The coexistence of obesity and insulin resistance is associated with elevated plasma amino acid concentrations. However, it remains unclear whether adiposity or insulin resistance is the stronger determinant of plasma amino acid dysregulation in this setting. Twenty-two adults (10 women, 12 men) spanning a broad range of body mass index (BMI) and insulin resistance underwent a 75-g oral glucose tolerance test (OGTT) after an overnight fast. Plasma glucose, insulin, and amino acid concentrations were measured serially, and insulin resistance/sensitivity was estimated from OGTT-derived glucose and insulin responses, using the homeostasis model assessment of insulin resistance (HOMA-IR) and the Matsuda insulin sensitivity index (Matsuda-ISI). Principal component analysis (PCA) of fasting plasma amino acid concentrations showed no clear separation by obesity or insulin resistance classifications. In contrast, PCA of OGTT-stimulated plasma amino acid concentrations revealed clearer clustering by BMI, fat mass, and waist circumference, whereas separation by HOMA-IR and Matsuda-ISI was less distinct. Importantly, regression analyses showed that BMI, fat mass, and waist circumference were significant predictors of OGTT-stimulated, but not fasting, amino acid responses, with waist circumference accounting for the greatest proportion of the variance in branched-chain amino acid responses during the OGTT (R2 = 0.54). In conclusion, measures of adiposity, particularly total fat mass and waist circumference, accounted for a greater proportion of the variance in plasma amino acid responses under physiologically stimulated conditions than indices of insulin resistance. These findings support the view that plasma amino acid concentrations reflect adiposity-related metabolic alterations more strongly than insulin resistance.

Background: In healthy individuals, exercise and amino acid availability act synergistically to stimulate muscle anabolism. However, this interaction may be impaired in individuals with obesity. Objective: We examined whether acute aerobic exercise alters amino acid-stimulated muscle protein synthesis during immediate postexercise recovery in adults with obesity. Methods: Sixteen sedentary adults with a body mass index >30 kg/m2 underwent a stable-isotope tracer infusion to measure mixed-muscle protein fractional synthesis rate (FSR) in the basal/fasted state and during an amino acid infusion, either with or without prior aerobic exercise. Participants were randomly assigned to receive either amino acid infusion alone (AA) or 45 min of cycling exercise at ~65% heart rate reserve immediately before amino acid infusion (EX + AA). Results: Amino acid infusion increased muscle protein FSR in the AA group (P < 0.0001) but not in the EX + AA group (P > 0.05), and the amino acid-stimulated increase in FSR was 78% lower in EX + AA than in AA (P < 0.01). The amino acid infusion increased (P < 0.05) plasma amino acid concentrations in both groups. However, during the amino acid infusion, plasma concentrations of essential and branched-chain amino acids, including leucine, were lower in EX + AA than in AA (P < 0.05). Moreover, across participants, absolute changes in muscle protein FSR were positively associated with plasma leucine concentrations during the amino acid infusion (P < 0.05). Conclusions: These findings show that, in individuals with obesity, acute aerobic exercise markedly attenuates amino acid-stimulated muscle protein synthesis during early postexercise recovery. These findings have important implications for designing nutritional strategies to optimize muscle anabolism in this population.

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs) improve glycaemia and reduce body weight, yet their organ-level actions on skeletal muscle remain incompletely defined. Framing skeletal muscle as an integrated unit of vasculature and muscle cells, we synthesize evidence with emphasis on glucose and protein metabolism. GLP-1 and GLP-1 RAs recruit microvasculature in muscle, expanding capillary surface area and increasing delivery of insulin, glucose, and amino acids. Microvascular recruitment increases interstitial insulin availability and potentiates insulin-stimulated glucose uptake and glycogen synthesis, whereas direct effects of GLP-1 on muscle cells remain under investigation. For protein metabolism, microvascular recruitment can enhance muscle protein synthesis when plasma amino acid availability is elevated, whereas effects under basal (fasted) conditions remain unclear. Elucidating the uncertainty regarding GLP-1 receptor localization in human muscle cells will clarify whether direct signaling occurs within muscle cells, thereby improving our understanding of the relative contribution of direct versus perfusion-mediated actions of GLP-1 RAs. Clinically, GLP-1 RAs reduce lean body mass, likely reflecting energy-deficit-mediated effects, but studies directly assessing muscle mass are still limited. Overall, current evidence indicates that GLP-1 RAs exert beneficial effects on muscle vasculature and muscle glucose metabolism. However, their influence on muscle protein turnover remains unclear-primarily due to observed reductions in muscle mass-despite preclinical data suggesting potential favorable effects on muscle protein metabolism that remain to be confirmed in humans.

