Cyclin-dependent kinase 4/6 inhibitors require an arcuate to paraventricular hypothalamus melanocortin circuit to treat diet-induced obesity.

The arcuate nucleus (ARC) of the hypothalamus comprises two antagonistic neuron populations critical for energy balance: the anorexigenic pro-opiomelanocortin (POMC) and the orexigenic agouti-related peptide (AgRP) neurons, which act as agonists and antagonists for neurons expressing the type IV melanocortin receptor (MC4R). MC4R activation increases energy expenditure and decreases food intake during positive energy balance states to prevent diet-induced obesity (DIO). Work from our group identified aberrant neuronal cell cycle events as both a novel biomarker and druggable target in the ARC for the treatment of DIO, demonstrating pharmacological restoration of retinoblastoma protein function in the ARC using cyclin-dependent kinase 4/6 (CDK4/6) inhibitors could treat DIO in mice by increasing lipid oxidation to selectively decrease fat mass. However, the role of CDK4/6 inhibitors on food intake was not examined. 4-week-old MC4R-lox mice were continuously administered high fat diet (60% Kcal fat). At 8 weeks of age, animals were administered 60 mg/kg abemaciclib orally or a saline control and monitored every two weeks for fat mass changes by MRI. At 11 weeks of age, all animals were injected bi-laterally in the paraventricular hypothalamus with AAV8 serotype virus expressing a Cre-mCherry and monitored for another five weeks. Restoration of MC4R expression in the PVN reduced food intake in hyperphagic-obese mice when given CDK4/6 inhibitor therapy. The reduced food intake was responsible for reduced fat mass in mice treated with abemaciclib. These results indicate that targeting POMC neurons could be an effective strategy in treating diet related obesity.