# Assessing the effect of diet on hypothalamic gliosis in humans

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2022 · $353,000

## Abstract

ABSTRACT
 Preclinical studies indicate that the neurobiology of obesity may be related to diet-induced cellular
inflammatory responses in hypothalamic areas that regulate body weight. In rodent models of diet-induced
obesity, overfeeding by high-fat diet rapidly induces inflammation and gliosis in the arcuate nucleus of the
hypothalamus. Moreover, these glial cell inflammatory responses are both necessary and sufficient to
induce hyperphagia and weight gain, suggesting that gliosis plays a mechanistic role in the ability of diet to
induce obesity in rodent models. Using magnetic resonance imaging (MRI), the investigators discovered the
first evidence of hypothalamic gliosis in humans with obesity. These findings have since been replicated in
adults and children with obesity as well as in type 2 diabetes and insulin resistance. However, the current
evidence in humans is observational, and the lack of controlled clinical experiments limits our
understanding of whether findings of hypothalamic gliosis are diet-induced in humans. The overall goal of
the proposed research is to determine the feasibility, promise, and safety of an experimental model
in humans to test the effects of hypercaloric, obesogenic diets on hypothalamic gliosis as
measured by MRI. The proposed mechanistic clinical trial is in response to PA-20-160 (Small R01s for
Clinical Trials Targeting Diseases within the Mission of NIDDK). Using a randomized clinical trial design
and a eucaloric control group, the proposal aims to compare the effect of two overfeeding regimens that
vary in caloric load (but not macronutrient composition) on hypothalamic gliosis as measured by MRI. A
second goal is to determine whether a standardized hypocaloric diet following the overfeeding regimen is a
feasible strategy to mitigate any observed weight gain and/or hypothalamic gliosis due to overfeeding.
Finally, the feasibility, acceptability, and long-term weight effects of study participation will be assessed.
Forty-two participants with overweight will undergo serial MRI scans before, during, and at completion of 7
days of overfeeding or eucaloric diet as well as before, during, and at completion of a 7-day hypocaloric or
eucaloric diet period. Diet composition during overfeeding will be based on preclinical studies of gliosis and
utilize a robust stimulus that is high in dietary fat, saturated fat, and refined carbohydrates and most would
consider obesogenic. Effect sizes, feasibility, and safety data will contribute to the design of future
mechanistic clinical trials. Additional future directions include parsing which diet elements (e.g., caloric
excess, saturated fatty acids) elicit radiologic evidence of inflammation and gliosis in the mediobasal
hypothalamus. The proposed study represents a necessary first step in testing the hypothesis that a
hypercaloric, obesogenic diet induces inflammation and structural changes in body-weight-regulating areas
of the brain in humans—changes that promote the de...

## Key facts

- **NIH application ID:** 10499319
- **Project number:** 1R01DK133356-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Ellen A Schur
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $353,000
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10499319

## Citation

> US National Institutes of Health, RePORTER application 10499319, Assessing the effect of diet on hypothalamic gliosis in humans (1R01DK133356-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10499319. Licensed CC0.

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