# Neuronal pathways regulating metabolic adaptation

> **NIH NIH K01** · HARVARD MEDICAL SCHOOL · 2020 · $116,293

## Abstract

PROJECT SUMMARY
Two thirds of the US population are overweight or obese. Stably lowering the body weight is highly challenging
due to a compensatory homeostatic mechanism - metabolic adaptation - which lowers the body’s metabolic rate
to prevent further weight loss. Preventing or reversing metabolic adaptation would provide a powerful new
treatment for obesity; however, the molecular and neuronal basis of metabolic adaptation and body weight
homeostasis remain poorly understood. Calorically restricted (CR) mice display decreased metabolic rates,
suggesting that mice could be used as a model to study metabolic adaptation. Using a CR mouse model, this
proposal aims to investigate the neuronal basis of metabolic adaptation. In preliminary studies, the applicant
used recently developed genetic tools to label neurons, across the brain, that are active during caloric restriction.
Subsequent chemogenetic reactivation of these neurons in a non-fasted state was sufficient to lower the
metabolic rate suggesting that this strategy successfully captured, or TRAPed, a population of metabolic-
adaptation-regulating (MAR) neurons. The goal of this proposal is to first identify and then molecularly and
physiologically characterize MAR neurons during calorie restriction to shed light on the mechanism by which
they induce metabolic adaptation. This proposal contains a comprehensive training and research plan to build
upon these initial findings by characterizing these neurons in the short-term, and by facilitating the establishment
of an innovative and multidisciplinary research program focused on studying energy balance and body weight
homeostasis in the long-term. In Aim 1, the applicant will complete the preliminary functional screen across brain
regions to identify the anatomical location of MAR neurons and test whether their activity is both sufficient and
necessary for metabolic adaptation to caloric restriction. In Aim 2, the applicant will learn and apply tools to map
the synaptic inputs and targets of MAR neurons to identify new components of the metabolic adaptation circuit.
In Aim 3, the applicant will learn and apply techniques to monitor neuronal activity in awake, behaving CR
animals to determine the information encoded by MAR neurons and generate hypotheses regarding their
function in the body weight homeostasis feedback circuit. Finally, in Aim 4, the applicant will use single-cell
transcriptomics to molecularly identify MAR neurons, enabling the generation of cell-type-specific reagents and
the discovery of new targets to modulate their activity and prevent or reverse metabolic adaptation during weight
loss. Specific technical training activities to investigate neuron’s activity patterns and map their synaptic
connections will be augmented by focused mentorship from several highly successful scientists who are
committed to aiding in the applicant’s acquisition of professional and intellectual skills in the highly energetic and
collaborative traini...

## Key facts

- **NIH application ID:** 9871302
- **Project number:** 1K01DK123197-01
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Sinisa Hrvatin
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $116,293
- **Award type:** 1
- **Project period:** 2020-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9871302

## Citation

> US National Institutes of Health, RePORTER application 9871302, Neuronal pathways regulating metabolic adaptation (1K01DK123197-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9871302. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*