# THE ROLE OF HEPATOKINE ORM2 IN ADIPOSE TISSUE INFLAMMATION

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2022 · $390,000

## Abstract

ABSTRACT
Bile acids (BAs) have recently emerged as metabolic regulators in obesity and type 2 diabetes. We discovered
that the BA overload in farnesoid X receptor (FXR) and small heterodimer partner (SHP) double knockout mice
unexpectedly exerts anti-obesity and anti-diabetic effects. Intriguingly, liver-specific FXR/SHP ablation
phenocopies the global knockout mice with striking beneficial impacts on white adipose tissue (WAT) fatty acid
utilization and inflammation. This raises the possibility that hepatic BA overload confers metabolic crosstalk
between the liver and adipose tissues. Our preliminary results indicate that hepatic secretion of orosomucoid 2
(ORM2) is dramatically increased by not only BA overload, but also weight-loss Roux-en Y gastric bypass (RYGB)
surgery. Hepatic Orm2 overexpression greatly reduces white adipose tissue (WAT) mass, coupled with marked
improvement in whole-body insulin sensitivity. Importantly, ORM2 dampens proinflammatory interferon-gamma
(IFNγ) and signal transducer and activator of transcription 1 (STAT1) signaling in WAT. These exciting data
support the hypothesis that the hepatokine ORM2 exerts anti-inflammatory effects in WAT, which improves
insulin sensitivity. The goal of this proposal is to critically test our hypothesis by challenging mouse models of
ORM2 expression with various metabolic interventions. In Aim 1, we will determine the metabolic impact of
hepatic ORM2 induction on WAT function in mouse models of obesity and type 2 diabetes. Aim 2 will determine
the contribution of ORM2 to the broad beneficial effects of BA overload and RYGB surgery using Orm2-deficient
mice. Lastly, Aim 3 will define anti-inflammatory effects of ORM2 on CCR5-IFNγ-STAT1 axis in WAT. Our studies
will identify the molecular and cellular basis of hepatokine ORM2 function on WAT inflammation, which
coordinately improves metabolic phenotypes. Ultimately, we expect to provide detailed insight into BA-induced
liver-adipose tissue crosstalk with direct therapeutic potential for treating obesity and type 2 diabetes.

## Key facts

- **NIH application ID:** 10473983
- **Project number:** 5R01DK126656-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Kangho Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2021-08-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10473983

## Citation

> US National Institutes of Health, RePORTER application 10473983, THE ROLE OF HEPATOKINE ORM2 IN ADIPOSE TISSUE INFLAMMATION (5R01DK126656-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10473983. Licensed CC0.

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