# Feeding Drives HSF1 Transcriptional Programs Required for Global Protein Synthesis

> **NIH NIH R01** · JOSLIN DIABETES CENTER · 2020 · $422,500

## Abstract

Project summary
We have found that HSF1 and a proteostasis network – the 375 chaperones, co-chaperones and proteosome
subunits in the genome – respond dramatically during feeding. Proteostasis changes in liver and skeletal
muscle are the primary topics of the parent grant, but we also found proteostasis responses in cardiac muscle,
kidney, adipose, jejunum and lung, so the feeding responses occur broadly across tissues. But most surprising
are the feeding responses in brain, with upregulated proteostasis networks in cerebellum and hypothalamus;
presumably other regions are similarly affected. These findings could be impactful, because pathophysiology in
Alzheimer’s and other neurodegenerative diseases is directly linked to proteostasis. Alzheimer’s disease is
characterized by the accumulation of abnormally folded proteins, e.g. extracellular Aβ in plaques and
intracellular tau in neurofibrillary tangles, in the face of declining proteostasis capacity with age. It hasn’t been
realized previously that proteostasis networks throughout the body, including brain, are dynamically regulated
and highly responsive to meals and nutrients. Moreover, effect sizes for feeding are several-fold greater and
more statistically robust than effect sizes in aging, suggesting inducible proteostasis may represent an
untapped reservoir for translation. We therefore wish to expand on previous static, single point assessments by
further characterizing these dynamic changes in brain regions relevant to Alzheimer’s disease. This
supplement will provide the first data to show physiological regulation of proteostasis networks cycling daily in
relevant regions of mouse brain, including cerebellum, hippocampus and cortex. We will document the effects
of aging on proteostasis responses by comparing fast-fed responses in the brains of young (10-12 wk) vs. old
(>90 wk) mice. Preliminary results show no change with age for fasting but seriously diminished fed responses
in 22 month old mouse cerebellum. Preliminary results also show diminished fast-fed responses in liver of
chow- vs HFD-fed mice, and since type 2 diabetes, insulin resistance and obesity also increase risk for
Alzheimer’s, we wish to compare fast-fed responses in the same relevant regions of brain but comparing chow-
vs HFD-fed mouse. Our findings are providing exciting new insights into the physiological drivers and dynamics
of proteostasis, as induction by feeding occurs daily and in many tissues. Studies in brain are among the most
important, as pathophysiology in Alzheimer’s disease is directly linked to the accumulation of misfolded
proteins and aggregates in the face of insufficient proteostasis capacity. We hope to provide the Alzheimer’s
research community with data showing that proteostasis in brain is highly dynamic as opposed to static, and
readily inducible through established, potentially druggable, metabolic mechanisms and pathways. These
findings are thus directly relevant to Alzheimer’s disease, and ...

## Key facts

- **NIH application ID:** 10123223
- **Project number:** 3R01DK112153-03S1
- **Recipient organization:** JOSLIN DIABETES CENTER
- **Principal Investigator:** STEVEN E SHOELSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $422,500
- **Award type:** 3
- **Project period:** 2018-05-02 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10123223

## Citation

> US National Institutes of Health, RePORTER application 10123223, Feeding Drives HSF1 Transcriptional Programs Required for Global Protein Synthesis (3R01DK112153-03S1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10123223. Licensed CC0.

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