# Them1-Mediated Metabolic Regulation and Pathogenic Role in NAFLD

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $680,547

## Abstract

PROJECT SUMMARY/ABSTRACT
 Insulin resistance due to obesity is central to the pathogenesis of non-alcoholic fatty liver disease (NAFLD).
This research proposal addresses the unanswered question of how molecular mechanisms that normally
promote energy conservation become maladaptive and contribute to NAFLD. The long-term goal of this
research is to understand the regulatory relationships between cellular lipid molecules and metabolism,
particularly as they present therapeutic opportunities. The objective of this research is to understand
fundamental mechanisms for the regulation of energy homeostasis and nutrient metabolism. Our central
hypothesis is that Them1 conserves energy by limiting thermogenesis in brown and beige adipose tissue
through its functions both as a lipid-regulated enzyme that reduces rates of fatty acid oxidation and as a
transcriptional coregulator. In obesity, we postulate that Them1 becomes maladaptive. In addition to limiting
energy expenditure in thermogenic adipose tissue, high fat diet-induced Them1 upregulation in liver leads to
steatosis and excess gluconeogenesis and in white adipose tissue to inflammation and insulin resistance. The
rationale for the proposed research is that the mechanisms by which Them1 limits energy expenditure, while
promoting hepatic steatosis and insulin resistance, will reveal specific new targets for the management of
NAFLD. Guided by extensive preliminary data, the central hypothesis will be tested in three specific aims: 1)
To define the maladaptive mechanisms whereby Them1 promotes obesity and NAFLD; 2) To determine the
cellular mechanisms for suppression of thermogenesis by Them1; and 3) To elucidate regulation of Them1
activity by the lipid-binding START domain. In Aim 1, genetically engineered mice will be used to test the
hypothesis that increased Them1 expression in white adipose tissue promotes inflammation, which leads to
insulin resistance, hepatic inflammation and endoplasmic reticulum stress, and in beige adipose tissue reduces
thermogenesis. Aim 2 will test the hypothesis that Them1 in brown adipose tissue organizes into membrane-
less organelles (puncta) that conserve energy by suppressing fatty acid oxidation, except during peak energy
demand, when Them1 is directed to the nucleus to support thermogenesis by suppressing lipogenic gene
expression. We will visualize puncta by 3-D electron microscopy and elucidate the phase transition that
promotes their formation, and will characterize Them1-mediated transcriptional regulation. Aim 3 will test the
hypothesis that lipids bound to the START domain allosterically regulate the enzymatic domains. Our approach
will include detailed structural analysis of Them1 lipid-binding and catalysis using complementary biophysical
approaches, along with the development of small molecule inhibitors, which could also prove to be of
therapeutic value in NAFLD. Overall, this proposal will elucidate Them1-mediated metabolic regulation, which
is signif...

## Key facts

- **NIH application ID:** 10433907
- **Project number:** 5R01DK103046-09
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** DAVID E. COHEN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $680,547
- **Award type:** 5
- **Project period:** 2015-07-05 → 2023-03-13

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10433907

## Citation

> US National Institutes of Health, RePORTER application 10433907, Them1-Mediated Metabolic Regulation and Pathogenic Role in NAFLD (5R01DK103046-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10433907. Licensed CC0.

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