# Regulation of body weight, energy expenditure, and nutrient metabolism by hypothalamic Slug (Snai2) neural circuits

> **NIH NIH F32** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $67,446

## Abstract

Project Abstract
Obesity produces adverse health consequences such as dyslipidemia, cardiovascular disease, insulin resistance,
and Type 2 diabetes. Obesity has become a heavy social burden as about 500 million adults worldwide are now
considered obese. Leptin is the critical adipokine that maintains energy homeostasis and body weight by
modulating feeding behavior and energy expenditure. In most cases, plasma leptin levels are abnormally higher
in obesity patients than in normal individuals (leptin resistance), thus administration of additional leptin fails to
reverse the obese state. It is essential to understand the molecular mechanism and regulation of leptin resistance
for the effective leptin therapies. During a search for factors that affect leptin sensitivity and body weight, we
identified Slug (also called Snai2) epigenetic factor. Slug elicits deacetylation, demethylation, and/or methylation
of H3K4, H3K9, and/or H3K27, thereby repressing its target genes. However, its action in the brain has not been
explored. The preliminary data indicate that Slug-expressing neurons are highly enriched in a subset of
hypothalamic neurons which are implicated in regulating energy balance and body weight. A high fat diet (HFD)
increases both the levels of hypothalamic Slug and the number of hypothalamic Slug+ neurons. Importantly, both
global (KO) and LepR+ cell-specific Slug knockout (LKO) mice resist HFD-induced leptin resistance, obesity,
type 2 diabetes, and nonalcoholic fatty liver disease, owing to increasing energy expenditure. My working
hypothesis is that hypothalamic Slug+ neurons, particularly the Slug+LepR+ subpopulations are the hub of the
energy metabolism circuits. At the molecular level, Slug epigenetically regulates expression of key molecules
involved in leptin signaling. To test this hypothesis, I have developed two aims. Aim 1 is to delineate the anatomic,
chemical, and functional properties of Slug+ neurons. To determine hypothalamic Slug+ neural circuits, I will map
the upstream and the downstream of Slug+ neurons using Cre/loxp-dependent and viral-based neural tracing
techniques. In addition, I will identify signature neuropeptides expressed by Slug+ neurons in order to gain insight
into the mechanism by which the Slug+ circuitry controls energy metabolism and body weight. Furthermore, I will
define the distinct function of Slug+ neurons using chemogenetic approaches. Aim 2 is to interrogate the
molecular mechanisms by which Slug controls the ability of the Slug+LepR+ circuits to regulate energy balance
and body weight. My preliminary data suggests that Slug likely inhibits leptin signaling, leading to leptin
resistance. To extend these exciting findings, I will assess hypothalamic leptin signaling in LKO mice. I will test
the hypothesis that Slug epigenetically suppresses expression of leptin receptor, contributing to leptin resistance.
Additionally, I will analyze the translational profile of hypothalamic Slug+ neurons in order...

## Key facts

- **NIH application ID:** 10001030
- **Project number:** 5F32DK120111-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Min Hyun Kim
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $67,446
- **Award type:** 5
- **Project period:** 2018-09-10 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001030

## Citation

> US National Institutes of Health, RePORTER application 10001030, Regulation of body weight, energy expenditure, and nutrient metabolism by hypothalamic Slug (Snai2) neural circuits (5F32DK120111-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001030. Licensed CC0.

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