# The Circadian System as a Neuronal Regulator of Feeding Time and Body Weight Setpoint

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2020 · $427,752

## Abstract

Project Summary
The escalating prevalence of obesity and metabolic syndrome suggest that both underlying genetic and
environmental factors contribute to this epidemic. We have made the exciting discoveries that genetic ablation
of the clock leads to obesity and metabolic syndrome, and high-fat feeding to wild-type mice induces circadian
disruption and increases food intake during the incorrect circadian time (i.e., their normal rest period) that is
directly linked to obesity and insulin resistance. While these observations suggest a fundamental role for the
“timing” of food intake in energy balance, the underlying central nervous system clock mechanisms
coordinating behavioral and metabolic rhythms remain poorly understood. A springboard for our studies has
been the transformative discovery of the core molecular components of the clock, a negative transcription
feedback loop that cycles in both pacemaker neurons of the suprachiasmatic nucleus (SCN) and nearly all
peripheral metabolic cells. However, how the brain pacemaker cells entrain extra-SCN clocks to the light cycle,
and the role of clocks within genetically distinct cells of the SCN in the regulation of energy balance, remains
unknown. Given the mounting evidence that circadian and sleep cycle disruption lead to metabolic disorders
through impeding signaling at the level of brain, a primary challenge is now to define the function of pacemaker
neurons and clocks within energy-sensing neurons in establishing body weight setpoint. Our approach herein
is to exploit powerful new genetic models in the mouse, with the ability to cause adult-onset ablation of the core
clock machinery, and to do so within specific region of the hypothalamus, focusing on the master pacemaker,
the SCN. We also implement stereotactically-guided DREADD technology (Designer Receptors Exclusively
Activated by Designer Drugs) to pharmacologically manipulate the phase of SCN firing in distinct
subpopulations, thus causing genetic jetlag, and to then probe the impact of this “on/off” switch of the central
clock on behavior and energy balance. We seek to integrate behavioral, physiological, and molecular analyses
to dissect actions of the clock within SCN and appetitive neurons in feeding and glucose metabolism. Our work
has direct translation to human health since we will elucidate how the clock system contributes to weight loss
with hypocaloric diets and maintenance of weight loss following cessation of dieting. In summary, our proposed
research will provide detailed mechanistic insight into how disruption of pacemaker neuron activity and clock
transcription factor regulation of neuronal gene transcription impacts the coordination of hunger, energy
balance, and health. In summary, our proposed research will provide detailed mechanistic insight into how
disruption of pacemaker neuron activity and clock-regulated neuronal gene transcription in both SCN and
extra-SCN regions impact the coordination of hunger, energy balance a...

## Key facts

- **NIH application ID:** 9934189
- **Project number:** 5R01DK113011-03
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Joseph Bass
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $427,752
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934189

## Citation

> US National Institutes of Health, RePORTER application 9934189, The Circadian System as a Neuronal Regulator of Feeding Time and Body Weight Setpoint (5R01DK113011-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934189. Licensed CC0.

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