# Mechanisms of Regulation of Retinoic Acid Homeostasis

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $377,912

## Abstract

Obesity is a major public health problem with 38% of American adults being obese and rates of obesity increasing
dramatically worldwide. It is estimated that obesity is second only to smoking as a cause of premature
preventable death. This is largely due to the comorbidities associated with obesity including metabolic syndrome,
diabetes, cardiovascular disease and nonalcoholic fatty liver disease. Yet, very little progress has been made in
the development of treatments to prevent obesity and its comorbidities, and the mechanistic link between obesity
and development of comorbidities is not completely understood. Several studies have shown that obese rodents
develop tissue vitamin A deficiency, with tissue retinoid concentrations decreasing by a stunning 75-90%,
suggesting profound metabolic dysregulation. Findings in cell systems and animal models demonstrate that
retinoids regulate adipocyte differentiation and glucose and lipid metabolism and, further, that decreased retinoid
concentrations are associated with progressive obesity, insulin resistance and glucose intolerance. Thus,
aggregate preclinical data suggest that altered vitamin A metabolism may contribute directly to obesity
progression and the development of obesity-related co-morbidities. Critically, the mechanisms underlying this
dysregulated vitamin A metabolism remain poorly understood, and the relevance of these preclinical findings to
human obesity is unclear. A central premise of this proposal is that altered vitamin A metabolism in obesity is a
result of increased inflammatory cytokines (IL-1, IL-6 and TNF in metabolic tissues, which regulate the
expression of the retinoid metabolizing enzymes CYP26, LRAT, ALDH1A and RDH in adipocytes and various
liver cell types. We further hypothesize that this dysregulation of vitamin A metabolism occurs in human obesity
as well as in animal models. We will test our hypotheses in two specific aims: 1) to identify the enzymes and the
key regulatory signals that control all-trans-retinoic acid (atRA) concentrations and vitamin A metabolic flux in
human liver and adipose tissue, and 2) to establish whether adipose tissue and liver vitamin A metabolomes are
altered in obese humans. We will use our state-of-the-art mass spectrometry methods, innovative metabolic flux
experiments and kinetic modeling in specific cell types to characterize the key enzymes that metabolize retinoids
in liver and adipose tissue and determine how the activity of these enzymes is altered in obesity. To determine
whether tissue retinoids are altered in human obesity, we will conduct a cross sectional clinical study comparing
visceral and subcutaneous adipose tissue, liver and serum vitamin A metabolomes in obese and non-obese
subjects. The proposed studies will lay the foundation for understanding the regulation of vitamin A metabolism
in human liver and adipose tissue and for determing how vitamin A metabolism may become dysregulated in
obesity contributing to progres...

## Key facts

- **NIH application ID:** 10232253
- **Project number:** 5R01GM111772-08
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Nina Isoherranen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $377,912
- **Award type:** 5
- **Project period:** 2014-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232253

## Citation

> US National Institutes of Health, RePORTER application 10232253, Mechanisms of Regulation of Retinoic Acid Homeostasis (5R01GM111772-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10232253. Licensed CC0.

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