Daily cold exposure – A therapy to stimulate beige fat or a recipe for diabesity in mice?

Abstract

Since the discovery that cold exposure stimulates browning of human white fat, clinical trials have been investigating cold exposure as a potential treatment for obesity. However, cold exposure is a form of stress and might be expected to have some adverse consequences. We thus investigated the effects of chronic daily cold exposure (standing in iced water for 1 hour/day for 6 weeks) on food intake, body weight and serum glucose in male C57/Bl6 mice fed either normal chow or a high fat diet (HFD), and potential neuronal pathways for any effects. Chronic daily cold exposure increased energy intake, body weight and serum glucose levels compared to control values, significantly so in mice on the HFD. One hour after the final cold exposure in mice on the HFD, c-fos immunoreactivity was significantly increased in the medial amygdala compared to control mice on the HFD, indicating neuronal activation in this brain region. Notably, 60% of these c-fos-immunopositive neurons also expressed the anorexigenic peptide neuropeptide Y (NPY), and NPY mRNA and peptide levels were significantly increased in the medial amygdala of cold-exposed versus control mice. Interestingly, cold exposure also led to a significant decrease in ventromedial hypothalamic (VMH) mRNA levels of the anorexigenic brain-derived neurotrophic factor (BDNF), and an increase in mRNA for growth hormone releasing hormone (GHRH), which stimulates circulating glucose levels. Taken together, we thus hypothesize that NPYergic neurons in the amygdala are activated by chronic cold exposure combined with a high fat diet, leading via direct or indirect neuronal pathways to decreased BDNF and increased GHRH mRNA expression in the VMH, in turn contributing to positive energy balance and deregulated glucose homeostasis. Further work is required to test this hypothesis, but such potential adverse effects should be taken into consideration whenmanipulating temperature to stimulate the browning of white fat.