Social media for obesity education: a general overview for the novice creator.

Rates of obesity continue to rise in the United States and across the globe. Obesity is a risk factor for developing insulin resistance, type 2 diabetes, and cardiovascular disease. For clinicians, other health care providers, and educators, providing patients with accurate and meaningful information about obesity, including lifestyle (diet and exercise) interventions and symptom monitoring, is challenging because of infrequent contact, methods of communication, a lack of effective patient education resources, and inefficient patient feedback methods. Evidence suggests that significantly more patients are now getting their health care information online from general medical websites, disease-specific network communities, and social media. Thus, harnessing the power of technologies, including personal computers and smartphones, with attention to social media may equip health care providers with methods to serve their patients better by addressing challenges, improving indirect patient contact, and enhancing health outcomes. This article aims to provide an overview of technology with a focus on social media use in obesity education and outreach. Practical information is provided related to creating content, delivering content, and managing the social media space for the novice creator.NEW & NOTEWORTHY Rates of obesity continue to increase. Health care providers have a limited time to cover the nuances of obesity. Technology and social media are tools that can help health care workers provide obesity education to a large audience. This article provides the foundations for obesity education content generation and delivery for the novice creator.

Lower mitochondrial respiration does not lead to decreased fat oxidation in young African American women without obesity.

OBJECTIVE: The prevalence of type 2 diabetes in African American women (AAW) is nearly twice that of White women. Lower insulin sensitivity and decreased mitochondrial function may be contributing factors. The purpose of this study was to compare fat oxidation in AAW and White women. METHODS: Participants were 22 AAW and 22 White women, matched for age (18.7-38.3 years) and BMI (< 28 kg/m2). Participants completed two submaximal (50% VO2max) exercise tests with indirect calorimetry and stable isotope tracers to assess total, plasma, and intramyocellular triglyceride fat oxidation. RESULTS: The respiratory quotient during the exercise test was nearly identical in AAW and White women (0.813 ± 0.008 vs. 0.810 ± 0.008, p = 0.83). Although absolute total and plasma fat oxidation was lower in AAW, adjusting for the lower workload in AAW eliminated these racial differences. There was no racial difference in plasma and intramyocellular triglyceride source of fat for oxidation. No racial differences were observed in rates of ex vivo fat oxidation. Exercise efficiency was lower in AAW when adjusted to leg fat free mass. CONCLUSIONS: The data suggest that fat oxidation is not lower in AAW compared with White women, but additional studies are needed across exercise intensity, body weight, and age to confirm these results.

Decreased Mitochondrial Dynamics Is Associated with Insulin Resistance, Metabolic Rate, and Fitness in African Americans.

CONTEXT: African American women (AAW) have a higher incidence of insulin resistance and are at a greater risk for the development of obesity and type 2 diabetes than Caucasian women (CW). Although several factors have been proposed to mediate these racial disparities, the mechanisms remain poorly defined. We previously demonstrated that sedentary lean AAW have lower peripheral insulin sensitivity, reduced maximal aerobic fitness (VO2max), and lower resting metabolic rate (RMR) than CW. We have also demonstrated that skeletal muscle mitochondrial respiration is lower in AAW and appears to play a role in these racial differences. OBJECTIVE: The goal of this study was to assess mitochondrial pathways and dynamics to examine the potential mechanisms of lower insulin sensitivity, RMR, VO2max, and mitochondrial capacity in AAW. DESIGN: To achieve this goal, we assessed several mitochondrial pathways in skeletal muscle using gene array technology and semiquantitative protein analysis. RESULTS: We report alterations in mitochondrial pathways associated with inner membrane small molecule transport genes, fusion-fission, and autophagy in lean AAW. These differences were associated with lower insulin sensitivity, RMR, and VO2max. CONCLUSIONS: Together these data suggest that the metabolic racial disparity of insulin resistance, RMR, VO2max, and mitochondrial capacity may be mediated by perturbations in mitochondrial pathways associated with membrane transport, fission-fusion, and autophagy. The mechanisms contributing to these differences remain unknown.

