# Investigating how cellular mechanisms interface to maintain energy balance

> **NIH NIH R35** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2021 · $420,522

## Abstract

Project Summary: 
Organisms, from bacteria to humans, modulate their food intake and energy expenditure in accordance with
their internal nutrient state, allowing for maintenance of healthy energy balance. During evolution conserved
homeostatic mechanisms developed to cope with potential nutrient deprivation from a fluctuating food supply.
Hence when food was plentiful the excess energy is stored as fat reserves, which can be mobilized during a
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 progression of cancer and
neurodegeneration, accelerates aging and impedes a healthy lifestyle. Previously, a number of studies
focused on how organisms respond to nutritional scarcity, and have resulted in elucidation of evolutionarily
conserved mechanisms that orchestrate a response to food scarcity. Our aim is to understand the opposite
nutritional state, by focusing on how organisms respond to chronic ‘over-nutrition’. We expect that these
mechanisms will be both short-range, acute, local cell biological changes and also prolonged time-scale, inter-
organ systemic physiological responses. Thus far, we identified previously uncharacterized surplus signaling
components. Unexpectedly we found molecules that are critical for scarcity responses, are also key regulators
of nutritional surplus. Given that storage of surplus evolved as a protective strategy to survive future nutritional
scarcity, it is likely that an overlapping set of molecules is employed to allow organisms to sense and respond
to these two mutually exclusive states. Premised on our observations, we hypothesize that a suite of
‘bidirectional’ switch proteins couple scarcity and surplus mechanisms, allowing organisms to toggle between
the two as needed. We further surmise that chronic nutrient surplus, a state that was rare during the evolution,
impairs the capacity of this ‘bidirectional molecular switch’ to efficiently alternate in response to nutritional
state, resulting in energy imbalance. Our short-term goal is to a) codify the molecular suite underpinning the
bidirectional nutritional switch; b) identify new bidirectional nutrient switches that facilitate inter-organ
communication required for energy balance. Then, in the medium-term we will c) systematically dissect how
the bidirectional mechanisms degrade and lose plasticity when subject to chronic nutrient surplus. Finally, our
long-term goal is to d) develop pharmaceutical interventions that target the bidirectional molecular suite, and
test their effect in restoring energy balance in systems that have been nutritionally stressed. The fundamental
principles we derive from this work will illuminate how molecular components designed to function in a certain
physiological state can be co-opted to achieve an antagonistic response. The principles garnered from our
studies will be applicable to understanding ...

## Key facts

- **NIH application ID:** 10224827
- **Project number:** 5R35GM124593-05
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** Akhila Rajan
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $420,522
- **Award type:** 5
- **Project period:** 2017-09-11 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10224827

## Citation

> US National Institutes of Health, RePORTER application 10224827, Investigating how cellular mechanisms interface to maintain energy balance (5R35GM124593-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10224827. Licensed CC0.

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