Cyclin-dependent kinase 4 is a preclinical target for diet-induced obesity.

Niloy Jafar Iqbal,Zhonglei Lu,Liang Zhu,Gary J. Schwartz,Shun Mei Liu,Streamson Chua

doi:10.1172/jci.insight.123000

Abstract

When obesity is caused by consumption of a high-fat diet, the tumor suppressor pRb is phosphoinactivated in the neurons of the mediobasal hypothalamus, a brain area critical for energy-balance regulation. However, the functional relevance of pRb phosphoinactivation in the mediobasal hypothalamus to diet-induced obesity remains unknown. Here, we show that inhibiting pRb phosphorylation in the mediobasal hypothalamus can prevent and treat diet-induced obesity in mice. Expressing an unphosphorylable pRb nonselectively in the mediobasal hypothalamus or conditionally in anorexigenic POMC neurons inhibits diet-induced obesity. Intracerebroventricular delivery of US Food and Drug Administration–approved (FDA-approved) cyclin-dependent kinase 4 (CDK4) inhibitor abemaciclib inhibits pRb phosphorylation in the mediobasal hypothalamus and prevents diet-induced obesity. Oral administration of abemaciclib at doses approved for human use reduces fat mass in diet-induced obese mice by increasing lipid oxidation without significantly reducing lean mass. With analysis of recent literature identifying CDK4 as the most abundantly expressed neuronal CDK in the mediobasal hypothalamus, our work uncovers CDK4 as the major kinase for hypothalamic pRb phosphoinactivation and a highly effective central antiobesity target. As three CDK4/6 inhibitors have recently received FDA approval for life-long breast cancer therapy, our study provides a preclinical basis for their expedient repurposing for obesity management.

Highlights

Diet-induced obesity (DIO) is a growing pandemic with significant comorbidities, such as type 2 diabetes and cardiovascular disease
We found that LSL-pRbΔP–injected POMC-Cre female mice showed significantly reduced body weight gain (Figure 3B) and fat mass gain (Figure 3C) on HFD 35 days after injection, compared with LSL-GFP control–injected mice
Current medical and surgical obesity management treatments all involve varying methods of calorie restriction leading to negative energy balance and are, accompanied by the undesirable but obligatory loss of lean skeletal muscle mass [29]

Summary

Introduction

Diet-induced obesity (DIO) is a growing pandemic with significant comorbidities, such as type 2 diabetes and cardiovascular disease. The vast majority of obese patients lack such mutations but, instead, have elevated leptin in the circulation, which can be modeled in C57BL/6J mice fed a high-fat diet (HFD, 60%KCal from fat) This suggests that reductions in leptin action can cause DIO. It is believed that circulating proinflammatory mediators and other circulating by-products of HFD can directly affect the MBH, with ARC neurons susceptible due to their anatomic proximity to the incomplete blood-brain barrier of the median eminence [4, 5]; once present in the ARC, these circulating factors are thought to directly perturb neuron homeostasis, disrupting neuronal postmitotic quiescence and neuronal turnover [6] This further suggests that the direct disruption of ARC energy-balance neurons by HFD may lead to their subsequent leptin insensitivity during an obesogenic state [7]. We validated this hypothesis using molecular and pharmacological approaches and, in so doing, obtained a preclinical basis for repurposing FDA-approved cyclin-dependent kinase 4/6 (CDK4/6) inhibitors for obesity management

Results

Discussion

Methods