Katsanos, Christos S.

ABSTRACT 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 (R 2 = 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.

ABSTRACT 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/m 2 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.

Skeletal muscle is a heterogenous tissue composed of fibers (i.e., cells) with distinct metabolic and contractile properties. Muscle fibers are classified into 2 separate groups: Type 1 fibers which are primarily oxidative, and Type 2 fibers (further subdivided to Types 2a and 2x) which are predominantly glycolytic. Acute exercise induces transcriptional changes in skeletal muscle. However, these changes have been studied at the whole muscle level. The effects of exercise on differential gene expression in distinct muscle fiber types in response to acute exercise remains unclear. In this study, we evaluated gene expression in Type 1, 2a, and 2x muscle fibers in response to acute aerobic exercise. Muscle biopsies were collected from 5 (31±3 yrs) apparently healthy individuals before and 3hrs following an acute 45 min session of cycling exercise performed at 65% of maximal heart rate. Individual muscle fibers (n=138) were isolated from the muscle biopsy sample manually under a microscope. Half of the fiber was used to characterize it as Type 1, 2a, or 2x based on its myosin heavy chain isoform expression content using single fiber SDS-PAGE. The other half of the fiber underwent RNA sequencing. The effects of exercise on fiber types were analyzed using subject specific pseudo-bulk differential expression before and after exercise (Type 1 n=28, 2a n=28, and 2x n=12). Gene counts were normalized as counts per million (CPM) and log2 transformed with a pseudocount of +1. The top 200 differentially expressed genes (DEG’s) were then used to calculate fold changes between fiber types at baseline and in response to exercise. After exercise, 73.5% of DEG’s were upregulated in Type 1 fibers, 52% were upregulated in Type 2a fibers, and 60.5% were downregulated in 2x fibers, relative to baseline. Type 1 fibers showed the greatest increases in gene expression (notably, TPM1 log2FC = 2.46, ATP2A1 log2FC = 3.23, and UQCRB log2FC=0.39) and displayed transcriptional changes consistent with oxidative phosphorylation, calcium signaling, and cytoskeletal remodeling pathways. Type 2a fibers displayed modest increases (ATP2A1 log2FC = 0.34, TNNC2 log2FC = 0.21 and ENO3 log2FC=0.35) and an overall upregulation of glycogenic/gluconeogenesis pathways. Conversely, Type 2x fibers exhibited broad transcriptional suppression and downregulation of calcium signaling pathways. In conclusion, acute aerobic exercise induces gene expression in muscle that is fiber type-specific. Type 1 fibers upregulate genes related to oxidative phosphorylation and calcium signaling, whereas Type 2a fibers upregulate genes related to glycolysis. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

ABSTRACT 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.

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.

AbstractWe 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.

Abstract The growing prevalence of obesity, a risk factor for disorders such as Alzheimer’s Disease (AD), raises concerns about the effects on cognitive health. AD currently impacts 6.9 million Americans aged 65 and older and is characterized by the presence of amyloid beta (Aβ) plaques, neurofibrillary tau tangles, and neuroinflammation, all of which contribute to cognitive impairment. Insulin resistance, common in both obesity and AD, disrupts brain glucose metabolism and accelerates neurodegeneration. Understanding the factors that link these conditions could lead to new strategies for combating disease. Notably, the B-like vitamin choline is necessary for fat metabolism and has been shown to help reduce obesity incidence. However, ∼90% of Americans are deficient, and decreases in this nutrient have been associated with cognitive decline. Here, we examined circulating choline levels, inflammation, and metabolic dysfunction in human participants with obesity (BMI > 30) compared to normal BMIs (18.5–24.9), as well as in 3xTg-AD mice, an AD model, fed a choline-deficient diet throughout adulthood. Our results revealed that obese participants exhibited significantly lower circulating choline levels compared to those with a healthy BMI. Lower choline levels correlated with higher %Body fat and increased markers of insulin resistance. Elevated inflammatory cytokines in obese participants were also seen in 3xTg-AD mice on a choline-deficient diet, which exhibited significant weight gain and metabolic dysfunction. AD-like pathology was also exacerbated in choline deficient 3xTg-AD mice. These findings underscore the relationship between low choline levels, obesity, insulin resistance, and cognitive decline risk. Adequate choline intake may mitigate the risk of obesity, potentially preventing cognitive decline and associated diseases. Highlights Obesity is linked to increased insulin resistance (IR) and systemic inflammation, both of which are recognized risk factors for Alzheimer’s disease (AD). Women exhibit lower circulating choline levels compared to men, and obese individuals display significantly lower choline levels than those with a healthy BMI. Lower circulating choline levels are linked to a higher body fat percentage, increased markers of IR and liver dysfunction, as well as heightened systemic inflammation. 3xTg-AD mice on a choline-deficient diet experience considerable weight gain, metabolic dysfunction, heightened systemic inflammation, and AD-like pathology, resembling the conditions observed in obese human participants.

Abstract 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.

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.