Effects of Individualized Treadmill Endurance Training on Oxidative Stress in Skeletal Muscles of Transgenic Sickle Mice.

Oxidative stress is a key feature in the pathophysiology of sickle cell disease. Endurance training has been shown to reduce oxidative stress in the heart and the liver of sickle mice. However, the effects of endurance training on skeletal muscles, which are major producers of reactive oxygen species during exercise, are currently unknown. The aim of this study was to evaluate the effect of sickle genotype on prooxidant/antioxidant response to individualized endurance training in skeletal muscles of sickle mice. Healthy and homozygous Townes sickle mice were divided into trained or sedentary groups. Maximal aerobic speed and V̇O2 peak were determined using an incremental test on a treadmill. Trained mice ran at 40% to 60% of maximal aerobic speed, 1 h/day, 5 days/week for 8 weeks. Oxidative stress markers, prooxidant/antioxidant response, and citrate synthase enzyme activities were assessed in the gastrocnemius, in the plantaris, and in the soleus muscles. Maximal aerobic speed and V̇O2 peak were significantly reduced in sickle compared to healthy mice (-57% and -17%; p < 0.001). NADPH oxidase, superoxide dismutase, and catalase activities significantly increased after training in the gastrocnemius of sickle mice only. A similar trend was observed for citrate synthase activity in sickle mice (p = 0.06). In this study, we showed an adaptive response to individualized endurance training on the prooxidant/antioxidant balance in the gastrocnemius, but neither in the plantaris nor in the soleus of trained sickle mice, suggesting an effect of sickle genotype on skeletal muscle response to endurance treadmill training.

Mitochondrial Respiration is Associated with Lower Energy Expenditure and Lower Aerobic Capacity in African American Women.

OBJECTIVE: Reasons for the higher obesity prevalence in African American women (AAW) compared with Caucasian women (CW) are unknown. Energy expenditure and maximal aerobic capacity (VO2 max) are lower in AAW. It was hypothesized that these differences are explained by skeletal muscle characteristics, particularly mitochondrial content and function. METHODS: Multivariate regression analyses were used to examine the relationships between energy expenditure (resting and during a hyperinsulinemic-euglycemic clamp) and VO2 max versus body composition, physical activity, and skeletal muscle mitochondrial measurements in AAW and CW. RESULTS: In AAW, VO2 max was lower (P < 0.0001). Body-composition-adjusted energy expenditure during the clamp was lower in AAW (P < 0.002). Physical activity was similar in both groups. After adjusting for mitochondrial respiration, racial differences in energy expenditure and VO2 max were no longer present. Another novel finding was that a thermogenic response to the clamp was observed in CW (+53 ± 22 kcal/d; P < 0.03) but not in AAW (-19 ± 24 kcal/d; P = 0.43). CONCLUSIONS: AAW and CW show differences in adjusted energy expenditure and aerobic capacity that are largely accounted for by differences in skeletal muscle mitochondrial oxidative characteristics. Further research is needed to determine whether lower mitochondrial respiration and lower thermogenesis are risk factors for obesity in AAW.

Moderate exercise training decreases inflammation in transgenic sickle cell mice.

Chronic systemic inflammation is a pathophysiological feature of sickle cell disease (SCD). Considering that regular exercise exerts multiple beneficial health effects including anti-inflammatory actions, we investigated whether a treadmill training program could minimize the inflammatory state in transgenic sickle cell (SS) mice. To test this hypothesis, SS mice were subjected to a treadmill training protocol of 1h/day, 5days a week for 8weeks. Exercise training increased the percent of venous oxyhemoglobin and sharply decreased the percent of carboxyhemoglobin suggesting that exercise training may limit the proportion of erythrocytes that were deoxygenated in the venous circulation. Exercise training attenuated systemic inflammation as attested by a significant drop in white blood cell (WBC) count and plasma Th1/Th2 cytokine ratio. There was reduction in interleukin-1ß and endothelin-1 mRNA expression in trained sickle mice. The spleen/body mass ratio was significantly decreased in trained sickle mice and there was a strong correlation between the magnitude of congestion and the relative spleen mass in all animals (trained and untrained). We conclude that moderate intensity exercise training, without any noticeable complications, may be associated with limited baseline blood deoxygenation and inflammation in sickle cell mice, and reduce sequestration of sickle erythrocytes/congestion in the spleen.

