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Updated: Feb 5, 2026
Identification of Cyclin-dependent Kinase 1 Specific Phosphorylation Sites by an In Vitro Kinase Assay
Published on: May 3, 2018
Cyclin-dependent kinase 4 is a preclinical target for diet-induced obesity
Niloy Jafar Iqbal1, Zhonglei Lu1, Shun Mei Liu2
1Department of Developmental and Molecular Biology and.
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.
Insights
Inhibiting tumor suppressor pRb phosphorylation in the brain
Area of Science:
- Neuroscience
- Metabolic Regulation
- Oncology Drug Repurposing
Background:
- Obesity induced by high-fat diets causes tumor suppressor pRb phosphoinactivation in the mediobasal hypothalamus.
- The functional significance of this pRb inactivation in diet-induced obesity is not understood.
- The mediobasal hypothalamus is crucial for regulating energy balance.
Purpose of the Study:
- To investigate the role of pRb phosphoinactivation in diet-induced obesity.
- To explore the potential of targeting pRb phosphorylation for obesity treatment.
Main Methods:
- Mice models were used to study diet-induced obesity.
- pRb phosphorylation was inhibited in the mediobasal hypothalamus using genetic manipulation and pharmacological agents.
- The effects on body weight, fat mass, and lipid oxidation were assessed.
- Cyclin-dependent kinase 4 (CDK4) was identified as the primary kinase responsible for pRb phosphoinactivation.
Main Results:
- Inhibiting pRb phosphorylation in the mediobasal hypothalamus prevented and treated diet-induced obesity in mice.
- Genetic inhibition of pRb in POMC neurons also reduced obesity.
- Administration of the FDA-approved CDK4 inhibitor abemaciclib prevented diet-induced obesity and reduced fat mass in obese mice.
- Abemaciclib increased lipid oxidation without affecting lean mass.
Conclusions:
- CDK4 is the major kinase for hypothalamic pRb phosphoinactivation and a viable therapeutic target for obesity.
- FDA-approved CDK4/6 inhibitors show promise for repurposing in obesity management.
- This study provides a preclinical foundation for using these drugs to combat obesity.
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