# Hepatokine Regulation of Thermogenesis and Metabolic Physiology

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $390,000

## Abstract

Abstract
The mammalian liver functions as a hub for nutrient and energy metabolism that helps
maintain systemic homeostasis. Hepatic metabolism is highly responsive to
physiological signals and undergoes drastic reprogramming in insulin resistant state.
The liver also provides an important source of secreted proteins in circulation, including
lipoproteins, coagulation factors, and endocrine factors (hepatokines). Upon release into
circulation, hepatokines may act locally or on other peripheral tissues and the central
nervous system to exert pleiotropic metabolic effects, as illustrated by recent studies on
FGF21. Despite the expanding role of liver-derived secreted factors in systemic energy
metabolism, the molecular nature and physiological action of the endocrine liver remains
an important unsolved problem in molecular metabolism. Addressing this challenge
provides a significant opportunity for the discovery of novel therapeutic targets and
approaches for the treatment of metabolic disease. In preliminary studies, we identified
Tsukushin (TSKU) as a novel liver-derived endocrine factor that exhibits markedly
elevated levels in plasma from diet-induced and genetic obese mice. Genetic
inactivation of this hepatokine stimulates thermogenesis and energy expenditure and
protects mice from high-fat diet-induced obesity and metabolic disorders. Based on
these exciting findings, we hypothesize that TSKU exacerbates diet-induced
deterioration of metabolic health through attenuating thermogenesis and energy
expenditure. We will test this hypothesis using a combination of in vivo and in vitro gain-
and loss-of-function model systems. In Aim 1, we will examine the association of plasma
TSKU levels with obesity in obese patients and establish the causative role of TSKU in
diet-induced metabolic disorders. In Aim 2, we will dissect the role of TSKU in
physiological regulation of adipose thermogenesis. In Aim 3, we will dissect the
mechanisms through which TSKU modulates adipose sympathetic innovation using a
combination of 3D imaging and molecular cellular tools. Successful completion of this
highly innovative project will generate high-impact discoveries of significant scientific and
translational value.

## Key facts

- **NIH application ID:** 9894795
- **Project number:** 5R01DK118731-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jiandie D Lin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894795

## Citation

> US National Institutes of Health, RePORTER application 9894795, Hepatokine Regulation of Thermogenesis and Metabolic Physiology (5R01DK118731-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9894795. Licensed CC0.

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