This narrative review explores the influence of obesity on colorectal cancer, focusing on obesity-related factors, including chronic inflammation, metabolic dysregulation, and gut microbiota imbalance, which collectively create a pro-carcinogenic environment that increases colorectal cancer risk and complicates treatment outcomes. The findings indicate that obesity not only accelerates tumor progression but also presents challenges in colorectal cancer treatment, such as higher rates of surgical complications due to excess adipose tissue and altered pharmacokinetics that can reduce chemotherapy efficacy. Nutritional and lifestyle interventions, particularly weight management and anti-inflammatory nutritional therapies, are highlighted as effective strategies to reduce colorectal cancer risk and support treatment in patients with obesity. The study emphasizes the importance of personalized colorectal cancer treatment approaches for individuals with obesity and calls for public health policies targeting obesity prevention, which could significantly decrease colorectal cancer incidence and healthcare burdens associated with this high-risk population.

Overweight and obesity are significant public health concerns worldwide due to their association with many chronic health conditions. This has resulted in the development of various interventions focused on weight loss to reduce the associated health burden. Physical activity is an important lifestyle behavior associated with enhanced health. Evidence supports that many of the benefits of physical activity are realized independent of initial weight status or whether weight loss is achieved, with some benefits additive to what is achieved with weight loss alone. These benefits include enhanced cardiometabolic, brain, cognitive and psychological health, and others. Moreover, in adults with overweight or obesity, physical activity has independent effects on cardiorespiratory fitness, muscular strength, physical function, and mobility. There are also benefits to body composition, with physical activity improving the quality of key tissues, such as skeletal muscle, which may not occur with diet-induced weight loss. Therefore, physical activity is an important public health target for adults with overweight or obesity to provide a wide range of health benefits that extend beyond those of weight loss alone. However, physical activity recommendations and programming efforts should consider the unique characteristics of adults with overweight or obesity to be most effective, and should support a focus on mobility, physical function, and other health outcomes.

Individuals with obesity and endurance exercise-trained athletes both exhibit excess lipid content in their skeletal muscle compared with healthy, sedentary individuals, yet they experience vastly different health outcomes. Lipids taken up from the circulation contribute to lipid stored in muscle in both populations. Differences in the muscle uptake of plasma non-esterified fatty acids (NEFA) and fatty acids derived from plasma triacylglycerol (TG) between individuals with obesity and endurance-trained athletes have not been systematically examined. In athletes, muscle actively regulates the uptake of TG-derived fatty acids through upregulation of the activity of muscle lipoprotein lipase-the enzyme responsible for the intravascular hydrolysis of TG, a phenomenon evident in the fasting state. In contrast, in individuals with obesity, skeletal muscle functions as a passive recipient of TG-derived fatty acids, an event that becomes quantitively more important when the plasma TG concentrations increase during the postprandial state. Considerable differences in the muscle uptake of plasma NEFA between athletes and individuals with obesity are less evident. These observations indicate mechanistic differences in the regulation of plasma TG-derived fatty acids uptake in muscle between individuals with obesity and endurance-trained athletes in shaping the excess lipid content in their muscles. Moreover, this evidence highlights the need for targeting a reduction in plasma TG in the postprandial state when aiming to attenuate lipid accumulation in muscle in the pathophysiology of obesity.

