# Rho-kinase signaling in energy balance

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2024 · $432,250

## Abstract

The melanocortin signaling pathway has emerged as a key signaling system regulating normal body-weight
homeostasis and energy balance. Activation of melanocortin-4 receptor (MC4R) by ?-MSH reduces fat stores
by decreasing food intake and increasing energy expenditure. Yet, the cellular mechanism(s) underlying
melanocortin actions remains poorly understood. Our preliminary data point to the importance of ROCK1 action
in MC4R-expressing neurons that is significant for the development of obesity in mice and humans. We found
that selective deletion of ROCK1 in MC4R-expressing or Sim1-expressing neurons significantly increases body
weight and adiposity. Interestingly, we found that ROCK1 activation in MC4R-containing neurons is required for
the anorexigenic action of melanocortin through suppressing AMPK. Evidence demonstrates that UBE2O is an
upstream mediator of AMPK that targets ?2AMPK for ubiquitination and degradation. Furthermore, we observed
that human ROCK1 variant (2824G<A, E942K) from a consanguineous population in Pakistan displays severe
obesity, and the mutant mice carrying the human ROCK1 mutation (E942K) are obese. We therefore hypothesize
that ROCK1 in MC4R-expressing neurons is necessary for the metabolic regulation of normal body-weight
homeostasis and energy balance and is linked with the UBE2O-AMPK signaling cascade for anorexigenic action
of melanocortin. Thus, an impaired ROCK1 signaling axis leads to energy imbalance, causing obesity. To this
end, we will (i) elucidate the functional importance of ROCK1 in MC4R-expressing neurons in the control of
energy balance; (ii) establish the mechanism(s) by which ROCK1 mediates the effect of melanocortin on feeding;
and (iii) explore the significance of the human ROCK1 mutation (E942K) in regulating energy balance. To
accomplish these goals, we will employ state-of-the-art biochemical, molecular, cellular, and metabolic
physiological techniques, including genetically engineered tissue-specific transgenic mouse models, mutant
mice carrying the human ROCK1-E942K mutation, Cre-inducible AAV, DREADD, and the rAAV-FlexON switch
system. These studies will provide a unique opportunity to establish a novel mechanism implicating ROCK1 as
a key determinant of hypothalamic energy balance. The data generated from these timely studies may offer
further insights into the pathogenesis of obesity-linked metabolic diseases and lead to new therapeutic targets
for the treatment of obesity.

## Key facts

- **NIH application ID:** 11108189
- **Project number:** 3R01DK129946-03S1
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** YOUNG-BUM KIM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $432,250
- **Award type:** 3
- **Project period:** 2022-07-05 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11108189

## Citation

> US National Institutes of Health, RePORTER application 11108189, Rho-kinase signaling in energy balance (3R01DK129946-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11108189. Licensed CC0.

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