# Mechanisms for activation of beige adipose tissue in humans

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2024 · $584,748

## Abstract

We have been studying subcutaneous white adipose tissue (SC WAT) beiging in response to mirabegron,
which is a β3 adrenergic receptor (β3AR) agonist. β3ARs are found in adipocytes and smooth muscle, and
mirabegron is an FDA approved drug for overactive bladder. Treatment of obese, insulin resistant humans for
twelve weeks with mirabegron consistently induced SC WAT beiging and this led to improved oral glucose
tolerance and a lower HbA1c. The mechanism for improved glucose homeostasis involved both a small
improvement in insulin sensitivity and a significant improvement in β-cell function (insulin secretion) along with
an increase in muscle oxidative type 1 fibers; however, there was no weight loss or induction of brown fat.
Since pancreatic β-cells and muscle do not express the β3AR, the beneficial effects of mirabegron in these
cells likely occurred by an indirect mechanism.
 The physiological effects of mirabegron are likely mediated in part by the induction of beige adipose, which
represents a metabolic sink for glucose and lipids and which may alter adipose remodeling. In addition, the
changes in adipose tissue and other organs may result in secondary effects that target other tissues.
 Specific Aim 1. To examine the effects of the β3 agonist mirabegron on glucose metabolism, we will
comprehensively analyze glucose tolerance, insulin sensitivity, and β-cell function in prediabetic subjects in a
4-month, placebo-controlled, randomized trial. We will assess changes in adipose tissue including beiging,
inflammation, fibrosis, and insulin-stimulated glucose uptake by adipocytes. We will also fully characterize
gene expression in SC WAT by RNA-seq to identify potential mechanisms such as altered adipokine profiles.
 Specific Aim 2. We hypothesize that mirabegron causes cells that express the β3AR to change the levels
of secreted factors that affect peripheral cell types such as β-cells and muscle. We will use biochemical and
pharmacological approaches to identify the mechanism by which conditioned medium from mirabegron-treated
adipocytes increases PGC1α expression in muscle in vitro. We will utilize unbiased approaches to identify
changes in lipids, metabolites, and exosome miRNA composition in the adipocyte conditioned media. We will
use these approaches to identify molecules altered in plasma by mirabegron treatment that are responsible for
the improvement in β-cell and muscle function.
 Clinical relevance: Mirabegron treatment has positive effects on glucose tolerance due to improvements
in insulin sensitivity and β-cell function. This may be exploited to prevent conversion of prediabetes to
diabetes or used as a therapeutic in diabetics. This application will also increase our understanding of the
mechanism(s) by which mirabegron acts, which may reveal new therapeutic targets

## Key facts

- **NIH application ID:** 10746421
- **Project number:** 5R01DK124626-04
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Philip A Kern
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $584,748
- **Award type:** 5
- **Project period:** 2020-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10746421

## Citation

> US National Institutes of Health, RePORTER application 10746421, Mechanisms for activation of beige adipose tissue in humans (5R01DK124626-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10746421. Licensed CC0.

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