We investigated how obesity impacts the response of circulating insulin-like growth factor-1 (IGF-1) to a single bout of endurance exercise in humans with and without obesity. Blood samples were collected before exercise, at 15 and 40 min during a 45-min cycling session at 65% of heart rate reserve, and 15 min post-exercise. Serum levels of total IGF-1, free IGF-1, IGF binding proteins 1 (IGFBP-1) and 3 (IGFBP-3), growth hormone, and insulin were measured. Both total IGF-1 and IGFBP-3 serum concentrations increased significantly (p < 0.05) during exercise in the study participants without obesity but not in those with obesity, returning to basal levels immediately after exercise. There was a statistically significant main effect on the growth hormone response, with circulating levels being higher in participants without obesity (p < 0.05). No significant effects were observed for either free IGF-1 or IGFBP-1 serum concentrations in response to exercise in either group (p > 0.05). We conclude that humans with obesity have blunted serum total IGF-1 response during exercise. However, a concurrent attenuation in serum IGFBP-3 response, which regulates free (i.e., biologically active) IGF-1 in circulation, results in no change in circulating free IGF-1 levels during endurance exercise in individuals with obesity.

Isolating individual muscle fibers and characterizing their myosin heavy chain (MHC) content using SDS-PAGE has become an increasingly common method for describing skeletal muscle fiber type proportions. In this study, we aimed to assess how the number of muscle fibers analyzed, and whether they are characterized in the order of isolation or randomly selected from a larger pool of muscle fibers, affects the precision of fiber type proportion estimates. A total of 170 individual muscle fibers were isolated from vastus lateralis biopsies from each of eight human subjects, and their MHC isoform content was analyzed using SDS-PAGE. To evaluate the precision of fiber type proportion estimates, we employed a resampling approach, varying both the muscle fiber sample size (25, 50, or 100 fibers) and the selection method (ordered vs. random selection). Our results indicate that when analyzing a small number of muscle fibers, precision improves if the fibers are randomly selected from a larger pool rather than characterized in the order they were isolated. These findings have important implications for designing experiments to assess skeletal muscle fiber heterogeneity and its role in health and disease.

Obesity significantly affects gastrointestinal cancer surgery outcomes by creating complex challenges throughout the preoperative, intraoperative, and postoperative stages. This narrative review explores the intricate relationship between obesity and GIC surgery, highlighting the dual burden of obesity as a global public health issue and a determinant of surgical complications. The review aims to analyze physiological and technical hurdles, including limited visibility, prolonged operative times, increased perioperative risks, and adverse recovery outcomes associated with obesity. Evidence emphasizes the critical role of excess visceral fat, systemic inflammation, and insulin resistance in elevating surgical risks. Mitigation strategies involve preoperative nutritional optimization, use of advanced surgical technologies such as robotic-assisted and laparoscopic systems, and individualized postoperative care, encompassing early mobilization, tailored pain management, and close monitoring of metabolic parameters. Despite advancements, knowledge gaps remain, particularly regarding sarcopenic obesity and the long-term impact of preoperative dietary interventions. Future research should focus on refining minimally invasive techniques, integrating personalized medicine, and exploring innovative perioperative protocols to address obesity-related risks effectively. By fostering a multidisciplinary approach, this review underscores the necessity for targeted interventions to enhance outcomes and improve the quality of care for patients with obesity undergoing gastrointestinal cancer surgery.

Purpose of Review This review aims to explore in-depth the different aspects of the association between very low-calorie ketogenic diet (VLCKD), obesity and obesity-related thyroid dysfunction. Recent Findings The VLCKD, proposed as a non-pharmacological strategy for the management of certain chronic diseases, is becoming increasingly popular worldwide. Initially used to treat epilepsy, it has been shown to be effective in controlling body weight gain and addressing various pathophysiological conditions. Research has shown that a low-calorie, high-fat diet can affect thyroid hormone levels. Weight loss can also influence thyroid hormone levels. Studies have suggested that long-term use of VLCKD for refractory epilepsy may be related to the development of hypothyroidism, with an effect seen in various populations. In particular, women with obesity following VLCKD tend to have reduced T3 levels. Summary We propose further research to unravel the underlying mechanisms linking VLCKD to obesity and obesity-related thyroid dysfunction.

