Over-expression of miR-34c leads to early-life visceral fat accumulation and insulin resistance.

Overweight children and adolescents are at high risk for adult and late life obesity. This report investigates some underlying mechanisms contributing to obesity during early life in an animal model. We generated a strain of transgenic mice, cU2, overexpressing human microRNA 34c, a microRNA functionally implicated in adipogenesis. Male and female cU2 mice exhibit significant weight gain, accompanied by marked increase in abdominal fat mass and metabolic abnormalities, including reduction of both glucose clearance rate and insulin sensitivity, as early as two months of age. Adipogenesis derailment at this early age is suggested by decreased expression of adiponectin, the fat mass and obesity-associated gene, and the adiponectin receptor R1, coupled with a reduction of the brown fat biomarker PAT2 and the adipogenesis inhibitor SIRT1. Notably, adiponectin is an important adipokine and an essential regulator of glucose and fatty acid homeostasis. cU2 mice may provide a crucial animal model for investigating the role of miR-34c in early onset insulin resistance and visceral fat mass increase, contributing to accelerated body weight gain and metabolic disorders. Intervention in this dysregulation may open a new preventive strategy to control early-life weight gain and abnormal insulin resistance, and thus prevalent adult and late life obesity.