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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]

The liver is the primary metabolic organ involved in the endogenous production of glucose through glycogenolysis and gluconeogenesis. Hepatic glucose production (HGP) is increased via neural‐hormonal mechanisms such as increases in catecholamines. To date, the effects of prior exercise training on the hepatic response to epinephrine have not been fully elucidated. To examine the role of epinephrine signaling on indices of HGP in trained mice, male C57BL/6 mice were either subjected to 12 days of voluntary wheel running or remained sedentary. Epinephrine, or vehicle control, was injected intraperitoneally on day 12 prior to sacrifice with blood glucose being measured 15 min postinjection. Epinephrine caused a larger glucose response in sedentary mice and this was paralleled by a greater reduction in liver glycogen in sedentary compared to trained mice. There was a main effect of epinephrine to increase the phosphorylation of protein kinase‐A (p‐PKA) substrates in the liver, which was driven by increases in the sedentary, but not trained, mice. Similarly, epinephrine‐induced increases in the mRNA expression of hepatic adrenergic receptors (Adra1/2a, Adrb1), and glucose‐6‐phosphatase (G6pc) were greater in sedentary compared to trained mice. The mRNA expression of cAMP‐degrading enzymes phosphodiesterase 3B and 4B (Pde3b, Pde4b) was greater in trained compared to sedentary mice. Taken together, our data suggest that prior exercise training reduces the liver's response to epinephrine. This could be beneficial in the context of training‐induced glycogen sparing during exercise. [ABSTRACT FROM AUTHOR]