Effect of acute physiological free fatty acid elevation in the context of hyperinsulinemia on fiber type-specific IMCL accumulation.

It is well described that increasing free fatty acids (FFAs) to high physiological levels reduces insulin sensitivity. In sedentary humans, intramyocellular lipid (IMCL) is inversely related to insulin sensitivity. Since muscle fiber composition affects muscle metabolism, whether FFAs induce IMCL accumulation in a fiber type-specific manner remains unknown. We hypothesized that in the setting of acute FFA elevation by lipid infusion within the context of a hyperinsulinemic-euglycemic clamp, IMCL will preferentially accumulate in type 1 fibers. Normal-weight participants (n = 57, mean ± SE: age 24 ± 0.6 yr, BMI 22.2 ± 0.3 kg/m2) who were either endurance trained or sedentary by self-report were recruited from the University of Minnesota (n = 31, n = 15 trained) and University of Pittsburgh (n = 26, n = 14 trained). All participants underwent a hyperinsulinemic-euglycemic clamp in the context of a 6-h infusion of either lipid or glycerol control. A vastus lateralis muscle biopsy was obtained at baseline and end-infusion (6 h). The muscle biopsies were processed and analyzed at the University of Pittsburgh for fiber type-specific IMCL accumulation by Oil-Red-O staining. Regardless of training status, acute elevation of FFAs to high physiological levels (~400-600 meq/l) increased IMCL preferentially in type 1 fibers (+35 ± 11% compared with baseline, +29 ± 11% compared with glycerol control: P < 0.05). The increase in IMCL correlated with a decline in insulin sensitivity as measured by the hyperinsulinemic-euglycemic clamp (r = -0.32, P < 0.01) independent of training status. Regardless of training status, increase of FFAs to a physiological range within the context of hyperinsulinemia shows preferential IMCL accumulation in type 1 fibers.NEW & NOTEWORTHY This novel human study examined the effects of FFA elevation in the setting of hyperinsulinemia on accumulation of fat in specific types of muscle fibers. Within the context of the hyperinsulinemic-euglycemic clamp, we found that an increase of FFAs to a physiological range sufficient to reduce insulin sensitivity is associated with preferential IMCL accumulation in type 1 fibers.

Calorie Restriction-induced Weight Loss and Exercise Have Differential Effects on Skeletal Muscle Mitochondria Despite Similar Effects on Insulin Sensitivity.

BACKGROUND: Skeletal muscle insulin resistance and reduced mitochondrial capacity have both been reported to be affected by aging. The purpose of this study was to compare the effects of calorie restriction-induced weight loss and exercise on insulin resistance, skeletal muscle mitochondrial content, and mitochondrial enzyme activities in older overweight to obese individuals. METHODS: Insulin-stimulated rates of glucose disposal (Rd) were determined using the hyperinsulinemic euglycemic clamp before and after completing 16 weeks of either calorie restriction to induce weight loss (N = 7) or moderate exercise (N = 10). Mitochondrial volume density, mitochondria membrane content (cardiolipin), and activities of electron transport chain (rotenone-sensitive NADH-oxidase), tricarboxylic acid (TCA) cycle (citrate synthase) and ß-oxidation pathway (ß-hydroxyacyl CoA dehydrogenase; ß-HAD) were measured in percutaneous biopsies of the vastus lateralis before and after the interventions. RESULTS: Rd improved similarly (18.2% ± 9.0%, p < .04) with both weight loss and exercise. Moderate exercise significantly increased mitochondrial volume density (14.5% ± 2.0%, p < .05), cardiolipin content (22.5% ± 13.4%, p < .05), rotenone-sensitive NADH-oxidase (65.7% ± 13.2%, p = .02) and ß-HAD (30.7% ± 6.8%, p ≤ .03) activity, but not citrate synthase activity (10.1% ± 4.0%). In contrast, calorie restriction-induced weight loss did not affect mitochondrial content, NADH-oxidase or ß-HAD, yet increased citrate synthase activity (44.1% ± 21.1%, p ≤ .04). Exercise (increase) or weight loss (decrease) induced a remodeling of cardiolipin with a small (2%-3%), but significant change in the relative content of tetralinoleoyl cardiolipin. CONCLUSION: Exercise increases both mitochondria content and mitochondrial electron transport chain and fatty acid oxidation enzyme activities within skeletal muscle, while calorie restriction-induced weight loss did not, despite similar improvements in insulin sensitivity in overweight older adults.

