Insulin receptors (IRs) and insulin signaling proteins are widely distributed throughout the central nervous system (CNS). To study the physiological role of insulin signaling in the brain, we created mice with a neuron-specific disruption of the IR gene (NIRKO mice). Inactivation of the IR had no impact 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, mild insulin resistance, elevated plasma insulin levels, and hypertriglyceridemia. NIRKO mice also exhibited impaired spermatogenesis and ovarian follicle maturation because of hypothalamic dysregulation of luteinizing hormone. Thus, IR signaling in the CNS plays an important role in regulation of energy disposal, fuel metabolism, and reproduction.

Impairment of insulin signaling in the brain has been linked to neurodegenerative diseases. To test the hypothesis that neuronal insulin resistance contributes to defects in neuronal function, we have performed a detailed analysis of brain͞neuron-specific insulin receptor knockout (NIRKO) mice. We find that NIRKO mice exhibit a complete loss of insulin-mediated activation of phosphatidylinositol 3-kinase and inhibition of neuronal apoptosis. In intact animals, this loss results in markedly reduced phosphorylation of Akt and GSK3␤, leading to substantially increased phosphorylation of the microtubule-associated protein Tau, a hallmark of neurodegenerative diseases. Nevertheless, these animals exhibit no alteration in neuronal proliferation͞survival, memory, or basal brain glucose metabolism. Thus, lack of insulin signaling in the brain may lead to changes in Akt and GSK3␤ activity and Tau hyperphosphorylation but must interact with other mechanisms for development of Alzheimer's disease.

A Pro115Gln mutation in PPARgamma2 accelerates the differentiation of adipocytes and may cause obesity.