# High Fat Feeding Reduces Energy Expenditure in Brown Adipose Tissue

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $465,464

## Abstract

PROJECT ABSTRACT
Obesity develops when food intake chronically exceeds total energy expenditure. Prolonged ingestion of a
high-fat diet (HFD) results in obesity. We and others have shown that HFD induces hyperphagia; however, the
HFD effect on energy expenditure is not clear. Brown adipose tissue (BAT) effectively dissipates energy and
produces heat via BAT-specific mitochondrial uncoupling protein (UCP1). BAT is innervated by stellate
ganglion sympathetic nerves (SGN) that modulate BAT thermogenesis. Our pilot studies describe a novel
hypothalamic R-spondin 1/POMC neurocircuit that mediates the central actions of insulin and leptin on BAT
thermogenesis. Separate studies show HFD reduces SGN response and UCP1 gene expression, contributing
to obesity. A higher relative abundance of gram-positive Firmicutes and fewer gram-negative Bacteroides also
occurs. Involvement of gut dysbiosis is evident as HFD fails to reduce BAT thermogenesis and cause obesity
in germ-free mice. Our objectives are to investigate mechanisms by which HFD reduces BAT thermogenesis.
We hypothesize that HFD causes gut dysbiosis, leading to elevated circulating lipoteichoic acid (LTA), a key
molecule in gram-positive bacterial cell walls; LTA, in turn, acts via toll-like receptor 2 (TLR2) signaling in the
hypothalamus, reducing SGN firing and decreasing BAT thermogenesis. We will test this hypothesis with 3
specific aims: Aim 1: Define neurocircuits and signal transduction pathways in the hypothalamus responsible
for insulin and leptin actions on energy expenditure. We hypothesize that the Rspo1-LGR4/POMC/BDNF
neurocircuit mediates the central actions of insulin and leptin on sympathetic nerve activity (SNA) and BAT
thermogenesis. Chemical phenotyping of POMC neurons and mapping of LGR4 expressing neurons in the
ARC will be performed using in situ hybridization and immunofluorescence studies. Trans-synaptic tracing
studies will define the Rspo1-POMC-BDNF circuit that regulates the sympathetic outflow to BAT. Aim 2:
Investigate the effects of HFD on the hypothalamic Rspo1/POMC/BDNF neurocircuits. We hypothesize HFD
alters this neurocircuit, downregulating the actions of insulin and leptin on SNA and BAT thermogenesis, and
this is mediated by gut dysbiosis evoked by HFD. Fecal transplant from HFD mice to germ-free mice will be
used to investigate the role of HFD induced gut dysbiosis; Aim 3: Examine mechanisms by which gut dysbiosis
alters the hypothalamic neurocircuits, impairing SNA and BAT thermogenesis. We hypothesize elevated
circulating LTA caused by gram-positive gut dysbiosis acts via hypothalamic TLR2 signaling to release TNFα
which results in impaired insulin and leptin signaling and reduced SNA and decreased BAT thermogenesis.
Mouse stool microbiota analysis by MiSeq will be accompanied by stool and circulating LTA measurement.
TLR2 knockout mice will show TLR2’s critical role in impairing the hypothalamic neurocircuit response to
insulin and leptin stimulation followin...

## Key facts

- **NIH application ID:** 10800646
- **Project number:** 5R01DK058913-16
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jiande Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $465,464
- **Award type:** 5
- **Project period:** 2001-09-20 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10800646

## Citation

> US National Institutes of Health, RePORTER application 10800646, High Fat Feeding Reduces Energy Expenditure in Brown Adipose Tissue (5R01DK058913-16). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10800646. Licensed CC0.

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