This review aims to critically examine how VLCKD affects plasma lipoprotein, lipid and cholesterol metabolism. Cardiovascular disease is a worldwide health problem affecting millions of people and leading to high rates of mortality and morbidity. There is a well-established association between cardiovascular disease and circulating cholesterol. Various dietary recommendations are currently available for the management of dyslipidemia. The very low-calorie ketogenic diet (VLCKD) is becoming increasingly popular as a treatment option for several pathological conditions, including dyslipidemia. In addition to being low in calories, the VLCKD's main feature is its unique calorie distribution, emphasizing a reduction in carbohydrate consumption in favor of fat as the primary calorie source. Lowering calorie intake through a VLCKD can reduce the endogenous production of cholesterol. However, if the foods consumed are from animal sources, dietary cholesterol intake may increase due to the higher fat content of animal products. When combined, these dietary practices may have opposing effects on plasma cholesterol levels. Studies investigating the impact of VLCKD on plasma cholesterol and low-density lipoprotein cholesterol levels report contradictory findings. While some studies found an increase in low-density lipoprotein cholesterol levels, others showed a decrease in total cholesterol and low-density lipoprotein cholesterol, along with an increase in high-density lipoprotein cholesterol.

Context: Humans with obesity and insulin resistance exhibit lipid accumulation in skeletal muscle, but the underlying biological mechanisms responsible for the accumulation of lipid in the muscle of these individuals remain unknown. Objective: We investigated how plasma insulin modulates the extraction of circulating triglycerides (TGs) and nonesterified fatty acids (NEFAs) from ingested and endogenous origin in the muscle of lean, insulin-sensitive humans (Lean-IS) and contrasted these responses to those in humans with obesity and insulin resistance (Obese-IR). Methods: The studies were performed in a postprandial state associated with steady-state plasma TG concentrations. The arterio-venous blood sampling technique was employed to determine the extraction of circulating lipids across the forearm muscle before and after insulin infusion. We distinguished the kinetics of TGs and NEFAs from ingested origin from those from endogenous origin across muscle by incorporating stable isotope-labeled triolein in the ingested fat. Results: Insulin infusion rapidly suppressed the extraction of plasma TGs from endogenous but not ingested origin in the muscle of the Lean-IS, but this response was absent in the muscle of the Obese-IR. Furthermore, in the muscle of the Lean-IS, insulin infusion decreased the extraction of circulating NEFAs from both ingested and endogenous origin; however, this response was absent for NEFAs from ingested origin in the muscle of the Obese-IR subjects. Conclusion: Partitioning of circulating lipids away from the skeletal muscle when plasma insulin increases during the postprandial period is impaired in humans with obesity and insulin resistance.

