Fish oil-derived n-3 polyunsaturated fatty acids for the prevention and treatment of sarcopenia

Purpose of review: Muscle mass and function decline progressively starting in middle age, which can result in sarcopenia and affect people's mobility and independence later in life. Exercise training and increased protein intake are typically recommended to counteract the age-associated decline in muscle mass and function. However, few people comply with exercise recommendations and the effectiveness of high-protein intake to halt the decline in muscle mass and function has not been proven. This review aims to explore recent developments in the potential for fish-oil derived n-3 polyunsaturated fatty acids (n-3 PUFA) to improve muscle mass and function in older people. Recent findings: The results from several recent studies demonstrate that dietary supplementation with fish oil-derived n-3 PUFA stimulates muscle protein synthesis and improves muscle mass and function in sedentary older adults and augments the resistance exercise training-induced increase in muscle strength in older adults. The exact mechanisms by which fish oil-derived n-3 PUFAs exert their beneficial effects on muscle mass and function remain to be elucidated. Summary: Fish-oil supplementation has antisarcopenic effects and should be considered in the clinical care of older adults

Metabolically healthy obesity: Facts and fantasies

Although obesity is typically associated with metabolic dysfunction and cardiometabolic diseases, some people with obesity are protected from many of the adverse metabolic effects of excess body fat and are considered metabolically healthy. However, there is no universally accepted definition of metabolically healthy obesity (MHO). Most studies define MHO as having either 0, 1, or 2 metabolic syndrome components, whereas many others define MHO using the homeostasis model assessment of insulin resistance (HOMA-IR). Therefore, numerous people reported as having MHO are not metabolically healthy, but simply have fewer metabolic abnormalities than those with metabolically unhealthy obesity (MUO). Nonetheless, a small subset of people with obesity have a normal HOMA-IR and no metabolic syndrome components. The mechanism(s) responsible for the divergent effects of obesity on metabolic health is not clear, but studies conducted in rodent models suggest that differences in adipose tissue biology in response to weight gain can cause or prevent systemic metabolic dysfunction. In this article, we review the definition, stability over time, and clinical outcomes of MHO, and discuss the potential factors that could explain differences in metabolic health in people with MHO and MUO - specifically, modifiable lifestyle factors and adipose tissue biology. Better understanding of the factors that distinguish people with MHO and MUO can produce new insights into mechanism(s) responsible for obesity-related metabolic dysfunction and disease

β Cell function and plasma insulin clearance in people with obesity and different glycemic status

BackgroundIt is unclear how excess adiposity and insulin resistance affect β cell function, insulin secretion, and insulin clearance in people with obesity.MethodsWe used a hyperinsulinemic-euglycemic clamp procedure and a modified oral glucose tolerance test to evaluate the interrelationships among obesity, insulin sensitivity, insulin kinetics, and glycemic status in 5 groups of individuals: normoglycemic lean and obese individuals with (a) normal fasting glucose and normal glucose tolerance (Ob-NFG-NGT), (b) NFG and impaired glucose tolerance (Ob-NFG-IGT), (c) impaired fasting glucose and IGT (Ob-IFG-IGT), or (d) type 2 diabetes (Ob-T2D).ResultsGlucose-stimulated insulin secretion (GSIS), an assessment of β cell function, was greater in the Ob-NFG-NGT and Ob-NFG-IGT groups than in the lean group, even when insulin sensitivity was matched in the obese and lean groups. Insulin sensitivity, not GSIS, was decreased in the Ob-NFG-IGT group compared with the Ob-NFG-NGT group, whereas GSIS, not insulin sensitivity, was decreased in the Ob-IFG-IGT and Ob-T2D groups compared with the Ob-NFG-NGT and Ob-NFG-IGT groups. Insulin clearance was directly related to insulin sensitivity and inversely related to the postprandial increase in insulin secretion and plasma insulin concentration.ConclusionIncreased adiposity per se, not insulin resistance, enhanced insulin secretion in people with obesity. The obesity-induced increase in insulin secretion, in conjunction with a decrease in insulin clearance, sufficiently raised the plasma insulin concentrations needed to maintain normoglycemia in individuals with moderate, but not severe, insulin resistance. A deterioration in β cell function, not a decrease in insulin sensitivity, was a determinant of IFG and ultimately leads to T2D.CLINICAL TRIALS REGISTRATIONClinicalTrials.gov NCT02706262, NCT04131166, and NCT01977560.FUNDINGNIH (P30 DK056341, P30 DK020579, and UL1 TR000448); American Diabetes Association (1-18-ICTS-119); Longer Life Foundation; Pershing Square Foundation; and Washington University-Centene ARCH Personalized Medicine Initiative (P19-00559)

