The Brain Expresses the Insulin and Ins2+/- Mice Display Increased High-fat Food Intake

It is well established that insulin can act in the brain as a satiety factor. However, the source of insulin acting in the brain has been subject of much debate. Though, insulin can cross the blood-brain barrier from the circulation, we confirmed previous reports of local Ins2 production in the brain using Ins2-/- negative controls, Ins2bgal knock-in alleles, and a number of complementary techniques. Taqman RT-qPCR, deep sequencing, histone methylation enhancer analysis, immunohistochemistry all demonstrated that Ins2, but not Ins1, is expressed in several brain regions, including the hippocampus, cerebral cortex, olfactory nucleus and cerebellum. Since these regions are known to control and project to feeding, reward and memory centers, we hypothesized that central Ins2 regulates food intake or food preference. Indeed, mice with reduced Ins2 gene dosage (Ins2+/-) exhibited weight gain and increased food intake on the high-fat diet, but not a control diet. No significant differences were observed in circulating insulin levels, glucose homeostasis, insulin sensitivity, or energy expenditure. These data support a model whereby insulin expressed locally in the brain, at levels too low to affect circulating insulin, plays a critical role as a diet-specific satiety factor.