Restoration of metabolic health by decreased consumption of branched‐chain amino acids

Abstract

Key pointsr We recently found that feeding healthy mice a diet with reduced levels of branched-chain amino acids (BCAAs), which are associated with insulin resistance in both humans and rodents, modestly improves glucose tolerance and slows fat mass gain.r In the present study, we show that a reduced BCAA diet promotes rapid fat mass loss without calorie restriction in obese mice.r Selective reduction of dietary BCAAs also restores glucose tolerance and insulin sensitivity to obese mice, even as they continue to consume a high-fat, high-sugar diet.r A low BCAA diet transiently induces FGF21 (fibroblast growth factor 21) and increases energy expenditure.r We suggest that dietary protein quality (i.e. the precise macronutrient composition of dietary protein) may impact the effectiveness of weight loss diets.Abstract Obesity and diabetes are increasing problems around the world, and although even moderate weight loss can improve metabolic health, reduced calorie diets are notoriously difficult to sustain. Branched-chain amino acids (BCAAs; leucine, isoleucine and valine) are elevated in the blood of obese, insulin-resistant humans and rodents. We recently demonstrated that specifically reducing dietary levels of BCAAs has beneficial effects on the metabolic health of young, growing mice, improving glucose tolerance and modestly slowing fat mass gain. In the present study, we examine the hypothesis that reducing dietary BCAAs will promote weight loss, reduce adiposity, and improve blood glucose control in diet-induced obese mice with pre-existing metabolic syndrome. We find that specifically reducing dietary BCAAs rapidly reverses diet-induced obesity and improves glucoregulatory control in diet-induced obese mice. Most dramatically, mice eating an otherwise unhealthy high-calorie, high-sugar Western diet with reduced levels of BCAAs lost weight and fat mass rapidly until regaining a normal weight. Importantly, this normalization of weight was mediated not by caloric restriction or increased activity, but by increased energy expenditure, and was accompanied by a transient induction of the energy balance regulating hormone FGF21 (fibroblast growth factor 21). Consumption of a Western diet reduced in BCAAs was also accompanied by a dramatic improvement in glucose tolerance and insulin resistance. Our results link dietary BCAAs with the regulation of metabolic health and energy balance in obese animals, and suggest that specifically reducing dietary BCAAs may represent a highly translatable option for the treatment of obesity and insulin resistance.

Targeting BCAA Catabolism to Treat Obesity-Associated Insulin Resistance

“…In obese New Zealand mice, reducing protein intake significantly improved glucose homeostasis, whereas BCAA repletion did not reverse it (52). In a mouse model of preexisting DIO, reducing dietary BCAAs improved glucoregulatory control while reducing body weight (53). In this study, however, the causal role of BCAAs remains unclear, because its impact on glucose regulation could be attributed to changes in body weight rather than BCAAs.…”

Quantitative Analysis of the Whole-Body Metabolic Fate of Branched-Chain Amino Acids

“…In contrast, mice fed an HFD do not consume more BCAAs than chow-fed controls, achieving obesity via fat-based caloric intake instead. Thus, while excess BCAA consumption and oxidation likely contribute to the development of insulin resistance in db/db mice, the same mechanism may be less critical for HFD, although it is important to note that low-BCAA diets also do protect against insulin resistance in HFD models (White et al, 2016;Maida et al, 2016;Cummings et al, 2018). These differences underscore the need for comprehensive and integrated studies, such as this one, in order to understand whole-body metabolic fate of metabolites in health and diseases.…”

Diabetes and branched‐chain amino acids: What is the link?

“…A way to address this may be to understand the effects of changes in diet and other interventions on BCAA, as well as on IR and T2D. In an animal model, lowering dietary BCAA increased energy expenditure and improved insulin sensitivity . Two large human population studies showed an association of estimated dietary BCAA intake with T2D risk, although another population study showed higher dietary BCAA to be associated with lower T2D risk .…”