Chronological Age Does not Influence Ex-vivo Mitochondrial Respiration and Quality Control in Skeletal Muscle.

BACKGROUND: Considerable debate continues to surround the concept of mitochondrial dysfunction in aging muscle. We tested the overall hypothesis that age per se does not influence mitochondrial function and markers of mitochondria quality control, that is, expression of fusion, fission, and autophagy proteins. We also investigated the influence of cardiorespiratory fitness (VO2max) and adiposity (body mass index) on these associations. METHODS: Percutaneous biopsies of the vastus lateralis were obtained from sedentary young (n = 14, 24±3 years), middle-aged (n = 24, 41±9 years) and older adults (n = 20, 78±5 years). A physically active group of young adults (n = 10, 27±5 years) was studied as a control. Mitochondrial respiration was determined in saponin permeabilized fiber bundles. Fusion, fission and autophagy protein expression was determined by Western blot. Cardiorespiratory fitness was determined by a graded exercise test. RESULTS: Mitochondrial respiratory capacity and expression of fusion (OPA1 and MFN2) and fission (FIS1) proteins were not different among sedentary groups despite a wide age range (21 to 88 years). Mitochondrial respiratory capacity and fusion and fission proteins were, however, negatively associated with body mass index, and mitochondrial respiratory capacity was positively associated with cardiorespiratory fitness. The young active group had higher respiration, complex I and II respiratory control ratios, and expression of fusion and fission proteins. Finally, the expression of fusion, fission, and autophagy proteins were linked with mitochondrial respiration. CONCLUSIONS: Mitochondrial respiration and markers of mitochondrial dynamics (fusion and fission) are not associated with chronological age per se, but rather are more strongly associated with body mass index and cardiorespiratory fitness.

Resting and exercise energy metabolism in weight-reduced adults with severe obesity.

OBJECTIVE: To determine effects of physical activity (PA) with diet-induced weight loss on energy metabolism in adults with severe obesity. METHODS: Adults with severe obesity (n = 11) were studied across 6 months of intervention, then compared with controls with less severe obesity (n = 7) or normal weight (n = 9). Indirect calorimetry measured energy metabolism during exercise and rest. Markers of muscle oxidation were determined by immunohistochemistry. Data were presented as medians. RESULTS: The intervention induced 7% weight loss (P = 0.001) and increased vigorous PA by 24 min/wk (P = 0.02). During exercise, energy expenditure decreased, efficiency increased (P ≤ 0.03), and fatty acid oxidation (FAO) did not change. Succinate dehydrogenase increased (P = 0.001), but fiber type remained the same. Post-intervention subjects' resting metabolism remained similar to controls. Efficiency was lower in post-intervention subjects compared with normal-weight controls exercising at 25 W (P ≤ 0.002) and compared with all controls exercising at 60% VO2peak (P ≤ 0.019). Resting and exercise FAO of post-intervention subjects remained similar to adults with less severe obesity. Succinate dehydrogenase and fiber type were similar across all body weight statuses. CONCLUSIONS: While metabolic adaptations to PA during weight loss occur in adults with severe obesity, FAO does not change. Resulting FAO during rest and exercise remains similar to adults with less severe obesity.

