Introduction and Objective: Long-term low-protein diets (LPD) have been shown to improve metabolic health and extend lifespan in mice, with potential relevance to humans. However, most studies focus on preventive effects, leaving their therapeutic potential for existing metabolic dysfunction underexplored. Previously, we showed that LPD (5.1% kcal from protein) significantly improved postprandial blood glucose (BG) in lipodystrophic IRFKO (adipose-specific insulin receptor knockout) mice after 14 days, accompanied by strong activation of interscapular brown adipose tissue (iBAT) and increased energy expenditure.Methods: To determine the amino acid responsible for the beneficial effects of LPD, we fed the IRFKO mice a diet low in branched-chain amino acids (BCAA). To determine whether the BG-lowering effect of acute LPD treatment was sustainable, we first treated both male and female IRFKO mice with LPD for 2-3 weeks, then switched them back to a chow diet and continued to monitor the BG levels weekly for about 3 months.Results: Interestingly, our preliminary data showed that, similar to LPD, the BCAA-reduced diet also markedly reduced hyperglycemia in the IRFKO mice. Our data show that the beneficial effects of LPD were largely sustainable across all the IRFKO mice, especially in female mice. Our preliminary H&E data suggest that, despite still being lipodystrophic, the BAT of the IRFKO mice remained brown and multilocular, potentially contributing to the observed phenotype.Conclusion: Prompted by a recent study demonstrating epigenetic memory in adipose tissue, we aim to investigate whether LPD induces permanent functional changes in the BAT of IRFKO mice via epigenetic modifications. Taken together, our data suggest that short-term LPD or possibly the reduction of BCAA alone is sufficient to improve whole-body glucose homeostasis.
A. Kumar: None. C. LIew: None. A. Ter-Zakaryan: None.
1R01DK135542A1
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