Branched-chain amino acids impact health and lifespan indirectly via amino acid balance and appetite control

• DOI: 10.1038/s42255-019-0059-2
• Publication Date: 2019-04-29T20:16:28Z
• Authors: Samantha M. Solon...; Victoria C. Cogger; Tamara Pulpitel; Devin Wahl; Ximonie Clark; Elena E. Bagley; Gabrielle C. Greg...; Alistair M. Senior; Qiao-Ping Wang; Amanda E. Brandon; Ruth Perks; John O’Sullivan; Yen Chin Koay; Kim Bell-Anderson; Melkam Kebede; Belinda Yau; Clare Atkinson; Gunbjorg Svineng; Tim Dodgson; Jibran A. Wali; Matthew D. W. Piper; Paula Juricic; Linda Partridge; Adam J. Rose; David Raubenheimer; Gregory J. Cooney; David G. Le Couteur; Stephen J. Simpson
• Keywords: Male; 2. Zero hunger; 0301 basic medicine; Serotonin; Appetite Regulation; Hypothalamus; Tryptophan; Metabolic diseases; Hyperphagia; 3. Good health; Mice, Inbred C57BL; Ageing; Mice; 03 medical and health sciences; Life Expectancy; Gene Expression Regulation; Feeding behaviour; Animals; Female; Obesity; Amino Acids; Insulin Resistance; Amino Acids, Branched-Chain; Nutrition

Elevated branched chain amino acids (BCAAs) are associated with obesity and insulin resistance. How long-term dietary BCAAs impact late-life health and lifespan is unknown. Here, we show that when dietary BCAAs are varied against a fixed, isocaloric macronutrient background, long-term exposure to high BCAA diets leads to hyperphagia, obesity and reduced lifespan. These effects are not due to elevated BCAA per se or hepatic mTOR activation, but rather due to a shift in the relative quantity of dietary BCAAs and other AAs, notably tryptophan and threonine. Increasing the ratio of BCAAs to these AAs resulted in hyperphagia and is associated with central serotonin depletion. Preventing hyperphagia by calorie restriction or pair-feeding averts the health costs of a high BCAA diet. Our data highlight a role for amino acid quality in energy balance and show that health costs of chronic high BCAA intakes need not be due to intrinsic toxicity but, rather, a consequence of hyperphagia driven by AA imbalance.