# Investigating How Cellular Mechanisms Interface To Maintain Energy Balance

> **NIH NIH R35** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2021 · $124,965

## Abstract

Project Summary (AS STATED IN PARENT GRANT)
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 app...

## Key facts

- **NIH application ID:** 10386531
- **Project number:** 3R35GM124593-05S1
- **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:** $124,965
- **Award type:** 3
- **Project period:** 2017-09-11 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10386531

## Citation

> US National Institutes of Health, RePORTER application 10386531, Investigating How Cellular Mechanisms Interface To Maintain Energy Balance (3R35GM124593-05S1). Retrieved via AI Analytics 2026-06-04 from https://api.ai-analytics.org/grant/nih/10386531. Licensed CC0.

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