# Promoting metabolic health through the reduction of dietary branched chain amino acids

> **NIH VA I01** · WM S. MIDDLETON MEMORIAL VETERANS HOSP · 2022 · —

## Abstract

Type 2 diabetes affects over 29 million Americans (12.3% of adults over the age of 20). The prevalence of
diabetes in Veterans is approximately double that in the general population and continues to rise. Dietary
interventions to control or prevent type 2 diabetes could be highly effective and affordable, but reduced calorie
diets have proven to be unsustainable over the long term. Diet plans without a decrease in caloric consumption
that instead alter the level of specific macronutrients have therefore been seen as more sustainable by both
researchers and the public. Intriguingly, recent studies in mice and humans have found that low dietary protein
intake is positively associated with health and insulin sensitivity; however, the physiological and molecular
mechanisms by which a low protein diet promotes metabolic health is not fully understood.
We recently determined that decreased dietary intake of the three branched chain amino acids (BCAAs;
leucine, isoleucine, and valine) recapitulates many metabolic benefits of a low protein diet, promoting leanness
and glycemic control even in mice with pre-existing diet-induced obesity and type 2 diabetes. Our preliminary
data suggests that a low BCAA diet promotes glucose tolerance in part by reducing hepatic gluconeogenesis
and increasing hepatic insulin sensitivity, an effect that may be mediated by the AA-sensing kinase, GCN2.
The central hypothesis examined here is that reducing levels of one or more dietary BCAAs alters signaling
through the amino acid-sensing kinase GCN2 or other mediators, leading to favorable physiological changes
that promote metabolic health in both inbred and genetically heterogeneous mice as well as in humans. Our
long-term goal is to gain mechanistic insight into how reducing dietary BCAAs promotes metabolic health,
identifying new points of intervention that may be targeted with pharmaceutical interventions or dietary
strategies and enabling better therapeutic options to prevent and treat obesity and type 2 diabetes in Veterans.
In this proposal, we will determine the specific contribution of each of the three BCAAs on metabolic health in
the context of a Western diet, performing metabolic phenotyping and quantitatively determining the effect of
altered BCAAs on the liver in vivo using hyperinsulinemic-euglycemic clamps and ex vivo in primary
hepatocytes. We will test if our findings are applicable beyond inbred C57BL/6J mice by determining if
reducing BCAAs promotes metabolic health in genetically heterogeneous mice. Finally, we will undertake a
two-pronged approach to gain mechanistic insight into the molecular mechanisms by which reduced BCAAs
promote metabolic health. First, we will test the role of GCN2 using a genetic mouse model lacking hepatic
Gcn2. Second, we will identify candidate molecular mediators by proteomic and metabolomics profiling of the
livers of mice fed a reduced BCAA diet, and test the role of these candidate mediators in the regulation of
hepatocyt...

## Key facts

- **NIH application ID:** 10409708
- **Project number:** 5I01BX004031-05
- **Recipient organization:** WM S. MIDDLETON MEMORIAL VETERANS HOSP
- **Principal Investigator:** Dudley William Lamming
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409708

## Citation

> US National Institutes of Health, RePORTER application 10409708, Promoting metabolic health through the reduction of dietary branched chain amino acids (5I01BX004031-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10409708. Licensed CC0.

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