Lipoprotein Lipase (LPL) hydrolyzes plasma triglycerides into free fatty acids in the circulation for use and/or storage in tissues (i.e., adipose tissue, skeletal muscle). Impaired LPL activity (LPLa) is associated with unfavorable health outcomes, such as elevated plasma triglyceride concentrations. We sought to determine how plasma LPLa relates to body composition measurements in individuals with varying degrees of adiposity. Eighteen subjects (ages 19 to 45 years) with body mass index (BMI) between 18 and 45 kg/m2 had their body composition measured by dual-energy X-ray absorptiometry (DEXA) and insulin sensitivity estimated from an oral glucose tolerance test by using the Matsuda Index (MI). Subjects ingested a bolus of 5g fat (i.e., whipping cream, 0.2 g fat/kg fat free mass), followed by small boluses of fat over the course of a 3-hour experimental period. This experimental protocol allows for the induction of a postprandial state without perturbation of the plasma triglyceride or insulin concentrations. LPLa was measured in the presence of increased plasma insulin induced by intravenous insulin infusion during the last 30 mins of the 3-hour experimental protocol. Insulin was infused at a rate of 0.5 mU/kg/min for subjects with MI-determined insulin sensitivity < 4 and 1 mU/kg/min for those with MI-determined insulin sensitivity > 4, in order to produce comparable levels of plasma insulin concentrations across subjects. To release endothelial-bound LPL, subjects received an injection of intravenous heparin (75 UI/kg) at the end of the plasma insulin infusion. Plasma samples were collected 10 minutes after the heparin infusion and analyzed for LPL concentration (LPLc) and LPLa using commercially available ELISA kits. Person’s correlation was used to evaluate relationships between several body composition parameters and LPLc as well as LPLa. LPLc was not correlated (P >0.05) with BMI (r = 0.03), total lean body mass (r = -0.20), total body fat (r = -0.02), or android fat (r = - 0.08). However, LPLa was positively correlated (P <0.05) with BMI (r = 0.49) and total lean body mass (r = 0.58), as well as total body fat (r = 0.54, P = 0.02) and android fat (r = 0.58, P = 0.01). In conclusion, increased body fat, including android fat, are associated with increased intravascular LPLa in the presence of insulin. Greater insulin-stimulated intravascular LPLa can enhance the release of triglyceride-associated free fatty acids and their uptake by tissues, resulting in insulin resistance as documented in individuals with increased android fat distribution. American Diabetes Association Grant #7-12-CT-40. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Changes in circulating insulin-like growth factor 1 (IGF-1) implicate regulation of skeletal muscle metabolism, including protein and glucose metabolism. Previous studies have shown that an acute bout of exercise increases serum IGF-1 concentrations in healthy, lean humans. However, exercise-induced changes in serum IGF-1 concentrations in humans with obesity remain unknown. We compared changes in plasma IGF-1 during and after an acute bout of endurance exercise between humans with and without obesity. Eight subjects with obesity (i.e., OB: BMI = 34.48 ± 2.96) and eight subjects without obesity (i.e., LN: BMI = 24.45 ± 2.43 kg/m2) exercised for 45 min in a cycle ergometer at 65% of their maximum oxygen uptake, after an overnight 10-h fast. Blood draws were taken immediately before exercise, at 15 and 30 minutes (i.e., during exercise), and at 55, 75, 95, and 115 minutes after the start of the exercise. Serum concentrations of total IGF-1 and insulin were determined using commercially available ELISA assays (Alpco 22-IGFHU-E01 and 80-INSHU-E10.1, respectively). Plasma glucose concentrations were determined using an automatic analyzer (YSI glucose analyzer). One-way repeated measures analyses of variance were carried out to detect significant changes over time within each group. Independent t tests were used to determine group differences at each time point. Alpha level was set at p ≤ 0.05 and data are reported as mean ± SD. There were no significant ( p > 0.05) differences between groups for IGF-1 serum concentrations at baseline (LN = 205.61 ± 40.07 ng/mL, OB = 200.89 ± 80.40 ng/mL) nor during or after exercise. Significant increases from baseline in serum IGF-1 concentrations were detected in the LN group at 15 min (231.30 ± 50.47 ng/mL, p = 0.007) and 30 min (227.94 ± 49.02 ng/mL, p = 0.04) during exercise, followed by significant decreases from baseline at 95 min (189.99 ± 34.73 ng/mL, p = 0.052) and 115 min (196.42 ± 40.39 ng/mL, p = 0.023). No significant ( p > 0.05) differences from baseline were observed in the obese group neither during nor after exercise. Higher serum insulin concentrations were observed in the OB group at baseline (LN = 5.55 ± 2.62 μIU/mL, OB = 11.07 ± 5.76 μIU/mL, p = 0.027) but significant group differences no longer existed ( p > 0.05) during exercise and up to 55 min after exercise; however, insulin concentrations for the OB group were significantly greater than those measured in the LN group at 75 min ( p = 0.028), 95 min ( p = 0.008), and 115 min ( p = 0.007) after exercise. Moreover, a significant increase from baseline was measured 55 min after exercise in the lean group (8.22 ± 3.13 μIU/mL, p = 0.005), whereas no significant changes were observed in the OB groups at any time point ( p > 0.05). No significant ( p > 0.05) group differences were detected for plasma glucose concentrations at any time point, and despite a significant decrease from baseline observed in the LN group at 115 min after exercise (baseline = 83.32 ± 7.66 mg/dL, 115 min = 81.02 ± 7.00 mg/dL, p = 0.044). In conclusion, endurance exercise increases serum IGF-1 concentrations in humans without obesity, but this response is impaired in humans with obesity. National Institute of Health (NIH)\National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Grant/Award Number: R01DK123441. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The proportion of the different types of fibers in a given skeletal muscle contributes to its overall metabolic and functional characteristics. Greater proportion of type I muscle fibers is associated with favorable oxidative metabolism and function of the muscle. Humans with obesity have a lower proportion of type I muscle fibers. We discuss how lower proportion of type I fibers in skeletal muscle of humans with obesity may explain metabolic and functional abnormalities reported in these individuals. These include lower muscle glucose disposal rate, mitochondrial content, protein synthesis, and quality/contractile function, as well as increased risk for heart disease, lower levels of physical activity, and propensity for weight gain/resistance to weight loss. We delineate future research directions and the need to examine hybrid muscle fiber populations, which are indicative of a transitory state of fiber phenotype within skeletal muscle. We also describe methodologies for precisely characterizing muscle fibers and gene expression at the single muscle fiber level to enhance our understanding of the regulation of muscle fiber phenotype in obesity. By contextualizing research in the field of muscle fiber type in obesity, we lay a foundation for future advancements and pave the way for translation of this knowledge to address impaired metabolism and function in obesity.

