# FUNCTION OF THE HYPOTHALAMIC MELANOCORTIN SYSTEM IN STIMULATING COUNTER-REGULATORY RESPONSE TO HYPOGLYCEMIA

> **NIH NIH K01** · UNIVERSITY OF ROCHESTER · 2020 · $47,571

## Abstract

The primary goal of this K01 award application is to acquire necessary training and research experience to facilitate my
transition to an independent research career. So far in my postdoctoral training, I have applied my skills and knowledge
that were learned during my PhD education in Dr. Eric Lazartigues' lab. Moving forward, I would like to acquire new
research skills and develop a project that is different from Dr. Malcolm Low's (my postdoc mentor) ongoing research. I
would like to integrate my current skills in studying peripheral organs with new techniques pertaining to the central
nervous system. I will undertake training and courses in neuropharmacology, neuroanatomy, developing transgenic mouse
models employing opto- and pharmaco- genetic tools. My long term career goal is to become an independent investigator
at a major academic research-focused institution and to contribute toward our understanding of the function of brain in
glucose homeostasis. Patients with both type 1 and type 2 (late stage) diabetes are at high risk of facing life-threating
hypoglycemia due to tight glucose control therapy. Normally, hormones such as epinephrine and glucagon are released to
counteract hypoglycemia; however, patients with diabetes exhibit impaired counter-regulatory response to hypoglycemia.
Consequently, the function of brain deteriorates due to lack of glucose and these patients may experience confusion,
seizures, unconsciousness, and death if not treated immediately. During K01 award period, I aim to determine the central
pathways involved in hypoglycemia counter-regulation. My preliminary data suggest that hypothalamic melanocortin
system is essential in counteracting hypoglycemia. Arcuate nucleus-specific Pomc knockout mice (ArcPomc-/-) exhibit
impaired response to glucose deficit. Therefore, in Aim 1, I will determine a physiological role of hypothalamic POMC in
counteracting hypoglycemia. I will employ immunohistochemistry, in situ hybridization, and hypoglycemic clamps to
accomplish Aim 1. I have observed that melanocortin 4 receptor (MC4R) agonist treatment improves, while its antagonist
worsens, the counter-regulatory response in ArcPomc-/- and WT mice, respectively. Hence, Aim 2 of this project is to
examine the function of the MC4R specifically in the paraventricular nucleus of the hypothalamus (PVH, a region that
regulates sympathetic nervous system activity) in stimulating counter-regulatory response to hypoglycemia. I will employ
opto- and pharmaco- genetic tools to elucidate the role of MC4RPVH in hypoglycemia counter-regulation. Finally, in Aim
3, I will examine the impact of diabetes on hypothalamic POMC and MC4R levels to ascertain the mechanism underlying
reduced response to hypoglycemia during diabetes. Moreover, I will test the potential of MC4R agonist in preventing life-
threatening hypoglycemia in streptozotocin (STZ) treated mice with diabetes. The outcome of this project will have direct
implication for prevention of fata...

## Key facts

- **NIH application ID:** 10219651
- **Project number:** 3K01DK113115-05S1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Kavaljit H Chhabra
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $47,571
- **Award type:** 3
- **Project period:** 2017-04-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10219651

## Citation

> US National Institutes of Health, RePORTER application 10219651, FUNCTION OF THE HYPOTHALAMIC MELANOCORTIN SYSTEM IN STIMULATING COUNTER-REGULATORY RESPONSE TO HYPOGLYCEMIA (3K01DK113115-05S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10219651. Licensed CC0.

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