Effect of dietary n‐3 PUFA supplementation on the muscle transcriptome in older adults

Dietary fish oil‐derived n‐3 PUFA supplementation can increase muscle mass, reduce oxygen demand during physical activity, and improve physical function (muscle strength and power, and endurance) in people. The results from several studies conducted in animals suggest that the anabolic and performance‐enhancing effects of n‐3 PUFA are at least in part transcriptionally regulated. The effect of n‐3 PUFA therapy on the muscle transcriptome in people is unknown. In this study, we used muscle biopsy samples collected during a recently completed randomized controlled trial that found that n‐3 PUFA therapy increased muscle mass and function in older adults to provide a comprehensive assessment of the effect of n‐3 PUFA therapy on the skeletal muscle gene expression profile in these people. Using the microarray technique, we found that several pathways involved in regulating mitochondrial function and extracellular matrix organization were increased and pathways related to calpain‐ and ubiquitin‐mediated proteolysis and inhibition of the key anabolic regulator mTOR were decreased by n‐3 PUFA therapy. However, the effect of n‐3 PUFA therapy on the expression of individual genes involved in regulating mitochondrial function and muscle growth, assessed by quantitative RT‐PCR, was very small. These data suggest that n‐3 PUFA therapy results in small but coordinated changes in the muscle transcriptome that may help explain the n‐3 PUFA‐induced improvements in muscle mass and function

Sexually dimorphic effect of aging on skeletal muscle protein synthesis

BACKGROUND: Although there appear to be no differences in muscle protein turnover in young and middle aged men and women, we have reported significant differences in the rate of muscle protein synthesis between older adult men and women. This suggests that aging may affect muscle protein turnover differently in men and women. METHODS: We measured the skeletal muscle protein fractional synthesis rate (FSR) by using stable isotope-labeled tracer methods during basal postabsorptive conditions and during a hyperaminoacidemic-hyperinsulinemic-euglycemic clamp in eight young men (25–45 y), ten young women (25–45 y), ten old men (65–85 y) and ten old women (65–85 y). RESULTS: The basal muscle protein FSR was not different in young and old men (0.040 ± 0.004 and 0.043 ± 0.005%·h(-1), respectively) and combined insulin, glucose and amino acid infusion significantly increased the muscle protein FSR both in young (to 0.063 ± 0.006%·h(-1)) and old (to 0.051 ± 0.008%·h(-1)) men but the increase (0.023 ± 0.004 vs. 0.009 ± 0.004%·h(-1), respectively) was ~60% less in the old men (P = 0.03). In contrast, the basal muscle protein FSR was ~30% greater in old than young women (0.060 ± 0.003 vs. 0.046 ± 0.004%·h(-1), respectively; P < 0.05) and combined insulin, glucose and amino acid infusion significantly increased the muscle protein FSR in young (P < 0.01) but not in old women (P = 0.10) so that the FSR was not different between young and old women during the clamp (0.074 ± 0.006%·h(-1) vs. 0.072 ± 0.006%·h(-1), respectively). CONCLUSIONS: There is sexual dimorphism in the age-related changes in muscle protein synthesis and thus the metabolic processes responsible for the age-related decline in muscle mass

β Cell function after Roux-en-Y gastric bypass surgery or reduced energy intake alone in people with obesity

BackgroundThe effects of diet-induced weight loss (WL) and WL after Roux-en-Y gastric bypass (RYGB) surgery on β cell function (BCF) are unclear because of conflicting results from different studies, presumably because of differences in the methods used to measure BCF, the amount of WL between treatment groups, and baseline BCF. We evaluated the effect of WL after RYGB surgery or reduced energy intake alone on BCF in people with obesity with and without type 2 diabetes.MethodsBCF (insulin secretion in relationship to plasma glucose) was assessed before and after glucose or mixed-meal ingestion before and after (a) progressive amounts (6%, 11%, 16%) of WL induced by a low-calorie diet (LCD) in people with obesity without diabetes, (b) ~20% WL after RYGB surgery or laparoscopic adjustable gastric banding (LAGB) in people with obesity without diabetes, and (c) ~20% WL after RYGB surgery or LCD alone in people with obesity and diabetes.ResultsDiet-induced progressive WL in people without diabetes progressively decreased BCF. Marked WL after LAGB or RYGB in people without diabetes did not alter BCF. Marked WL after LCD or RYGB in people with diabetes markedly increased BCF, without a difference between groups.ConclusionMarked WL increases BCF in people with obesity and diabetes but not in people with obesity without diabetes. The effect of RYGB-induced WL on BCF is not different from the effect of matched WL after LAGB or LCD alone.trial registrationNCT00981500, NCT02207777, NCT01299519.FundingNIH grants R01 DK037948, P30 DK056341, P30 DK020579, UL1 TR002345

