“You are what you eat,” is a well-known axiom coined over 100 years ago by the French politician and epicure Jean Anthelme Brillat-Savarin. With this in mind, it is unsurprising that as diets across the United States and around the globe have become increasingly unhealthy, we have become unhealthy as well. Linked closely with the obesity epidemic, diabetes now affects over 29 million Americans (12.3% of adults over the age of 20). An additional 86 million Americans over the age of 20 are estimated to have pre-diabetes, making this disease an urgent health care problem.As type 2 diabetes is so closely associated with diet and obesity, it is possible that dietary interventions might prove more effective and affordable than pharmaceutical options. Reduced-calorie diets are notoriously difficult to sustain, but altering the macronutrient composition of the diet while keeping the total number of calories constant is an intriguing alternative. Recent findings suggest that a low protein, high carbohydrate diet can increase lifespan and improve metabolic health in rodents, yet the applicability of these studies to humans as well as the mechanisms driving this effect remain unclear.Here, we demonstrate for the first time in a randomized controlled trial that placing humans on a moderately protein restricted (PR) diet for one month improves multiple markers of metabolic health in humans, including fasting blood glucose and body mass index. We observed similar beneficial effects of moderate PR on the metabolic health of mice over the course of 3 months, with improved glucose tolerance starting as early as three weeks after initiation of the diet. While the precise dietary components altered in a PR diet that promote metabolic health have never been defined, we hypothesized that decreased levels of specific amino acids – the building blocks of protein – might mediate these effects.Several studies have shown that insulin-resistant humans have increased serum levels of the three branched-chain amino acids (BCAAs) – leucine, isoleucine, and valine. To study the contribution of reduced BCAAs to the beneficial effects of a PR diet, we placed mice on one of four amino acid (AA) defined diets: Control (21% of calories from AAs), Low AA (7% of calories from AAs), a Low BCAA diet in which the level of the three BCAAs was the same as in the Low AA (7%) diet, but all other AAs were at the level of a Control (21%) diet; and a Low Leucine diet in which only the level of leucine was reduced by 2/3rds. The caloric density of the diet as well as dietary fat was kept constant. We tracked weight and body composition over the course of three months, periodically testing glycemic control through the use of glucose, insulin, and pyruvate tolerance tests and the analysis of circulating hormones. At the end of the experiment, we isolated islets for the ex vivo analysis of glucose stimulated insulin secretion, and collected tissues and blood for subsequent phosphoproteomic and genomic analysis.We find that a specific reduction in dietary branched chain amino acids (BCAAs) is sufficient to improve glucose tolerance and body composition equivalently to a PR diet in mice. Intriguingly, the improved metabolic health of mice fed a low BCAA diet is independent of increased FGF21, an insulin sensitizing hormone believed to be responsible for many of the positive metabolic effects of a PR diet. Switching mice induced to be obese and insulin resistant through high-fat diet feeding to a diet with reduced levels of BCAAs stimulates rapid improvements in glucose tolerance and fat mass loss. Our results highlight a critical role for dietary quality in glycemic control, and suggest that a reduction of dietary BCAAs, or pharmacological interventions in this pathway, may offer a novel and translatable therapy to promote metabolic health.
Branched-Chain Amino Acids Exacerbate Obesity-Related Hepatic Glucose and Lipid Metabolic Disorders via Attenuating Akt2 Signaling