Lipoprotein Receptor LRP1 Regulates Leptin Signaling and Energy Homeostasis in the Adult Central Nervous System

Abstract

Obesity is a growing epidemic characterized by excess fat storage in adipocytes. Although lipoprotein receptors play important roles in lipid uptake, their role in controlling food intake and obesity is not known. Here we show that the lipoprotein receptor LRP1 regulates leptin signaling and energy homeostasis. Conditional deletion of the Lrp1 gene in the brain resulted in an obese phenotype characterized by increased food intake, decreased energy consumption, and decreased leptin signaling. LRP1 directly binds to leptin and the leptin receptor complex and is required for leptin receptor phosphorylation and Stat3 activation. We further showed that deletion of the Lrp1 gene specifically in the hypothalamus by Cre lentivirus injection is sufficient to trigger accelerated weight gain. Together, our results demonstrate that the lipoprotein receptor LRP1, which is critical in lipid metabolism, also regulates food intake and energy homeostasis in the adult central nervous system. The World Health Organization estimates that at least 1 in 10 adults worldwide are obese, and in some western countries, a far greater percentage (25% or more) is affected. Obesity is a serious concern because it increases the risk of cardiovascular disease, type 2 diabetes, and some cancers, among other health problems. Despite recent advances in understanding the disease mechanism, effective treatments are still lacking. Lipoprotein receptors play critical roles in lipid metabolism, but their potential roles in controlling food intake and obesity in the central nervous system have not been examined. Here we show that deletion of LRP1, a member of the LDL (low density lipoprotein) receptor family, in the adult mouse brain results in obese phenotype characterized by increased food intake, decreased energy consumption and decreased leptin signaling. We further show that deletion of the Lrp1 gene specifically in the hypothalamus (a region of the brain) by using Cre lentivirus injection is sufficient to trigger accelerated weight gain. Together, our results present a novel function of LRP1: the direct regulation of leptin signaling and energy balance in the adult central nervous system. Hence, LRP1 represents a very promising new therapeutic target for the design of innovative and more effective therapies for obesity.