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Context Housing temperature is a critical regulator of mouse metabolism and thermoneutral housing can improve model translation to humans. However, the impact of housing temperature on the ability of wheel running exercise training to rescue the detrimental effect of diet-induced obese mice is currently not fully understood. Objective To investigate how housing temperature affects muscle metabolism in obese mice with regard to calcium handling and exercise training (ET) adaptations in skeletal muscle, and benefits of ET on adiposity and glucometabolic parameters. Methods Lean or obese female mice were housed at standard ambient temperature (22 °C) or thermoneutrality (30 °C) with/without access to running wheels. The metabolic phenotype was investigated using glucose tolerance tests, indirect calorimetry, and body composition. Molecular muscle adaptations were measured using immunoblotting, qPCR, and spectrophotometric/fluorescent assays. Results Obese female mice housed at 22 °C showed lower adiposity, lower circulating insulin levels, improved glucose tolerance, and elevated basal metabolic rate compared to 30 °C housing. Mice exposed to voluntary wheel running exhibited a larger fat loss and higher metabolic rate at 22 °C housing compared to thermoneutrality. In obese female mice, glucose tolerance improved after ET independent of housing temperature. Independent of diet and training, 22 °C housing increased skeletal muscle sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) activity. Additionally, housing at 22 °C elevated the induction of training-responsive muscle proteins in obese mice. Conclusion Our findings highlight that housing temperature significantly influences adiposity, insulin sensitivity, muscle physiology, and exercise adaptations in diet-induced obese female mice. [ABSTRACT FROM AUTHOR]

The molecular events governing skeletal muscle glucose uptake have pharmacological potential for managing insulin resistance in conditions such as obesity, diabetes, and cancer. With no current pharmacological treatments to target skeletal muscle insulin sensitivity, there is an unmet need to identify the molecular mechanisms that control insulin sensitivity in skeletal muscle. Here, the Rho guanine dissociation inhibitor α (RhoGDIα) is identified as a point of control in the regulation of insulin sensitivity. In skeletal muscle cells, RhoGDIα interacted with, and thereby inhibited, the Rho GTPase Rac1. In response to insulin, RhoGDIα was phosphorylated at S101 and Rac1 dissociated from RhoGDIα to facilitate skeletal muscle GLUT4 translocation. Accordingly, siRNA- mediated RhoGDIα depletion increased Rac1 activity and elevated GLUT4 translocation. Consistent with RhoGDIα's inhibitory effect, rAAV- mediated RhoGDIα overexpression in mouse muscle decreased insulin- stimulated glucose uptake and was detrimental to whole- body glucose tolerance. Aligning with RhoGDIα's negative role in insulin sensitivity, RhoGDIα protein content was elevated in skeletal muscle from insulin- resistant patients with type 2 diabetes. These data identify RhoGDIα as a clinically relevant controller of skeletal muscle insulin sensitivity and whole- body glucose homeostasis, mechanistically by modulating Rac1 activity. [ABSTRACT FROM AUTHOR]