Signal Transducers Regulating Dietary and Pharmacological BCAA Restriction in Obesity and Type II Diabetes: The Role of Mitochondrial BCAA Carrier Slc25a44
Obesity and type 2 diabetes are major public health challenges, with impaired branched-chain amino acid (BCAA) metabolism playing a key role. Restricting dietary BCAAs improves body composition, glucose control and lifespan in animal models. Exercise is also critical for weight loss and maintaining muscle mass, but its interaction with BCAA-targeted interventions is unknown. This project tested whether dietary BCAA restriction and exercise—alone or in combination—reverse obesity and improve metabolic health in mice. Findings demonstrate that selective dietary BCAA restriction induces anti-obesogenic metabolic remodeling in the liver and unexpectedly identifies the gene SLC25A47, rather than SLC25A44, as a key regulator of mitochondrial metabolism in the liver.
The Challenge
Obesity and type 2 diabetes remain major public health challenges and disproportionately impact underserved and Indigenous communities in Wisconsin, where rates of cardiometabolic disease are significantly higher than state and national averages. Many existing treatments are expensive, medication-dependent and difficult to sustain long-term, creating barriers to equitable care. This project addressed these gaps by identifying accessible, prevention-focused strategies that target dietary BCAA modifications and exercise to improve metabolic health through defined mitochondrial pathways.
Project Goals
The objective of this project was to determine the role of dietary BCAA restriction and exercise in reversing the negative effects of diet-induced obesity in mice.
Results
The research team placed male and female mice on dietary amino acid restriction for 12 weeks before collecting liver tissues. The dietary models induced dramatic weight loss, metabolic improvements and lifespan promoting effects. However, SLC25A44 expression in the liver was minimally altered. Broader analysis of the liver-specific SLC25 gene family revealed that SLC25A47 was significantly reduced, identifying it as a novel dietary-responsive mitochondrial node. This may have import implications given recent research demonstrating that liver-specific knockdown of SLC25A47 improves glucose tolerance, enhances insulin sensitivity and increases energy expenditure.
The researchers also examined the impact of voluntary weighted wheel running on circulating plasma, liver and muscle BCAA concentrations. In contrast to human studies that measured immediately and one hour post-exercise, the mice were fasted overnight after wheel removal before tissue collection. Under these conditions, they observed no significant differences between exercised and sedentary animals, suggesting that exercise-induced reductions in BCAAs are likely acute and transient rather than sustained adaptations.
Looking to the Future
Through this award, researchers have successfully established and validated an SLC25A44 knockout and wild-type colony at UW-Madison. This positions their laboratory to investigate SLC25A44 regulation not only in metabolic disease, but also in aging, Alzheimer’s disease and cancer biology. Additionally, the award generated critical preliminary data to be used in upcoming National Institutes of Health grant submissions.
