Abstract Obesity is a significant worldwide disease. The vast majority of obese patients contain higher levels of leptin in the circulation, which can be modeled in mice given high fat diet to promote diet induced obesity. Positive energy imbalance (causing obesity) in the presence of higher leptin levels indicates reduced or ineffective leptin action. Hypothalamus neurons are likely the most important leptin target cells that regulate energy balance, as leptin receptor knockout in the hypothalamus induces same degrees of obesity as leptin receptor deficiency in the whole body. It is thought that high fat diet can produce pro-inflammatory by-products in the circulation to impair hypothalamic neuron homeostasis. Neuron homeostasis is a healthy balance of post- mitotic quiescence, survival, and regeneration, and healthy hypothalamus neurons are the material basis for leptin to maintain energy balance. The tumor suppressor pRb is a central regulator of post-mitotic quiescence, survival, regeneration and differentiation. These are the fundamental aspects of cellular (and neuronal) homeostasis. In tumorigenesis, pRb is often functionally inactivated via phosphorylation by cyclin dependent kinases (CDKs). Reactivating pRb by inhibiting its kinases has been a successful cancer therapy rationale, and several CDK4/6 selective inhibitors have recently been approved by the FDA to treat cancers expressing wild type pRb. We discovered that high fat diet induces pRb phosphorylation in mediobasal hypothalamus (MBH) anorexigenic POMC neurons, inactivating pRb and activating E2F1 target gene expression in normally quiescent POMC neurons. Our study demonstrated that stereotaxic injection into the MBH to express an un- phosphorylatable pRb significantly inhibited diet induced obesity in mice. We further demonstrated that FDA approved CdDK4/6 selective inhibitor Abemaciclib, administered by intracerebral ventricular (ICV) or oral delivery, can also inhibit DIO. We propose (Aim 1) to determine molecular mechanisms by which central CDK4/6 inhibition enhances the hypothalamic energy balance circuit to inhibit DIO; (Aim 2) to determine the physiological contexts by which Abemaciclib inhibits DIO and further the pre-clinical analysis for their re- purposing as FDA approved obesity therapeutics. Successful completion of the above aims will shed new light on the etiological causes of obesity, and uncover novel therapies for obesity treatment and train the applicant for a successful career as a physician-scientist.