# BCFA Metabolism and the Regulation of Energy Balance

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2024 · $492,625

## Abstract

PROJECT SUMMARY
Targeting brown adipose tissue (BAT) function to increase energy expenditure represents an attractive strategy
to treat obesity and the associated type 2 diabetes. BAT and the related beige fat express uncoupling protein 1
(UCP1), a mitochondrial membrane protein that uncouples respiration from ATP synthesis and promotes
thermogenesis. Paradoxically, UCP1 null mice are only obese when maintained at thermoneutrality, suggesting
the existence of alternative mechanisms of thermogenesis. Consistent with this notion, several UCP1-
independent ATP-consuming futile cycles have been identified in brown and beige adipocytes. However, the
relative contribution of these pathways to the regulation of whole-body energy metabolism remains unclear.
Our preliminary studies suggest that peroxisomes, organelles specialized for lipid metabolism, are involved in
an alternative mechanism of adipose tissue thermogenesis based on peroxisomal metabolism of branched chain
fatty acids (BCFA). Peroxisomes account for up to 20% of total cellular oxygen consumption. Peroxisomal
respiration, unlike mitochondrial oxygen consumption, is not linked to ATP synthesis and instead generates heat.
Monomethyl (mm) BCFA are synthesized via de novo lipogenesis using a precursor derived from catabolism of
branched chain amino acids (BCAA). Our results reveal that cold treatment increases the gene expression of
factors involved in mmBCFA synthesis and beta-oxidation in thermogenic fat. A thermogenic stimulus promotes
translocation of BCFA synthetic proteins to peroxisomes, the site of BCFA beta-oxidation. Upregulation of BCFA
beta oxidation raises the intracellular temperature in brown adipocytes and increases oxygen consumption rate
in WT and UCP1 KO brown adipocytes. Together, these results lead us to hypothesize that peroxisomes are
involved in a UCP1-independent mechanism of thermogenesis characterized by a futile process of BCFA
synthesis and beta-oxidation. Since de novo synthesis of fatty acids is a highly energy-demanding process and
peroxisomal beta-oxidation is not linked to ATP production, we further hypothesize that this futile cycle promotes
negative energy balance, leading to protection against obesity and insulin resistance. To test this hypothesis,
we propose two specific aims. The first aim will use biochemical, cell culture-based, and in vivo approaches to
implicate peroxisomes in a futile process of BCFA metabolism. The second aim will use loss-of-function and
gain-of-function mouse models of BCFA beta-oxidation to study its role in thermogenesis and whole-body energy
metabolism.

## Key facts

- **NIH application ID:** 10848368
- **Project number:** 5R01DK133344-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Irfan J Lodhi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $492,625
- **Award type:** 5
- **Project period:** 2023-05-25 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10848368

## Citation

> US National Institutes of Health, RePORTER application 10848368, BCFA Metabolism and the Regulation of Energy Balance (5R01DK133344-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10848368. Licensed CC0.

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