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.

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 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.

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.

AbstractObjectiveThis study tested the hypothesis that expression of insulin‐like growth factor 1 (IGF‐1) protein and mRNA splice variants is lower in skeletal muscle of humans with obesity who have a lower mixed‐muscle protein fractional synthesis rate (MMP‐FSR) when compared with individuals without obesity.MethodsThe study included nine participants with obesity (OB, mean [SD], BMI = 35 [3] kg/m2, MMP‐FSR = 0.06%/h [0.02%/h]) and nine participants without obesity (W‐OB, BMI = 24 [3] kg/m2, MMP‐FSR = 0.08%/h [0.02%/h]; for both BMI and MMP‐FSR p < 0.05). MMP‐FSR and mitochondrial protein FSR were measured following an overnight fast.ResultsAlong with lower MMP‐FSR, OB participants displayed lower mitochondrial protein FSR (p = 0.03) compared with W‐OB participants. Expression of IGF‐1 (p = 0.04) and IGF‐1 receptor (p < 0.01) proteins was lower in muscle of OB participants. In addition, OB participants had lower (p < 0.05) mRNA expression of IGF1 variants Eb and Ec. This study demonstrates that lower protein synthesis in muscle of humans with obesity occurs concurrently with lower expression of muscle IGF‐1 and IGF‐1 receptor proteins, as well as lower mRNA expression of the IGF1 splice variants.ConclusionsThese findings indicate that lower protein synthesis observed in muscle of humans with obesity may result from diminished muscle IGF1 gene expression.

Mitochondria from skeletal muscle of humans with obesity often display alterations with respect to their morphology, proteome, biogenesis, and function. These changes in muscle mitochondria are considered to contribute to metabolic abnormalities observed in humans with obesity. Most of the evidence describing alterations in muscle mitochondria in humans with obesity, however, lacks reference to a specific subcellular location. This is despite data over the years showing differences in the morphology and function of subsarcolemmal (found near the plasma membrane) and intermyofibrillar (nested between the myofibrils) mitochondria in skeletal muscle. Recent studies reveal that impairments in mitochondrial function in obesity with respect to the subcellular location of the mitochondria in muscle are more readily evident following exposure of the skeletal muscle to physiological stimuli. In this review, we highlight the need to understand skeletal muscle mitochondria metabolism in obesity in a subpopulation-specific manner and in the presence of physiological stimuli that modify mitochondrial function in vivo. Experimental approaches employed under these conditions will allow for more precise characterization of impairments in skeletal muscle mitochondria and their implications in inducing metabolic dysfunction in human obesity.

New Findings What is the central question of this study? Humans with obesity have lower ATP synthesis in muscle along with lower content of the β‐subunit of the ATP synthase (β‐F1‐ATPase), the catalytic component of the ATP synthase. Does lower synthesis rate of β‐F1‐ATPase in muscle contribute to these responses in humans with obesity? What is the main finding and its importance? Humans with obesity have a lower synthesis rate of β‐F1‐ATPase and ATP synthase specific activity in muscle. These findings indicate that reduced production of subunits forming the ATP synthase in muscle may contribute to impaired generation of ATP in obesity. AbstractThe content of the β‐subunit of the ATP synthase (β‐F1‐ATPase), which forms the catalytic site of the enzyme ATP synthase, is reduced in muscle of obese humans, along with a reduced capacity for ATP synthesis. We studied 18 young (37 ± 8 years) subjects of which nine were lean (BMI = 23 ± 2 kg m−2) and nine were obese (BMI = 34 ± 3 kg m−2) to determine the fractional synthesis rate (FSR) and gene expression of β‐F1‐ATPase, as well as the specific activity of the ATP synthase. FSR of β‐F1‐ATPase was determined using a combination of isotope tracer infusion and muscle biopsies. Gene expression of β‐F1‐ATPase and specific activity of the ATP synthase were determined in the muscle biopsies. When compared to lean, obese subjects had lower muscle β‐F1‐ATPase FSR (0.10 ± 0.05 vs. 0.06 ± 0.03% h−1; P < 0.05) and protein expression (P < 0.05), but not mRNA expression (P > 0.05). Across subjects, abundance of β‐F1‐ATPase correlated with the FSR of β‐F1‐ATPase (P < 0.05). The specific activity of muscle ATP synthase was lower in obese compared to lean subjects (0.035 ± 0.004 vs. 0.042 ± 0.007 arbitrary units; P < 0.05), but this difference was not significant after the activity of the ATP synthase was adjusted to the β‐F1‐ATPase content (P > 0.05). Obesity impairs the synthesis of β‐F1‐ATPase in muscle at the translational level, reducing the content of β‐F1‐ATPase in parallel with reduced capacity for ATP generation via the ATP synthase complex.

ABSTRACT Introduction Current evidence indicates mitochondrial dysfunction in humans with obesity. Acute exercise appears to enhance mitochondrial function in the muscle of nonobese humans, but its effects on mitochondrial function in muscle of humans with obesity are not known. We sought to determine whether acute aerobic exercise stimulates mitochondrial function in subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondria in humans with obesity. Methods We assessed maximal adenosine triphosphate production rate (MAPR) and citrate synthase (CS) activity in isolated SS and IMF mitochondria from subjects with body mass index < 27 kg·m −2 (median age, 25 yr; interquartile range, 22–39 yr) and subjects with body mass index > 32 kg·m −2 (median age, 29 yr; interquartile range, 20–39 yr) before and 3 h after a 45-min cycling exercise at an intensity corresponding to 65% HR reserve. The SS and IMF mitochondria were isolated from muscle biopsies using differential centrifugation. Maximal adenosine triphosphate production rate and CS activities were determined using luciferase-based and spectrophotometric enzyme-based assays, respectively. Results Exercise increased MAPR in IMF mitochondria in both nonobese subjects and subjects with obesity ( P < 0.05), but CS-specific activity did not change in either group ( P > 0.05). Exercise increased MAPR supported by complex II in SS mitochondria, in both groups ( P < 0.05), but MAPR supported by complex I or palmitate did not increase by exercise in the subjects with obesity ( P > 0.05). Citrate synthase–specific activity increased in SS mitochondria in response to exercise only in nonobese subjects ( P < 0.05). Conclusions In nonobese humans, acute aerobic exercise increases MAPR in both SS and IMF mitochondria. In humans with obesity, the exercise increases MAPR in IMF mitochondria, but this response is less evident in SS mitochondria.