PURPOSE: There are currently discrepant findings describing the effects of obesity on skeletal muscle protein metabolism, with some, but not all, studies reporting impaired protein synthesis in skeletal muscle. The underlying causes for the different findings remain unknown. Considering the importance of the insulin-like growth factor one (IGF-1) on skeletal muscle protein metabolism and stimulation of protein synthesis, we investigated the effects of obesity on the expression of the different isoforms of IGF-1 in skeletal muscle and their association with the rates of mixed-muscle and mitochondrial protein synthesis. METHODS: Seventeen adults with obesity (OB, males = 9, females = 7, BMI = 34.70 ± 3.13 kg/m2, age = 34.12±9.95 yrs) and 19 lean adults (LN, males = 8, females = 9, BMI = 23.35 ± 2.63 kg/m2, age = 32.47 ± 9.43 yrs) underwent infusion of d10-leu coupled with vastus lateralis muscle biopsies to measure fractional synthesis rate (FSR) of mixed-muscle (MMP) and mitochondrial proteins (MITOP) after an overnight (~ 10-h) fast. Muscle protein synthesis was evaluated using standard precursor-product approach, after determination of enrichment of plasma leucine and muscle proteins leucine with d10-leu by mass spectrometry. Predesigned TaqMan gene expression assays (Thermo Fisher Scientific Inc) were used to measure the mRNA expression of IGF-1 Ea, IGF-1 Eb, and IGF-1 Ec isoforms and ACTB (used as control). RESULTS: There were no significant differences between LN and OB in the FSR of MMP (LN = 0.07 ± 0.02, OB = 0.07 ± 0.02, p = 0.50) or MITOP (LN = 0.09 ± 0.03, OB = 0.08 ± 0.03, p = 0.17). Moreover, there were no significant group differences in the mRNA expression of either Ea (LN = 1.00 ± 0.45, OB = 1.09 ± 0.45, p = 0.62) or Ec (LN = 1.06 ± 0.68, OB = 0.93 ± 0.44, p = 0.47) isoforms of IGF-1. However, a significantly ( p = 0.04) lower mRNA expression of the Eb isoform was observed in the OB group (0.73 ± 0.28) compared to the LN group (1.11 ± 0.50). Although no significant correlations were observed in the mRNA expression between either Ea or Ec IGF-1 isoforms and MMP and MITOP FSR, a significant correlation was observed between the Eb isoform mRNA expression and MITOP ( r = 0.53, p = 0.02), whereas the correlation with MMP FSR only approached statistical significance ( r = 0.38, p = 0.07). CONCLUSION: These results suggest that mRNA expression of the IGF-1 Eb isoform is reduced in humans with obesity compared to lean. Also, reduced expression of the IGF-1 Eb isoform is associated with lower production of mitochondrial proteins in skeletal muscle. Therefore, lower muscle mRNA expression of the IGF-1 Eb isoform may be a culprit impairing synthesis of protein previously documented in skeletal muscle of humans with obesity. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.