# Tumor Suppressor pRb is a Novel Target for Hypothalamic Inhibition of Diet Induced Obesity

> **NIH NIH F30** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $48,217

## Abstract

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.

## Key facts

- **NIH application ID:** 9957097
- **Project number:** 5F30DK116532-04
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Niloy Iqbal
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $48,217
- **Award type:** 5
- **Project period:** 2018-07-01 → 2021-05-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9957097

## Citation

> US National Institutes of Health, RePORTER application 9957097, Tumor Suppressor pRb is a Novel Target for Hypothalamic Inhibition of Diet Induced Obesity (5F30DK116532-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9957097. Licensed CC0.

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