# Cellular mechanisms governing nutrient sensing and organismal energy homeostasis

> **NIH NIH R35** · FRED HUTCHINSON CANCER CENTER · 2024 · $68,423

## Abstract

PROJECT SUMMARY
From bacteria to humans, organisms modulate their food intake and energy expenditure in accordance with their
internal nutrient state, allowing them to maintain a healthy energy balance. During evolution, conserved
homeostatic mechanisms developed to cope with potential nutrient deprivation from a fluctuating food supply.
Hence, when food is plentiful, excess energy is stored as fat reserves and mobilized during future scarcity.
However, in the 21st-century nutritional scarcity is the exception rather than the norm, resulting in an increasing
prevalence of obesity in humans. Obesity impacts cancer progression, accelerates aging, compromises
immunity, and impedes a healthy lifestyle. We posited that understanding mechanisms and molecules at the
interface of opposing nutrient states — scarcity and surplus — will reveal processes that control critical metabolic
outcomes. Furthermore, we proposed that certain proteins function as molecular switches to control processes
that allow an organism to operate in both states efficiently. We further surmised that chronic nutrient surplus
impairs the capacity of the ‘molecular switch’ proteins to efficiently alternate in response to the nutritional state,
resulting in energy imbalance. Once we identified such proteins, we determined to use them as an entry point to
identify cellular mechanisms critical to healthy energy balance. To this end, we investigated one process: how
do fat cells retain or release fat hormones – called adipokines— that serve as systemic nutrient surplus signals?
Our investigations led to identifying one critical molecular switch, which is recognized as playing a role in
membrane fusion events in previous studies. However, unexpectedly, we identified that this protein controls
nutrient-state-dependent adipokine intracellular localization and gene expression. Therefore, we have uncovered
a molecular switch mechanism that controls unanticipated cellular processes at the intersection of scarcity and
surplus. The cellular processes that we have uncovered represent strategic avenues to treat and manage
complex metabolic disorders. Hence, we propose to elucidate the following: i) define the molecular pathway by
which this molecular switch protein controls nucleocytoplasmic localization and gene expression; ii) understand
how diet-induced obesity disrupts this regulation, and iii) map consequences of this cell-intrinsic mechanism to
organism-level metabolic outcomes and behaviors. We will use fruit flies for short to medium-term goals, as we
have established a robust physiological Drosophila surplus model that mimics the diseased state. We will test
conservations of these findings in mammalian systems in the future. In summary, our goal is to address
outstanding issues in energy physiology by adopting a comprehensive and conceptually novel approach in a
highly tractable model.

## Key facts

- **NIH application ID:** 11035956
- **Project number:** 3R35GM124593-08S1
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Akhila Rajan
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $68,423
- **Award type:** 3
- **Project period:** 2017-09-11 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11035956

## Citation

> US National Institutes of Health, RePORTER application 11035956, Cellular mechanisms governing nutrient sensing and organismal energy homeostasis (3R35GM124593-08S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11035956. Licensed CC0.

---

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