Decreased consumption of specific dietary macronutrients restores metabolic health to diet‐induced obese mice
Authors: Lamming Dudley W. , Cummings Nicole E. , Pak Heidi , Williams Elizabeth M. , Konon Elizabeth N. , Walter Madalyn M. , Barnes Macy E. , Yu Deyang 
Published: June 2021

Obesity and diabetes are increasing problems in the United States and worldwide. While even moderate weight loss can improve metabolic health, reduced calorie diets are notoriously difficult to sustain. Plasma branched‐chain amino acids (BCAAs) are elevated in obese humans and rodents, and high protein or BCAA consumption is implicated in impaired metabolic health. We and others have found that reduced BCAA consumption is associated with reduced fat mass gain when begun at a young age. Here, we examined the hypothesis that reducing dietary BCAAs would promote weight normalization and improve blood glucose control in mice with pre‐existing metabolic syndrome, without requiring a reduction in caloric intake.C57BL/6J mice were pre‐conditioned with a high calorie, high‐fat, high‐sugar Western diet for 12 weeks until they were obese and pre‐diabetic. Mice were then randomized into several groups and fed amino acid defined diets with reduced or increased levels of the three BCAAs (Leucine, Isoleucine, Valine), in the context of either a normal calorie diet or a high‐calorie “Western” diet. We examined weight, body composition, glucose and insulin tolerance, food intake, activity and energy expenditure, over the following 4 months, as well as examining the effects of altering dietary BCAAs on the taxonomic composition of the gut microbiome.We find that specifically reducing dietary BCAAs rapidly reverses diet‐induced obesity and improves glucoregulatory control in diet‐induced obese mice. Mice switched to a diet with reduced levels of BCAAs lost weight and fat mass rapidly until returning to a normal weight, while mice consuming isocaloric diets with normal or increased levels of BCAAs remained obese. This normalization of weight was mediated by increased energy expenditure, and was accompanied by a dramatic improvement in glucose tolerance and insulin resistance. Subsequent experiments suggest this latter effect may be mediated by changes to the gut microbiome.Our results demonstrate that diets with decreased levels of BCAAs promote metabolic health and energy balance in obese animals, and link dietary protein quality – the specific amino acid composition of the diet – to metabolic health as well as the composition of the gut microbiome. Specifically reducing dietary BCAAs may represent a translatable option for the treatment of obesity and insulin resistance.Support or Funding InformationThe Lamming lab is supported by the NIH (AG041765, AG051974, and AG056771), a Glenn Foundation Award for Research in the Biological Mechanisms of Aging, and a New Investigator Program Award from the Wisconsin Partnership Program. This research was conducted while DWL was an AFAR Research Grant recipient. NEC is supported by a training grant from the UW Institute on Aging (T32 AG000213). EMW was supported by the Shapiro Summer Research Program. DY is supported in part by a fellowship from the AHA (17PRE33410983). This work was supported using facilities and resources from the William S. Middleton Memorial Veterans Hospital. This work does not represent the views of the Department of Veterans Affairs or the United States Government.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.