Intermittent Ambient Cold Exposure Is Not an Effective Obesity Treatment in Mice Housed at Thermoneutrality

Abstract

Chronic ambient cold exposure has been regarded as a promising obesity treatment given it potently increases energy expenditure. However, few mammals are chronically exposed to cold ambient conditions without reprieve highlighting the need to determine whether more physiologically relevant interventions, such as intermittent ambient cold exposure, could be utilized to treat obesity. Moreover, most preclinical cold exposure work to date has been conducted at housing temperatures below thermoneutrality, unintentionally confounding metabolic outcomes. As such, this study examined whether intermittent ambient cold exposure could abrogate the metabolic impairments of diet‐induced obesity, in mice housed under humanized thermoneutral conditions. Eight‐week‐old male and female C57Bl/6J mice (n ≥ 40/sex) were singly housed, acclimated to thermoneutrality (30 °C), and then weight matched into low‐fat (LFD; 10% kcal from fat) or high‐fat (HFD; 45% kcal from fat) diet fed groups. Male and female mice were given six weeks to feed on their respective diets before being weight‐matched into groups that remained unperturbed (CTRL) or underwent intermittent ambient cold exposure (ICE), respectively. ICE consisted of exposure to 4 °C for one hour/day, five days/week, for four weeks. Mice remained on their respective diets for the entire four‐week intervention period, during which time glucose and insulin tolerance were assessed. Following the intervention mice were sedated with sodium pentobarbital and sacrificed by exsanguination of the heart. The epididymal and inguinal white adipose tissue depots (eWAT and iWAT, respectively), the interscapular brown adipose tissue depot (BAT), as well as the liver, triceps, and hypothalamus were excised, snap‐frozen in liquid nitrogen, and stored at ‐80 °C. ICE induced hyperphagia that was rapid in onset and persistent, occurring with every exposure independent of diet. Over time, this exacerbated rather than attenuated HFD‐induced obesity in both male and female mice, increasing BAT, eWAT, and iWAT mass as well as cellular lipid deposition. Pair‐feeding revealed that these ICE‐induced increases in adiposity were energy intake dependent, as the pair‐fed, but not ad libitum fed, HFD‐ICE group was protected from ICE‐induced increases in body mass. Despite exacerbating HFD‐induced obesity, ICE improved glucose tolerance, independent of diet, in a sex‐dependent manner. The effects of ICE on glucose tolerance were not attributed to improvements in whole‐body insulin tolerance, tissue specific insulin action, nor to differences in hepatic insulin clearance. 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. Taken together, this data suggests that intermittent ambient cold exposure, despite improving glucose tolerance, is not an effective obesity treatment in mice housed under humanized conditions.