SIRT3-AMP-Activated Protein Kinase Activation by Nitrite and Metformin Improves Hyperglycemia and Normalizes Pulmonary Hypertension Associated With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Pulmonary hypertension associated with heart failure with preserved ejection fraction (PH-HFpEF) is an increasingly recognized clinical complication of metabolic syndrome. No adequate animal model of PH-HFpEF is available, and no effective therapies have been identified to date. A recent study suggested that dietary nitrate improves insulin resistance in endothelial nitric oxide synthase null mice, and multiple studies have reported that both nitrate and its active metabolite, nitrite, have therapeutic activity in preclinical models of pulmonary hypertension. METHODS AND RESULTS: To evaluate the efficacy and mechanism of nitrite in metabolic syndrome associated with PH-HFpEF, we developed a 2-hit PH-HFpEF model in rats with multiple features of metabolic syndrome attributable to double-leptin receptor defect (obese ZSF1) with the combined treatment of vascular endothelial growth factor receptor blocker SU5416. Chronic oral nitrite treatment improved hyperglycemia in obese ZSF1 rats by a process that requires skeletal muscle SIRT3-AMPK-GLUT4 signaling. The glucose-lowering effect of nitrite was abolished in SIRT3-deficient human skeletal muscle cells, and in SIRT3 knockout mice fed a high-fat diet, as well. Skeletal muscle biopsies from humans with metabolic syndrome after 12 weeks of oral sodium nitrite and nitrate treatment (IND#115926) displayed increased activation of SIRT3 and AMP-activated protein kinase. Finally, early treatments with nitrite and metformin at the time of SU5416 injection reduced pulmonary pressures and vascular remodeling in the PH-HFpEF model with robust activation of skeletal muscle SIRT3 and AMP-activated protein kinase. CONCLUSIONS: These studies validate a rodent model of metabolic syndrome and PH-HFpEF, suggesting a potential role of nitrite and metformin as a preventative treatment for this disease.

Muscle Characteristics and Substrate Energetics in Lifelong Endurance Athletes.

PURPOSE: The goal of this study was to explore the effect of lifelong aerobic exercise (i.e., chronic training) on skeletal muscle substrate stores (intramyocellular triglyceride [IMTG] and glycogen), skeletal muscle phenotypes, and oxidative capacity (ox), in older endurance-trained master athletes (OA) compared with noncompetitive recreational younger (YA) athletes matched by frequency and mode of training. METHODS: Thirteen OA (64.8 ± 4.9 yr) exercising 5 times per week or more were compared with 14 YA (27.8 ± 4.9 yr) males and females. IMTG, glycogen, fiber types, succinate dehydrogenase, and capillarization were measured by immunohistochemistry in vastus lateralis biopsies. Fat-ox and carbohydrate (CHO)-ox were measured by indirect calorimetry before and after an insulin clamp and during a cycle ergometer graded maximal test. RESULTS: V˙O2peak was lower in OA than YA. The OA had greater IMTG in all fiber types and lower glycogen stores than YA. This was reflected in greater proportion of type I and less type II fibers in OA. Type I fibers were similar in size, whereas type II fibers were smaller in OA compared with YA. Both groups had similar succinate dehydrogenase content. Numbers of capillaries per fiber were reduced in OA but with a higher number of capillaries per area. Metabolic flexibility and insulin sensitivity were similar in both groups. Exercise metabolic efficiency was higher in OA. At moderate exercise intensities, carbohydrate-ox was lower in OA but with similar Fat-ox. CONCLUSIONS: Lifelong exercise is associated with higher IMTG content in all muscle fibers and higher metabolic efficiency during exercise that are not explained by differences in muscle fibers types and other muscle characteristics when comparing older with younger athletes matched by exercise mode and frequency.

Adipose triglyceride lipase deletion from adipocytes, but not skeletal myocytes, impairs acute exercise performance in mice.

Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme mediating triacylglycerol hydrolysis in virtually all cells, including adipocytes and skeletal myocytes, and hence, plays a critical role in mobilizing fatty acids. Global ATGL deficiency promotes skeletal myopathy and exercise intolerance in mice and humans, and yet the tissue-specific contributions to these phenotypes remain unknown. The goal of this study was to determine the relative contribution of ATGL-mediated triacylglycerol hydrolysis in adipocytes vs. skeletal myocytes to acute exercise performance. To achieve this goal, we generated murine models with adipocyte- and skeletal myocyte-specific targeted deletion of ATGL. We then subjected untrained mice to acute peak and submaximal exercise interventions and assessed exercise performance and energy substrate metabolism. Impaired ATGL-mediated lipolysis within adipocytes reduced peak and submaximal exercise performance, reduced peripheral energy substrate availability, shifted energy substrate preference toward carbohydrate oxidation, and decreased HSL Ser(660) phosphorylation and mitochondrial respiration within skeletal muscle. In contrast, impaired ATGL-mediated lipolysis within skeletal myocytes was not sufficient to reduce peak and submaximal exercise performance or peripheral energy substrate availability and instead tended to enhance metabolic flexibility during peak exercise. Furthermore, the expanded intramyocellular triacylglycerol pool in these mice was reduced following exercise in association with preserved HSL phosphorylation, suggesting that HSL may compensate for impaired ATGL action in skeletal muscle during exercise. These data suggest that adipocyte rather than skeletal myocyte ATGL-mediated lipolysis plays a greater role during acute exercise in part because of compensatory mechanisms that maintain lipolysis in muscle, but not adipose tissue, when ATGL is absent.

Serum Autotaxin/ENPP2 correlates with insulin resistance in older humans with obesity.

OBJECTIVE: Autotaxin (ATX) is an adipocyte-derived lysophospholipase D that generates the lipid signaling molecule lysophosphatidic acid (LPA). The ATX/LPA pathway in adipose tissue has recently been implicated in obesity and insulin resistance in animal models, but the role of circulating ATX in humans remains unclear. The aim of the present study was to determine the relationship between serum ATX and insulin resistance. METHODS: Older (60-75 years), nondiabetic human participants with overweight or obesity (BMI 25-37 kg m(-2) ) were characterized for metabolic phenotype including measures of energy, glucose, and lipid homeostasis. The relationship between serum ATX and metabolic parameters was then determined using correlative and predictive statistics. RESULTS: Serum ATX was higher in females than in males. After controlling for sex, serum ATX correlated with multiple measures of adiposity and glucose homeostasis/insulin action. Serum ATX and BMI also independently predicted glucose infusion rate during a hyperinsulinemic euglycemic clamp and homeostatic model assessment of insulin resistance after controlling for sex and medication use. CONCLUSIONS: Serum ATX correlates with and predicts measures of glucose homeostasis and insulin sensitivity in older humans, suggesting that it may be a potential pathogenic factor and/or diagnostic/therapeutic target for insulin resistance in this population.

Effects of acute lipid overload on skeletal muscle insulin resistance, metabolic flexibility, and mitochondrial performance.

We hypothesized that acute lipid-induced insulin resistance would be attenuated in high-oxidative muscle of lean trained (LT) endurance athletes due to their enhanced metabolic flexibility and mitochondrial capacity. Lean sedentary (LS), obese sedentary (OS), and LT participants completed two hyperinsulinemic euglycemic clamp studies with and without (glycerol control) the coinfusion of Intralipid. Metabolic flexibility was measured by indirect calorimetry as the oxidation of fatty acids and glucose during fasted and insulin-stimulated conditions, the latter with and without lipid oversupply. Muscle biopsies were obtained for mitochondrial and insulin-signaling studies. During hyperinsulinemia without lipid, glucose infusion rate (GIR) was lowest in OS due to lower rates of nonoxidative glucose disposal (NOGD), whereas state 4 respiration was increased in all groups. Lipid infusion reduced GIR similarly in all subjects and reduced state 4 respiration. However, in LT subjects, fat oxidation was higher with lipid oversupply, and although glucose oxidation was reduced, NOGD was better preserved compared with LS and OS subjects. Mitochondrial performance was positively associated with better NOGD and insulin sensitivity in both conditions. We conclude that enhanced mitochondrial performance with exercise is related to better metabolic flexibility and insulin sensitivity in response to lipid overload.

