Relaxin Treatment Reverses Insulin Resistance in High Fat-Fed Mice Running title: Relaxin Reverses Insulin Resistance

The endogenous hormone relaxin increases vascular reactivity and angiogenesis. We demonstrate that acute relaxin infusion in lean C57BL/6J mice enhances skeletal muscle perfusion and augments muscle glucose uptake during a hyperinsulinemic-euglycemic clamp. However, acute effect was absent in mice fed a high fat (HF) diet for 13 weeks. In contrast, mice fed a HF diet for 13 weeks and continuously treated with relaxin for the final 3 weeks of the diet exhibit decreased fasting glucose. Insulin-stimulated whole-body glucose disappearance and percent suppression of hepatic glucose production are corrected by chronic relaxin. The increase in peripheral glucose utilization is a result of augmented in vivo skeletal muscle glucose uptake. Relaxin intervention improves endothelial-dependent vascular reactivity and induces a 2-fold proliferation in skeletal muscle capillarity. The metabolic effects of the treatment are not attributed to changes in myocellular insulin signaling. Relaxin intervention reverses the accumulation of collagen-III in the liver and collagen-III and -IV in the heart induced by high fat-feeding. These studies show the potential of relaxin in the treatment of diet-induced insulin resistance and vascular dysfunction. Relaxin provides a novel therapeutic approach targeting the extramyocellular barriers to insulin action, which are critical to the pathogenesis of insulin resistance. Page 2 of 35 Diabetes