Exercise alone is often ineffective for treating obesity despite the associated increase in metabolic requirements. Decreased nonexercise physical activity has been implicated in this resistance to weight loss, but the mechanisms responsible are unclear. We quantified the metabolic cost of nonexercise activity, or "off-wheel" activity (OWA), and voluntary wheel running (VWR) and examined whether changes in OWA during VWR altered energy balance in chow-fed C57BL/6J mice ( = 12). Energy expenditure (EE), energy intake, and behavior (VWR and OWA) were continuously monitored for 4 days with locked running wheels followed by 9 days with unlocked running wheels. Unlocking the running wheels increased EE as a function of VWR distance. The metabolic cost of exercise (kcal/m traveled) decreased with increasing VWR speed. Unlocking the wheel led to a negative energy balance but also decreased OWA, which was predicted to mitigate the expected change in energy balance by ∼45%. A novel behavioral circuit involved repeated bouts of VWR, and roaming was discovered and represented novel predictors of VWR behavior. The integrated analysis described here reveals that the weight loss effects of voluntary exercise can be countered by a reduction in nonexercise activity.
Integrins are a family of cell surface receptors that bind to the extracellular matrix (ECM). ECM‐integrin connections are necessary for skeletal muscle (SkM) contractile function, but also contribute to diet‐induced insulin resistance (IR). Parvins are key proteins in the integrin signaling pathway, with α‐parvin being the most highly expressed in SkM. α‐parvin is a critical regulator of cytoskeletal dynamics needed for organelle and protein function and localization within the cell; however, its function in SkM in vivo has not been previously explored. In these studies, we tested the hypothesis that SkM α‐parvin is a requisite component of the ECM‐integrin signaling that regulates exercise tolerance and glucose homeostasis.SkM‐specific α‐parvin knockout mice (mPar‐KO) were generated using α‐parvin floxed mice and mice expressing Cre recombinase on the human α‐skeletal actin (HSA) promoter. Studies were performed on littermate α‐parvin flox/flox mice with (KO) or without (WT) Cre recombinase. Fasting blood glucose was measured at 6 weeks of age in chow‐fed mice. At 12 weeks of age, oral glucose tolerance testing (2 g/kg bodyweight) was performed on 5‐hr fasted chow or 6‐week high fat diet (HFD; 60% calories from fat) fed mice. Whole body indirect calorimetry and contextual behavior mapping of lean and HFD‐fed mice was performed at 18 weeks of age in a Promethion Metabolic Analyzer. In a cohort of 18‐week old chow‐fed mice, forced exercise performance was assessed using a graded treadmill stress test and voluntary wheel running (VWR) distance and efficiency (kcal/m traveled) were measured during indirect calorimetry experiments.6‐week old mPar‐KO mice had normal body composition but fasting hyperglycemia compared to WT littermates (n=15/group). 12‐week old chow‐fed mPar‐KO mice were glucose intolerant despite normal fasting glucose (n=5/group). No differences in fasting glucose or glucose tolerance were observed in HF‐fed WT or mPar‐KO mice (n=16–18/group). Forced exercise performance was reduced in mPar‐KO mice. Furthermore, VWR distance was ~80% lower in mPar‐KO mice (n=7–9/group). mPar‐KO mice also had an increased metabolic cost of exercise during VWR that was accompanied by longer bouts of off‐wheel roaming. mPar‐KO mice with a running wheel had an elevated respiratory quotient at rest, indicating increased fat utilization. HFD‐fed mPar‐KO mice had no differences in metabolism or activity compared to WT littermates.These data demonstrate that loss of SkM α‐parvin impairs exercise tolerance and elicits an increase in resting whole body reliance on fatty acids. In contrast to previous studies showing that SkM integrins contribute to diet‐induced IR, these data demonstrate that SkM α‐parvin is necessary for maintaining normal glucose homeostasis in chow‐fed mice and does not contribute to HFD‐induced IR. Collectively, these experiments suggest that SkM α‐parvin is a point of divergence for the beneficial effects of ECM‐integrin connections on exercise and deleterious effects on glucose homeostasis.Support or Funding InformationD.S.L. (AHA 16POST29910001); D.H.W. (NIH DK054902, DK059637 and DK076169).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Diseases of metabolism pose an increasing threat to public health that has led to greater demand for effective treatments. Obesity is a highly prevalent metabolic disease that afflicts over 100 million Americans and increases the risk of developing diabetes and cardiovascular disease. Lifestyle modifications that incorporate exercise are a standard prescription for obesity, but its effectiveness is limited due to variability in compliance and physiological adaptations (e.g. compensatory increases in energy intake). Previous studies have shown that voluntary exercise fails to induce weight loss in high fat fed mice, but little is known regarding the onset of exercise. Here, we tested the hypothesis that chronic overnutrition from high fat feeding will mitigate the compensatory increase in food intake that commonly accompanies increased energy expenditure from voluntary exercise.Starting at 12 weeks of age, male C57BL/6J mice were weight matched, singly housed and fed a chow (n=8) or high fat diet (HFD; 60% calories from fat; n=6) for 4 weeks. At 18 weeks of age, mice were housed in a Promethion Metabolic Analyzer to measure energy expenditure, food intake and physical activity. Experiments were performed at 21°C with running wheels locked for four days then unlocked for the subsequent nine days. Body composition was assessed both prior to and immediately following indirect calorimetry experiments. Ethoscan (Sable Systems) analysis was performed to examine voluntary wheel running (VWR) distance, duration and speed and measured the time and distance for off‐wheel activities (i.e. roaming and feeding).HF‐fed mice were heavier (WT: 26.9 ± 1.1 vs. HF: 36.8 ± 4.2 g; p < 0.05) and had greater fat mass (WT: 3.5 ± 0.6 vs. HF: 11.1 ± 3.1 g; p < 0.05) than chow‐fed mice prior to energy balance studies. VWR caused a decrease in whole body (WT: −0.3 ± 0.8 vs. HF: −4.0 ± 1.3 g; p > 0.05) and fat mass (WT: 0.3 ± 0.6 vs. HF: −3.0 ± 0.9 g; p < 0.05) in HFD‐fed, but not in chow‐fed mice. VWR distance, duration, and speed were not affected by diet. VWR increased energy expenditure (EE) with both diets equally, but energy intake (EI) only increased in chow‐fed mice. VWR decreased overall off‐wheel activity (OWA) regardless of diet.These data demonstrate that 9 days of VWR cause weight loss in HFD‐fed mice but not mice fed a chow‐diet. Because VWR did not vary between diets, the efficacy of VWR in HFD‐fed mice could instead be attributed to resistance to specific behavioral compensations (i.e. increased food intake) that occur with the introduction of VWR in lean mice.Support or Funding InformationDSL (16POST29910001); D.H.W. (NIH DK054902 and DK076169)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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