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Key points: Ambient cold exposure is often regarded as a promising anti‐obesity treatment in mice.However, most preclinical studies aimed at treating obesity via cold‐induced thermogenesis have been confounded by subthermoneutral housing temperatures. Therefore, the ability of ambient cold to combat diet‐induced obesity in mice housed under humanized thermoneutral conditions is currently unknown.Moreover, mammals such as mice are rarely exposed to chronic ambient cold without reprieve, yet mice are often subjected to experimental conditions of chronic rather than intermittent cold exposure (ICE), despite ICE being more physiologically relevant.In the present study, we provide novel evidence that thermoneutral housing uncouples the effects of ICE on glucose and energy homeostasis suggesting that ICE, despite improving glucose tolerance, is not an effective obesity treatment when mice are housed under humanized thermoneutral conditions. The present study examines whether a physiologically relevant model of ambient cold exposure, intermittent cold exposure (ICE), could ameliorate the metabolic impairments of diet‐induced obesity in male and female mice housed under humanized thermoneutral conditions. Male and female C57BL/6J mice housed at thermoneutrality (29°C) were fed a low‐fat diet or high‐fat diet for 6 weeks before being weight matched into groups that remained unperturbed or underwent ICE for 4 weeks (4°C for 60 min day–1; 5 days week–1) when being maintained on their respective diets. ICE induced rapid and persistent hyperphagia exacerbating rather than attenuating high‐fat diet‐induced obesity over time. These ICE‐induced increases in adiposity were found to be energy intake‐dependent via pair‐feeding. Despite exacerbating high‐fat diet‐induced obesity, ICE improved glucose tolerance, independent of diet, in a sex‐specific manner. The effects of ICE on glucose tolerance were not attributed to improvements in whole‐body insulin tolerance, tissue specific insulin action, nor differences in markers of hepatic insulin clearance or pancreatic beta cell proliferation. Instead, ICE increased serum concentrations of insulin and C‐peptide in response to glucose, suggesting that ICE may improve glucose tolerance by potentiating pancreatic glucose‐stimulated insulin secretion. These data suggest that ICE, despite improving glucose tolerance, is not an effective obesity treatment in mice housed under humanized conditions. [ABSTRACT FROM AUTHOR]

Growth differentiating factor-15 (GDF15) is expressed, and secreted, from a wide range of tissues and serves as a marker of cellular stress. A key transcriptional regulator of this hormone is the endoplasmic reticulum stress protein, CHOP (C/EBP homologous protein). Exercise increases GDF15 levels but the underlying mechanisms of this are not known. To test whether CHOP regulates GDF15 during exercise, we used various models of altered ER stress. We examined the effects of acute exercise on circulating GDF15 and Gdf15 mRNA expression in liver, triceps skeletal muscle, and epididymal white adipose tissue and examined the GDF15 response to acute exercise in lean and high-fat diet-induced obese mice, sedentary and exercise trained mice, and CHOP-deficient mice. We found that obesity augments exercise-induced circulating GDF15 although ER stress markers were similar in lean and obese mice. Exercise-induced GDF15 was increased in trained and sedentary mice that ran at the same relative exercise intensity, despite trained mice being protected against increased markers of ER stress. Finally, exercise-induced increases in GDF15 at the tissue and whole body level were intact in CHOP-deficient mice. Together, these results provide evidence that exercise-induced GDF15 expression and secretion occurs independent of ER stress/CHOP. [ABSTRACT FROM AUTHOR]