# White Adipose Tissue Physiology, Mitochondrial Function and Adiponectin

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $624,266

## Abstract

White Adipose Tissue Physiology, Mitochondrial Function and Adiponectin
Metabolic dysregulation with all of it pathophysiological sequelae, including diabetes, cardiovascular disease
and cancer, continues to be on the rise. We need to identify new areas that can be targeted for improvements
in systemic metabolism. Over the last funding period, we have made significant progress towards defining key
processes in the white adipocyte that lead to mitochondrial challenges and consequently, impaired adipose
tissue function. These include challenges to the mitochondrial import machinery through overexpression of
Amyloid Precursor Protein , loss of mitochondrial DNA and a dysregulation in iron metabolism through
overexpression of mitoNEET and mitoferritin. We have applied many of these challenges to other cell types of
relevance in adipose tissue, such as macrophages and adipocyte precursor cells. Here, we propose to
integrate these challenges and observe how they feed into the Integrated Stress Response of
mitochondria. We will analyze how endoplasmic reticulum (ER) stress and the mitochondrial stress
pathways result in altered cellular physiology of the white adipocyte. We can carefully time and titrate
these mitochondrial manipulations, then probe them either in the presence or absence of the integral
mitochondrial stress sensor, DELE1. We will examine these phenomena in the following areas: A) at the
cellular level in the mature adipocyte; B) in the microenvironment at the level of whole adipose tissue
physiology; C) at the whole-body level, assessing the systemic effects of the Integrated Stress Response.
Specifically, we propose to address the underlying mechanisms with the following hierarchical approaches: In
Aim 1, we will measure and manipulate mitochondrial stress. In Aim 2, we will manipulate mitochondrial
matrix iron levels and assess the impact on the Integrated Stress Response. In Aim 3, we will address the
interplay between the mitochondrial and ER stress phenomena. In Aim 4, we will determine the role that
the Integrated Stress Response has in activating the removal and packaging of sub-mitochondrial
particles through exosomes.
 Combined, this proposal will provide significant novel insights into the downstream consequences of
mitochondrial dysfunction, ER stress and the Integrated Stress Response in the white adipocyte in vivo. We
are uniquely positioned to address these aims with mouse models that we have generated and characterized
during the initial ten years of this grant. In adipocytes, these interventions will severely tip the balance of
lipid storage, lipid oxidation and carbohydrate metabolism, thereby contributing directly to the
development of obesity and insulin resistance. These experiments will also enable us to carefully dissect
the effects of altered mitochondrial function on the production of the critical adipokine, adiponectin. These are
the first comprehensive in vivo experiments assessing the role of the Integrated S...

## Key facts

- **NIH application ID:** 10827680
- **Project number:** 2R01DK099110-11
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** PHILIPP E SCHERER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $624,266
- **Award type:** 2
- **Project period:** 2013-07-05 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10827680

## Citation

> US National Institutes of Health, RePORTER application 10827680, White Adipose Tissue Physiology, Mitochondrial Function and Adiponectin (2R01DK099110-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10827680. Licensed CC0.

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