Thermoneutral housing increases the obesogenic phenotype of mice, while some effects of exercise are reduced

Abstract

Introduction: Mice are extensively used to investigate the molecular foundations of obesity and the beneficial effect of exercise training (ET). Mice are most often housed at ambient temperature, ~22°C, which is below their thermoneutral environment (~30°C). Mild cold stress at ambient temperature accelerates mouse metabolic rate and may confound translation of results to humans. Aiming to determine the metabolic adaptations of ET in an obesogenic environment, we hypothesized that thermoneutral housing would increase adiposity during high-fat feeding. Moreover, thermoneutral housing would blunt the effects of ET by relieving the added cold stress. Methods: After temperature acclimatization (3 weeks, 22°C vs. 30°C), C57BL/6J mice (n=68, ♀, Age: 11 weeks) were dual-housed for 8 weeks receiving a chow diet or a 60%E high-fat diet (HFD). HFD mice were then separated into two additional groups with access to voluntary wheel running for another 8 weeks. Metabolic parameters were measured using magnetic resonance imaging, indirect calorimetry, glucose tolerance tests, and maximal running capacity on treadmill. Brown and white adipose tissues and gastrocnemius muscle mRNA and protein content were analyzed using qPCR and immunoblotting analyses, respectively. Results: In chow-fed mice, thermoneutral housing decreased metabolic rate (VO2), fasting plasma glucose, and thermogenic genes in adipose tissue depots, without changes in skeletal muscle mitochondrial protein content compared to 22°C. In HFD mice, thermoneutral housing increased fat mass, induced glucose intolerance, and fasting plasma insulin levels compared to 22°C housing. This was despite decreased food intake and metabolic rate compared to HFD mice housed at 22°C. ET mice improved the exercise capacity and glucose tolerance independent of housing temperature. Interestingly, while ET at 30°C prevented further fat gain during the intervention, ET at 22°C decreased fat mass. Moreover, only ET at 22°C increased the metabolic rate during the active phase. Gene expression responded similarly to ET independent of housing temperature in adipose tissue depots. ET induced GLUT4, peroxiredoxin 2 and pyruvate dehydrogenase protein content to a lesser extent in muscle at 30°C housing. Conclusion: Adaptations to diet-induced obesity and ET in mice critically depend upon housing temperature. Our findings underscore housing temperature as a key consideration in research related the beneficial effect of exercise in an obesogenic environment. Disclosure of funding: SHR is supported by the Lundbeck Foundation and Independent Research Fund Denmark. LS and EAR are supported by the Novo Nordisk Foundation and Independent Research Fund Denmark. IK is supported by the Novo Nordisk Foundation. This is the full abstract presented at the American Physiology Summit 2023 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.