesity with a hallmark feature of hepatic steatosis. Recent data from animal models of MAFLD have demonstrated substantial changes in macrophage composition in the fatty liver. In humans, the relationship between liver macrophage heterogeneity and liver steatosis is less clear. METHODS: Liver tissue from 21 participants was collected at time of bariatric surgery and analysed using flow cytometry, immunofluorescence, and H&E microscopy. Single-cell RNA sequencing was also conducted on a subset of samples (n = 3). Intrahepatic triglyceride content was assessed via MRI and tissue histology. Mouse models of hepatic steatosis were used to investigate observations made from human liver tissue. RESULTS: We observed variable degrees of liver steatosis with minimal fibrosis in our participants. Single-cell RNA sequencing revealed four macrophage clusters that exist in the human fatty liver encompassing Kupffer cells and monocyte-derived macrophages (MdMs). The genes expressed in these macrophage subsets were similar to those observed in mouse models of MAFLD. Hepatic CD14 CONCLUSIONS: The human liver in MAFLD contains macrophage subsets that align well with those that appear in mouse models of fatty liver disease. Recruited myeloid cells correlate well with the degree of liver steatosis in humans. MdMs appear to participate in lipid uptake during early stages of MALFD. IMPACT AND IMPLICATIONS: Metabolic dysfunction associated fatty liver disease (MAFLD) is extremely common; however, the early inflammatory responses that occur in human disease are not well understood. In this study, we investigated macrophage heterogeneity in human livers during early MAFLD and demonstrated that similar shifts in macrophage subsets occur in human disease that are similar to those seen in preclinical models. These findings are important as they establish a translational link between mouse and human models of disease, which is important for the development and testing of new therapeutic approaches for MAFLD

Human obesity and its influence on muscle protein synthesis

Improving skeletal muscle health is an important component of obesity treatment. Apart from locomotion, skeletal muscle tissue is fundamental for the regulation of macronutrient metabolism during the postprandial period, which is precisely where metabolic derangements are most often observed. In order for the skeletal muscle to adapt and retain its capacity for high throughput of macronutrients, damaged proteins must be degraded and replaced on a continual basis. Moreover, amino acids from meals are crucial for the muscle to replace those lost for other needs (e.g. gluconeogenesis and oxidation). Skeletal muscle appears to be more responsive to amino acid replacement in normal-weight than the muscle of obese individuals. However, no studies have assessed the impact of obesity on the muscle protein synthetic response to the fundamental anabolic stimuli (muscle contraction, protein ingestion) to human skeletal muscle tissue. Previous studies of obesity and muscle protein metabolism have employed intravenous amino acid infusions, which do not accurately reflect meal conditions. Therefore, this thesis details investigations that assessed muscle protein synthetic responses in both the myofibrillar and sarcoplasmic protein pools under a typical meal setting where a protein-dense food is consumed orally either at rest or after exercise. In study 1, we showed that the postprandial myofibrillar protein synthetic response to protein-dense food ingestion is blunted in overweight and obese compared with normal-weight adults. This finding was related to altered mTORC1 signaling in those groups. In study 2, we demonstrated that basal and postprandial mitochondrial protein synthesis rates are similar in young adults across a wide range of body mass indices. We also showed that muscle inflammatory protein content (e.g. TLR4 and MyD88) increases in response to protein-dense food ingestion in obese, but not normal-weight and overweight young adults. In study 3, we demonstrated that the resistance exercise-induced potentiation of postprandial myofibrillar protein synthesis rates is diminished in obesity young compared with normal-weight adults. However, resistance exercise blunts the obesity-related increase in TLR protein after protein-dense food ingestion. The studies contained in this dissertation show an anabolic resistance to protein-dense food ingestion in obese adults that appears to be limited to the myofibrillar protein sub-fraction of skeletal muscle. Our findings suggest that contractile protein remodeling is a primary impairment in muscles of people with obesity and that exercise strategies to overcome this anabolic resistance are needed

Human obesity and its influence on muscle protein synthesis

Improving skeletal muscle health is an important component of obesity treatment. Apart from locomotion, skeletal muscle tissue is fundamental for the regulation of macronutrient metabolism during the postprandial period, which is precisely where metabolic derangements are most often observed. In order for the skeletal muscle to adapt and retain its capacity for high throughput of macronutrients, damaged proteins must be degraded and replaced on a continual basis. Moreover, amino acids from meals are crucial for the muscle to replace those lost for other needs (e.g. gluconeogenesis and oxidation). Skeletal muscle appears to be more responsive to amino acid replacement in normal-weight than the muscle of obese individuals. However, no studies have assessed the impact of obesity on the muscle protein synthetic response to the fundamental anabolic stimuli (muscle contraction, protein ingestion) to human skeletal muscle tissue. Previous studies of obesity and muscle protein metabolism have employed intravenous amino acid infusions, which do not accurately reflect meal conditions. Therefore, this thesis details investigations that assessed muscle protein synthetic responses in both the myofibrillar and sarcoplasmic protein pools under a typical meal setting where a protein-dense food is consumed orally either at rest or after exercise. In study 1, we showed that the postprandial myofibrillar protein synthetic response to protein-dense food ingestion is blunted in overweight and obese compared with normal-weight adults. This finding was related to altered mTORC1 signaling in those groups. In study 2, we demonstrated that basal and postprandial mitochondrial protein synthesis rates are similar in young adults across a wide range of body mass indices. We also showed that muscle inflammatory protein content (e.g. TLR4 and MyD88) increases in response to protein-dense food ingestion in obese, but not normal-weight and overweight young adults. In study 3, we demonstrated that the resistance exercise-induced potentiation of postprandial myofibrillar protein synthesis rates is diminished in obesity young compared with normal-weight adults. However, resistance exercise blunts the obesity-related increase in TLR protein after protein-dense food ingestion. The studies contained in this dissertation show an anabolic resistance to protein-dense food ingestion in obese adults that appears to be limited to the myofibrillar protein sub-fraction of skeletal muscle. Our findings suggest that contractile protein remodeling is a primary impairment in muscles of people with obesity and that exercise strategies to overcome this anabolic resistance are needed.LimitedAuthor requested closed access (OA after 2yrs) in Vireo ETD syste

Achieving Optimal Post-Exercise Muscle Protein Remodeling in Physically Active Adults through Whole Food Consumption

Dietary protein ingestion is critical to maintaining the quality and quantity of skeletal muscle mass throughout adult life. The performance of acute exercise enhances muscle protein remodeling by stimulating protein synthesis rates for several hours after each bout, which can be optimized by consuming protein during the post-exercise recovery period. To date, the majority of the evidence regarding protein intake to optimize post-exercise muscle protein synthesis rates is limited to isolated protein sources. However, it is more common to ingest whole food sources of protein within a normal eating pattern. Emerging evidence demonstrates a promising role for the ingestion of whole foods as an effective nutritional strategy to support muscle protein remodeling and recovery after exercise. This review aims to evaluate the efficacy of the ingestion of nutrient-rich and protein-dense whole foods to support post-exercise muscle protein remodeling and recovery with pertinence towards physically active people