# Novel Mechanisms for Exercise Training Effects on Glucose Homeostasis

> **NIH NIH R01** · JOSLIN DIABETES CENTER · 2020 · $616,850

## Abstract

PROJECT SUMMARY/ABSTRACT
Regular physical activity is essential for overall health, including beneficial effects to improve whole-body
metabolic homeostasis and insulin sensitivity: adaptations that are critical for people with diabetes. While
these benefits of exercise training are well described, the underlying cellular and molecular mechanisms are
not well understood. The concept that exercise stimulates tissue-to-tissue communication to improve overall
metabolic health has emerged as an important area of scientific investigation. Exercise is a complex
physiological stimulus that regulates numerous molecules, signaling networks and tissues, and we hypothesize
that all of these adaptations contribute to mediating the beneficial effects of physical exercise on health.
Studies supported by this award have shown that exercise-induced adaptations to subcutaneous adipose
tissue (scWAT) play a fundamental role in this process. In the next phase of this project we propose to use
mouse models to investigate three critical areas of exercise and adipose tissue biology, all of which are based
on our compelling preliminary or published studies. Specific Aim 1 is based on our findings suggesting that the
mechanism for the beneficial role of exercise-trained scWAT on metabolism involves the secretion and
biological actions of multiple exercise-induced adipokines. We discovered that TGF-β2 is one such exercise-
specific adipokine, and demonstrated that TGF-β2 is regulated by lactate and has profound effects on tissue
and systemic metabolism. One goal of Specific Aim 1 is to elucidate the cellular signaling mechanisms
regulating this novel exercise-induced lactate-TGF-β2 axis. Given the potential clinical significance of
exercise-regulated adipokines, another goal of Aim 1 is to elucidate the complete exercise-regulated scWAT
secretome. In Specific Aim 2, we will investigate CRISP1, another newly identified exercise-regulated
adipokine. Importantly, our preliminary data show that CRISP1 is regulated by a lactate-independent
mechanism and has beneficial effects on tissue and systemic metabolism. In addition, CRISP1 appears to be
sex-specific, only increasing with exercise in male mice, and in Aim 2 we will investigate underlying
mechanisms for sex-specific adaptations to scWAT. Specific Aim 3 will investigate exercise regulation of
“lipokines”, signaling lipids that are a new class of molecules shown to have metabolic effects. We discovered
that 12,13-diHOME is a novel lipokine increased by both exercise and exercise training, released from brown
adipose tissue, and functions to increase skeletal muscle fatty acid metabolism. Specific Aim 3 will study the
metabolic consequences of exercise-regulated 12,13-diHOME. This innovative project should lead to a new
paradigm in which exercise-stimulated circulating factors derived from adipose tissues function to regulate the
beneficial effects of exercise on health. These studies have the potential to define novel biol...

## Key facts

- **NIH application ID:** 9972544
- **Project number:** 2R01DK099511-06A1
- **Recipient organization:** JOSLIN DIABETES CENTER
- **Principal Investigator:** LAURIE J GOODYEAR
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $616,850
- **Award type:** 2
- **Project period:** 2014-04-10 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9972544

## Citation

> US National Institutes of Health, RePORTER application 9972544, Novel Mechanisms for Exercise Training Effects on Glucose Homeostasis (2R01DK099511-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9972544. Licensed CC0.

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