# Post-translational control of whole body energy balance by hepatic ISGylation

> **NIH NIH R03** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $123,000

## Abstract

PROJECT SUMMARY
Mounting evidence supports a central role for chronic inflammation in obesity and metabolic dysfunction, yet our
understanding of actual causal links remains limited. We have identified and characterized numerous points of
crosstalk between inflammation and the metabolic effects of overnutrition. Activation of the innate immune
system triggers the robust production of interferon stimulated genes (ISGs), many of which have potent roles in
metabolism. One such gene encodes for the ubiquitin-like modifier ISG15 that is conjugated to target proteins in
a reversible process referred to as ISGylation. Our preliminary data show diet-induced obesity increases liver
expression of Isg15 and protein ISGylation. Deficiency in liver Isg15 (ISG15LKO) renders mice resistant to diet-
induced weight gain, and improves insulin sensitivity and hepatic steatosis. The liver, however, is not a
thermogenic organ. Therefore, the impact of liver ISGylation on the regulation of body weight is likely mediated
through endocrine signaling to other organs capable of influencing food intake, locomotor activity and/or energy
expenditure. To identify ISGylated proteins, we engineered endogenously tagged Isg15 mice, and mass
spectrometry proteomics data revealed robust enrichment of proteins involved in peroxisomal and mitochondrial
oxidation. The overall goal of this proposal is to interrogate the role of liver ISGylation in regulating organismal
energy balance. The central hypothesis is that in the liver, obesity triggers ISGylation of critical oxidative
proteins that influence the hepatocyte secretome and promote weight gain, either by increasing food intake or
decreasing energy expenditure. This hypothesis will be tested through the following two specific aims. Aim 1 will
determine the effects of hepatic ISGylation on energy balance, and Aim 2 will identify liver ISGylation targets
responsible for systemic metabolic regulation.

## Key facts

- **NIH application ID:** 10951455
- **Project number:** 1R03DK140295-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Suraj J Patel
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $123,000
- **Award type:** 1
- **Project period:** 2024-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10951455

## Citation

> US National Institutes of Health, RePORTER application 10951455, Post-translational control of whole body energy balance by hepatic ISGylation (1R03DK140295-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10951455. Licensed CC0.

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