Racial differences in peripheral insulin sensitivity and mitochondrial capacity in the absence of obesity.

CONTEXT: African-American women (AAW) have an increased risk of developing type 2 diabetes compared with Caucasian women (CW). Lower insulin sensitivity has been reported in AAW, but the reasons for this racial difference and the contributions of liver versus skeletal muscle are incompletely understood. OBJECTIVE: We tested the hypothesis that young, nonobese AAW manifest lower insulin sensitivity specific to skeletal muscle, not liver, and is accompanied by lower skeletal muscle mitochondrial oxidative capacity. PARTICIPANTS AND MAIN OUTCOME MEASURES: Twenty-two nonobese (body mass index 22.7 ± 3.1 kg/m(2)) AAW and 22 matched CW (body mass index 22.7 ± 3.1 kg/m(2)) underwent characterization of body composition, objectively assessed habitual physical activity, and insulin sensitivity with euglycemic clamps and stable-isotope tracers. Skeletal muscle biopsies were performed for lipid content, fiber typing, and mitochondrial measurements. RESULTS: Peripheral insulin sensitivity was 26% lower in AAW (P < .01), but hepatic insulin sensitivity was similar between groups. Physical activity levels were similar between groups. Lower insulin sensitivity in AAW was not explained by total or central adiposity. Skeletal muscle triglyceride content was similar, but mitochondrial content was lower in AAW. Mitochondrial respiration was 24% lower in AAW and correlated with skeletal muscle insulin sensitivity (r = 0.33, P < .05). CONCLUSION: When compared with CW, AAW have similar hepatic insulin sensitivity but a muscle phenotype characterized by both lower insulin sensitivity and lower mitochondrial oxidative capacity. These observations occur in the absence of obesity and are not explained by physical activity. The only factor associated with lower insulin sensitivity in AAW was mitochondrial oxidative capacity. Because exercise training improves both mitochondrial capacity and insulin sensitivity, we suggest that it may be of particular benefit as a strategy for diabetes prevention in AAW.

Skeletal muscle as a regulator of the longevity protein, Klotho.

Klotho is a powerful longevity protein that has been linked to the prevention of muscle atrophy, osteopenia, and cardiovascular disease. Similar anti-aging effects have also been ascribed to exercise and physical activity. While an association between muscle function and Klotho expression has been previously suggested from longitudinal cohort studies, a direct relationship between circulating Klotho and skeletal muscle has not been investigated. In this paper, we present a review of the literature and preliminary evidence that, together, suggests Klotho expression may be modulated by skeletal muscle activity. Our pilot clinical findings performed in young and aged individuals suggest that circulating Klotho levels are upregulated in response to an acute exercise bout, but that the response may be dependent on fitness level. A similar upregulation of circulating Klotho is also observed in response to an acute exercise in young and old mice, suggesting that this may be a good model for mechanistically probing the role of physical activity on Klotho expression. Finally, we highlight overlapping signaling pathways that are modulated by both Klotho and skeletal muscle and propose potential mechanisms for cross-talk between the two. It is hoped that this review will stimulate further consideration of the relationship between skeletal muscle activity and Klotho expression, potentially leading to important insights into the well-documented systemic anti-aging effects of exercise.

Effect of a sustained reduction in plasma free fatty acid concentration on insulin signalling and inflammation in skeletal muscle from human subjects.

