Stress and diet‐induced metabolic syndrome in mice: a “humanized” model of obesity

Obesity is exponentially increasing and the existing genetic models of obesity fall short of unraveling and treating this multi‐faceted disease. Previously, our lab found that sympathetic transmitter neuropeptide Y (NPY) is potently angiogenic in adipose tissue and stimulates preadipocyte proliferation and differentiation into lipid‐filled adipocytes via its Y2 receptors (Rs) which are up‐regulated in the process. Subcutaneous administration of a NPY pellet or chronic cold stress exposure (ST) (.5cm 4oC water/1hr/daily/14days), known to increase NPY release, increased fat and its vascularization. Here, we tested if ST superimposed on a high fat diet (HF) alters metabolism. Mice fed HF had 20% more total body fat, fasting hyperglycemia, impaired glucose tolerance, hyperleptinemia, and increased levels of resistin and corticosterone compared to non‐stressed and standard chow fed mice. HF+ST mice had a 50% increase in abdominal fat without increasing food intake. ST in HF‐fed mice augmented these changes and also NPY and mean arterial pressure (by telemetry), and disrupted diurnal rhythms. HF+ST mice also showed a decrease in leptin and corticosterone. ST, like the NPY pellet previously, increased the number of small adipocytes in the subcutaneous abdominal fat pads, resembling NPY’s proliferative effect on preadipocytes in vitro. In ST and HF mice, but not HF diet alone, there was increased Y2R expression in the subcutaneous abdominal fat, suggesting that these angiogenic and adipogenic Rs are activated by stress. Thus, this study suggests that chronic stress in conjunction with a HF diet promotes obesity and the metabolic syndrome by activating the sympathetic release of NPY, which, via its endothelial and preadipocytes Y2Rs, stimulates both angiogenesis and adipogenesis.