Role of Brain Insulin Receptor in Control of Body Weight and Reproduction

TLDR

Insulin receptors and signaling proteins are widely distributed throughout the central nervous system. The study aimed to investigate the physiological role of brain insulin signaling by generating mice with a neuron‑specific insulin receptor knockout. The authors created neuron‑specific insulin receptor knockout mice (NIRKO) to assess the effects of IR loss in the brain. Disruption of the insulin receptor in neurons does not affect brain development but leads to diet‑sensitive obesity, increased food intake, mild insulin resistance, hypertriglyceridemia, elevated leptin, and impaired spermatogenesis and ovarian follicle maturation, underscoring the CNS insulin receptor’s role in energy balance and reproduction.

Abstract

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.