Role of brain insulin receptor in control of body weight and reproduction

Insulin receptors (IRs) and insulin signaling proteins are widely distribut ed throughout the central nervous system (CNS). To study the physiological role of insulin signaling in the brain, we created mice with a neuron-speci fic disruption of the IR gene (NIRKO mice), Inactivation of the IR had no i mpact on brain development or neuronal survival. However, female NIRKO mice showed increased food intake, and both male and female mice developed diet -sensitive obesity with increases in body fat and plasma leptin levels, mil d insulin resistance, elevated plasma insulin Levels, and hypertriglyceride mia. NIRKO mice also exhibited impaired spermatogenesis and ovarian follicl e maturation because of hypothalamic dysregulation of luteinizing hormone. Thus, IR signaling in the CNS plays an important role in regulation of ener gy disposal, fuel metabolism, and reproduction.