Dietary branched-chain amino acids restriction in high-fat diet-induced obese mice: effects on metabolic homeostasis, adipose inflammation, and gut microbiota.

Abstract

Background: Numerous studies implicate a strong association between elevated circulating branched-chain amino acids (BCAAs) and obesity and related disorders. However, whether this association is causal, and if disrupted BCAA homeostasis can serve as a therapeutic target for obesity-related diseases remain to be established experimentally.

Objectives: We aimed to explore the long-term effects of BCAAs restriction on lipid and glucose metabolism, adipose inflammation, and gut microbiota in high-fat diet-induced obese mice.

Methods: Three-month-old male C57BL/6J mice were divided into three groups and received a semi-purified ingredient control diet, high-fat diet (HFD), or HFD with 50% BCAAs restriction for 24 weeks. Body weight, fasting serum BCAAs, glucose, insulin, total cholesterol, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol levels, and glucose tolerance were measured. Inflammation markers and macrophage infiltration in epididymal adipose tissue, as well as gut microbiota profiling were conducted. Differences between groups were analyzed by one-way analysis of variance or Wilcoxon rank-sum test.

Results: HFD feeding significantly increased circulating leucine, isoleucine, valine, and total BCAAs levels by 31%, 27%, 19%, and 25%, respectively, compared with the control group (P<0.05). Compared with the HFD group, dietary BCAA restriction significantly decreased circulating leucine, isoleucine, and total BCAAs levels by 21%, 17%, and 16%, respectively (P<0.05). However, this reduction was not sufficient to improve glucose and lipid homeostasis, except for a significant 20% reduction in serum LDL levels (P<0.05). Additionally, BCAA restriction failed to decrease white adipose tissue mass index or alleviate epididymal adipose tissue inflammation HFD-fed mice. Interestingly, BCAAs restriction ameliorated HFD-induced gut microbiota disorder by downregulating the Firmicutes/Bacteroidetes ratio (P<0.05) and reducing the relative abundance of obesity-linked bacteria, such as Lactococcus and Oscillibacter (P<0.05).

Conclusions: Collectively, the results suggest that although BCAA restriction may have limited benefits on HFD-induced obesity and metabolic disorders in mice, it improves gut microbiota dysbiosis.