The Statin Target Hmgcr Regulates Energy Metabolism and Food Intake through Central Mechanisms

Abstract

The statin drug target, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), is strongly linked to body mass index (BMI), yet how HMGCR influences BMI is not understood. In mammals, studies of peripheral HMGCR have not clearly identified a role in BMI maintenance and, despite considerable central nervous system expression, a function for central HMGCR has not been determined. Similar to mammals, Hmgcr is highly expressed in the <i>Drosophila melanogaster</i> brain. Therefore, genetic and pharmacological studies were performed to identify how central <i>Hmgcr</i> regulates <i>Drosophila</i> energy metabolism and feeding behavior. We found that inhibiting <i>Hmgcr</i>, in insulin-producing cells of the <i>Drosophila pars intercerebralis</i> (PI), the fly hypothalamic equivalent, significantly reduces the expression of insulin-like peptides, severely decreasing insulin signaling. In fact, reducing <i>Hmgcr</i> expression throughout development causes decreased body size, increased lipid storage, hyperglycemia, and hyperphagia. Furthermore, the <i>Hmgcr</i> induced hyperphagia phenotype requires a conserved insulin-regulated α-glucosidase, <i>target of brain insulin</i> (<i>tobi</i>). In rats and mice, acute inhibition of hypothalamic Hmgcr activity stimulates food intake. This study presents evidence of how central Hmgcr regulation of metabolism and food intake could influence BMI.