The prevalence of obesity and obesity-related metabolic disorders is rapidly increasing all over the world, increasing the risk to develop insulin resistance and diabetes. Consequently, approaches for reducing the current obesity epidemic are becoming a primary focus of human health care.

Leucine has been extensively explored for therapeutic intervention of obesity and its associated metabolic disorders. However, several studies have reported that increasing leucine levels in blood and adipose tissue of animals and humans with obesity prognosticates the risk to develop insulin resistance and diabetes. The negative effects of leucine is closely associated with the fact that adipocytes lose the ability to degrade and oxidize leucine. Interestingly, β-hydroxy-β-methylbutyrate (HMB) is a metabolite of leucine and cannot be reversibly converted to leucine and subsequently gives rise to enhancements in circulating leucine. Therefore, HMB has recently gained attention as a dietary supplement to modulate lipid metabolism. Using a swine model, we previously found that dietary supplementation of HMB (0.62%, half of the leucine content) improved lipid metabolism, leading to the decrease of adipose tissue mass. However, much about the exact mechanism by which HMB may stimulate these processes remains to be determined.

Recently, a team of researchers from China Agricultural University, the Institute of Subtropical Agriculture, Chinese Academy of Sciences (ISA) conducted a study to compare and contrast the effects of different dosages of HMB on lipid metabolism in a high-fat diet (HFD)-fed mice and unravel the underlying mechanisms of HMB action of lipid metabolism.

The researchers found that the optimal dosage of HMB is 1.0%. When at the optimal dosage, HMB reduced body weight, alleviated the whitening of brown adipose tissue, and improved insulin resistance in mice fed a HFD. High-throughput pyrosequencing of the 16S rRNA demonstrated that HMB administration significantly reversed the gut microbiota dysbiosis in HFD-fed mice, including the diversity of gut microbiota and relative abundances of Bacteroidetes and Firmicutes. Moreover, microbiota transplantation from HMB-treated mice attenuated HFD-induced lipid metabolic disorders. Furthermore, HFD-fed mice showed lower short-chain fatty acids while administration of HMB increased the propionic acid production. Correlation analysis identified a significant correlation between propionic acid production and the relative Bacteroidetes abundance. Sodium propionate treatment also attenuated HFD-induced lipid metabolic disorders. Collectively, our results indicated that HMB might be used as a probiotic agent to reverse HFD-induced obesity and the potential mechanism was associated with reprogramming gut microbiota and metabolism, especially Bacteroidetes-mediated propionic acid production.

The research was the jointly supported by the National Natural Science Foundation of China (31802077), the Science and Technology Project of Guangxi Province (2018JJB130239), the National Key R & D Program (2018YFD0500405, 2016YFD0501204, and 2017YFD0500503), the Youth Innovation Promotion Association CAS (2016326), the Science and Technology Projects of Hunan Province (2016SK3022, 2017RS3058), the Key Project of Research and Development Plan of Hunan Province (2016NK2170), the Youth Innovation Team Project of ISA (2017QNCXTD_ZCS), the Earmarked Fund for China Agriculture Research System (CARS-35), Special Fund for Ability Construction Supported by Guangdong Academy of Science (2017GDASCX-0702), the Major Project for Changsha City (kq1706147), the STS regional key project of the Chinese Academy of Sciences (KFJ-STS-QYZD-052), and the Talent Projects of Guangxi Science and Technology Department (AD17195043).

The study entitled “Gut microbiota mediates the protective effects of dietary β-hydroxy-β-methylbutyrate (HMB) against obesity induced by high-fat diets” has been published in Volume 33, January 2019 of FASEB Journal, details could be found at https://doi.org/10.1096/fj.201900665RR.

Contact: YIN Yulong

E-mail:yinyulong@isa.ac.cn

Institue of Subtropical Agriculture,Chinese Academy of Sciences