Influence of adiposity, insulin resistance, and intrahepatic triglyceride content on insulin kinetics

BACKGROUNDInsulin is a key regulator of metabolic function. The effects of excess adiposity, insulin resistance, and hepatic steatosis on the complex integration of insulin secretion and hepatic and extrahepatic tissue extraction are not clear.METHODSA hyperinsulinemic-euglycemic clamp and a 3-hour oral glucose tolerance test were performed to evaluate insulin sensitivity and insulin kinetics after glucose ingestion in 3 groups: (a) lean subjects with normal intrahepatic triglyceride (IHTG) and glucose tolerance (lean-NL; n = 14), (b) obese subjects with normal IHTG and glucose tolerance (obese-NL; n = 24), and (c) obese subjects with nonalcoholic fatty liver disease (NAFLD) and prediabetes (obese-NAFLD; n = 22).RESULTSInsulin sensitivity progressively decreased and insulin secretion progressively increased from the lean-NL to the obese-NL to the obese-NAFLD groups. Fractional hepatic insulin extraction progressively decreased from the lean-NL to the obese-NL to the obese-NAFLD groups, whereas total hepatic insulin extraction (molar amount removed) was greater in the obese-NL and obese-NAFLD subjects than in the lean-NL subjects. Insulin appearance in the systemic circulation and extrahepatic insulin extraction progressively increased from the lean-NL to the obese-NL to the obese-NAFLD groups. Total hepatic insulin extraction plateaued at high rates of insulin delivery, whereas the relationship between systemic insulin appearance and total extrahepatic extraction was linear.CONCLUSIONHyperinsulinemia after glucose ingestion in obese-NL and obese-NAFLD is due to an increase in insulin secretion, without a decrease in total hepatic or extrahepatic insulin extraction. However, the liver\u27s maximum capacity to remove insulin is limited because of a saturable extraction process. The increase in insulin delivery to the liver and extrahepatic tissues in obese-NAFLD is unable to compensate for the increase in insulin resistance, resulting in impaired glucose homeostasis.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGNIH grants DK56341 (Nutrition Obesity Research Center), DK052574 (Digestive Disease Research Center), RR024992 (Clinical and Translational Science Award), and T32 DK007120 (a T32 Ruth L. Kirschstein National Research Service Award); the American Diabetes Foundation (1-18-ICTS-119); Janssen Research & Development; and the Pershing Square Foundation

High-Protein Intake during Weight Loss Therapy Eliminates the Weight-Loss-Induced Improvement in Insulin Action in Obese Postmenopausal Women

SummaryHigh-protein (HP) intake during weight loss (WL) therapy is often recommended because it reduces the loss of lean tissue mass. However, HP intake could have adverse effects on metabolic function, because protein ingestion reduces postprandial insulin sensitivity. In this study, we compared the effects of ∼10% WL with a hypocaloric diet containing 0.8 g protein/kg/day and a hypocaloric diet containing 1.2 g protein/kg/day on muscle insulin action in postmenopausal women with obesity. We found that HP intake reduced the WL-induced decline in lean tissue mass by ∼45%. However, HP intake also prevented the WL-induced improvements in muscle insulin signaling and insulin-stimulated glucose uptake, as well as the WL-induced adaptations in oxidative stress and cell structural biology pathways. Our data demonstrate that the protein content of a WL diet can have profound effects on metabolic function and underscore the importance of considering dietary macronutrient composition during WL therapy for people with obesity

Evaluation of mTORC1 signaling in mouse atherosclerotic macrophages by flow cytometry and immunofluorescence

Previous studies have demonstrated that a high-protein diet leads to increased atherosclerosis in mice, and that this adverse effect is caused by activation of macrophage mTORC1 signaling. Here, we provide a detailed protocol for the evaluation of diet-induced mTORC1 signaling in plaque macrophages in atherosclerosis-prone apolipoprotein E (ApoE) knockout (KO) mice. This protocol includes flow cytometry and immunofluorescence analysis of atherosclerotic macrophages that can be used to study the atherogenic potential of a variety of mTORC1 modulators. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2020)