# Mechanisms connecting dysregulated BCAA, glucose & lipid metabolism in the pathogenesis of metabolic disease

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $659,801

## Abstract

.PROJECT SUMMARY – R01 Newgard/Herman .
Studies performed by our group have helped establish that branched-chain amino acids (BCAA) and related
metabolites are associated with insulin resistance and T2D, predictive of diabetes development and intervention
outcomes, and highly responsive to therapeutic interventions. The goal of this proposal is to fully understand the
metabolic and molecular mechanisms linking concerted dysregulation of BCAA, glucose and lipid metabolism.
Key recent findings leading to this proposal emerged when we altered branched-chain ketoacid dehydrogenase
(BCKDH) complex activity via pharmacologic and molecular manipulation of its regulatory kinase (BDK) and
phosphatase (PPM1K) in rodent models of obesity and metabolic disease. Treatment of Zucker-obese rats with
BT2, a small molecule inhibitor of BDK, or a recombinant adenovirus expressing PPM1K lowered circulating
BCAA and branched chain ketoacid levels, improved glucose tolerance and insulin sensitivity, and increased
fatty acid oxidation while markedly decreasing liver triglycerides. Phosphoproteomics analysis revealed that in
addition to their function to modify BCKDH activity, BDK and PPM1K also regulate the phosphorylation of the
key lipogenic enzyme, ATP-citrate lyase (ACL). Whereas phosphorylation of BCKDH inhibits its activity,
phosphorylation of ACL is an activating post-translational modification that leads to increased de novo
lipogenesis. We also demonstrated that overnutrition or fructose feeding activates the carbohydrate sensing
transcription factor, ChREBP, which upregulates both BDK and ACL expression while suppressing PPM1K.
Altogether, these studies define a novel regulatory node integrating glucose, lipid, and BCAA metabolism that
participates in the progression of metabolic disease. The current study seeks to understand the impact of chronic
manipulation of the ChREBP/BDK/PPM1K regulatory node in multiple dietary contexts, and to expand our human
studies to include evaluation of genetic and dietary variables, via the following specific aims: 1) To test the
hypothesis that chronic hepatic BDK overexpression will exacerbate metabolic disease phenotypes; 2) To test
the hypotheses that chronic hepatic PPM1K overexpression or ChREBP suppression will attenuate or prevent
development of metabolic disease phenotypes; 3) To determine whether consumption of sugar-sweetened
beverages (SSB) associates with circulating BCAA levels, and whether genetic variants in the
ChREBP/BDK/PPM1K regulatory node interact with sugar consumption to regulate BCAA levels and other
metabolic traits in human populations.

## Key facts

- **NIH application ID:** 10223286
- **Project number:** 5R01DK121710-03
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** MARK A HERMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $659,801
- **Award type:** 5
- **Project period:** 2019-08-19 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10223286

## Citation

> US National Institutes of Health, RePORTER application 10223286, Mechanisms connecting dysregulated BCAA, glucose & lipid metabolism in the pathogenesis of metabolic disease (5R01DK121710-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10223286. Licensed CC0.

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