Moderate intake of BCAA-rich protein improves glucose homeostasis in high-fat-fed mice

Abstract

Notwithstanding the fact that dietary branched-chain amino acids (BCAAs) have been considered to be a cause of insulin resistance (IR), evidence indicates that BCAA-rich whey proteins (WPs) do not lead to IR in animals consuming high-fat (HF) diets and may instead improve glucose homeostasis. To address the role of BCAA-rich WP as dietary protein in IR and inflammatory response, we fed C57BL/6J mice either high-fat (HF) or low-fat (LF) diets formulated with moderate protein levels (13% w/w) of either WP or hydrolyzed WP (WPH) and compared them with casein (CAS) as a reference. The muscle and plasma free amino acid profiles, inflammatory parameters and glycemic homeostasis were examined. While the LF/CAS diet promoted the rise in triglycerides and inflammatory parameters, the HF/CAS induced typical IR responses and impaired biochemical parameters. No differences in plasma BCAAs were detected, but the HF/WPH diet led to a twofold increase in gastrocnemius muscle free amino acids, including BCAAs. In general, ingestion of WPH was effective at averting or attenuating the damage caused by both the LF and HF diets. No high concentrations of BCAAs in the plasma or signs of IR were found in those mice fed an HF diet along with the hydrolyzed whey proteins. It is concluded that consumption of BCAA-rich whey proteins, especially WPH, does not result in the development of IR.

Introduction

Macronutrient imbalanced diets can lead to metabolic disorders such as excessive body fat and insulin resistance (IR). Fat-rich diets have a high inflammatory potential [1] and contribute effectively to expansion of adipose tissue in the body [2]. On the other hand, carbohydrate-rich diets may not influence weight gain [3] but can stimulate insulin levels, glucose uptake, glycogen storage [4] and hypertriglyceridemia [5]. Meanwhile, protein-rich diets can maximize animals' growth but may lead to significant undesirable alterations of the gut microbiota [6] as well as dysregulating nitrogen metabolism.

Increases in inflammatory markers such as IL-6 and TNF-α in adipose tissue and endotoxins translocation from the gut to the bloodstream are important events in the development of IR [7], [8], [9]. Studies by Newgard et al. [10], [11] have found that metabolic dysregulation of free branched-chain amino acids (BCAAs): valine, leucine and isoleucine, can be a signature of glucose intolerance and IR. The increased presence of such amino acids in the blood can activate mTOR [10] and subsequently phosphorylate IRS-1, thus inhibiting insulin action [10], [12], [13]. Therefore, it has been proposed that dietary BCAAs could trigger insulin resistance [14].

Despite such stimulating effects on metabolism, proteins have been found to display protective roles. Proteins counteract the development of obesity and inflammation-related comorbidities by a variety of mechanisms that may include the ability of proteins to increase satiety [15], induce chaperone synthesis [16], [17] and lower plasma lipids and cytokine levels [18], [19] in rats fed diets containing moderate levels of whey protein (WP) as the source of protein. Additionally, some whey peptides have been shown to improve glucose uptake [20].

Therefore, it appears that the antiobesogenic, anti-inflammatory and antihyperglycemic effects attributed to the BCAA-rich milk whey proteins are in conflict with those studies in rodents and humans. Thus, the present work aimed to verify if consumption of the BCAA-rich WP as a sole source of dietary protein affects the IR and inflammatory response. This has been accomplished by feeding mice with diets containing a moderate level of protein using an experimental animal model with both low-fat (LF) and high-FAT (HF) diets.