Free fatty acids (FFAs) have been implicated in the pathogenesis of insulin resistance. Reducing plasma FFA concentration in obese and type 2 diabetic (T2DM) subjects improves insulin sensitivity. However, the molecular mechanism by which FFA reduction improves insulin sensitivity in human subjects is not fully understood. In the present study, we tested the hypothesis that pharmacological FFA reduction enhances insulin action by reducing local (muscle) inflammation, leading to improved insulin signalling. Insulin-stimulated total glucose disposal (TGD), plasma FFA species, muscle insulin signalling, IBα protein, c-Jun phosphorylation, inflammatory gene (toll-like receptor 4 and monocyte chemotactic protein 1) expression, and ceramide and diacylglycerol (DAG) content were measured in muscle from a group of obese and T2DM subjects before and after administration of the antilipolytic drug acipimox for 7 days, and the results were compared to lean individuals. We found that obese and T2DM subjects had elevated saturated and unsaturated FFAs in plasma, and acipimox reduced all FFA species. Acipimox-induced reductions in plasma FFAs improved TGD and insulin signalling in obese and T2DM subjects. Acipimox increased IBα protein (an indication of decreased IB kinase-nuclear factor B signalling) in both obese and T2DM subjects, but did not affect c-Jun phosphorylation in any group. Acipimox also decreased inflammatory gene expression, although this reduction only occurred in T2DM subjects. Ceramide and DAG content did not change. To summarize, pharmacological FFA reduction improves insulin signalling in muscle from insulin-resistant subjects. This beneficial effect on insulin action could be related to a decrease in local inflammation. Notably, the improvements in insulin action were more pronounced in T2DM, indicating that these subjects are more susceptible to the toxic effect of FFAs.

Lower thigh subcutaneous and higher visceral abdominal adipose tissue content both contribute to insulin resistance.

It is well known that visceral adipose tissue (VAT) is associated with insulin resistance (IR). Considerable debate remains concerning the potential positive effect of thigh subcutaneous adipose tissue (TSAT). Our objective was to observe whether VAT and TSAT are opposite, synergistic or additive for both peripheral and hepatic IR. Fifty-two volunteers (21 male/31 female) between 30 and 75 years old were recruited from the general population. All subjects were sedentary overweight or obese (mean BMI 33.0 ± 3.4 kg/m(2)). Insulin sensitivity was determined by a 4-h hyperinsulinemic-euglycemic clamp with stable isotope tracer dilution. Total body fat and lean body mass were determined by dual X-ray absorptiometry. Abdominal and mid-thigh adiposity was determined by computed tomography. VAT was negatively associated with peripheral insulin sensitivity, while TSAT, in contrast, was positively associated with peripheral insulin sensitivity. Subjects with a combination of low VAT and high TSAT had the highest insulin sensitivity, subjects with a combination of high VAT and low TSAT were the most insulin resistant. These associations remained significant after adjusting for age and gender. These data confirm that visceral excess abdominal adiposity is associated with IR across a range of middle-age to older men and women, and further suggest that higher thigh subcutaneous fat is favorably associated with better insulin sensitivity. This strongly suggests that these two distinct fat distribution phenotypes should both be considered in IR as important determinants of cardiometabolic risk.

Exercise dose and insulin sensitivity: relevance for diabetes prevention.

PURPOSE: Exercise improves insulin resistance and is a first line for the prevention and treatment of type 2 diabetes. The extent, however, to which these responses are dose dependent is not known. The purpose of this study was to examine whether exercise dose was associated with improvements in insulin sensitivity after 4 months of exercise training in previously sedentary adults. METHODS: Fifty-five healthy volunteers participated in a 16-wk supervised endurance exercise intervention with a pre/postintervention design. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp, peak oxygen uptake by a graded exercise test, and body composition by dual-energy x-ray absorptiometry. The exercise intervention consisted of three to five sessions per week with a minimum of three sessions supervised. A ramped exercise prescription protocol was used to achieve 75% of peak HR for 45 min per session. Exercise dose, expressed as average kilocalories expended per week, was computed as the product of exercise intensity, duration and frequency. RESULTS: Improved insulin sensitivity was significantly related to exercise dose in a graded dose-response relationship. No evidence of threshold or maximal dose-response effect was observed. Age and gender did not influence this dose-response relationship. Exercise intensity was also significantly related to improvements in insulin sensitivity, whereas frequency was not. CONCLUSIONS: This study identifies a graded dose-response relationship between exercise dose and improvements in insulin sensitivity. The implication of this observation is of importance for the adaptation of exercise prescription in clinical situations.