Zeaxanthin Ameliorates Obesity by Activating β3-adrenergic Receptor to Stimulate Inguinal Fat Thermogenesis and Modulating Gut Microbiota

Stimulating fat thermogenesis and modulating gut microbiota is a promising therapeutic strategy against obesity. Zeaxanthin (ZEA), a plant pigment that belongs to carotenoids, has been shown to prevent various diseases, but the therapeutic mechanism for obesity remains unclear. The purpose of the current study was to verify whether ZEA could improve obesity by activating β3-adrenergic receptor (β3-AR) to stimulate white adipose tissue (WAT) thermogenesis and modulating gut microbiota. C57BL6/N mice were fed a HFD administrated with ZEA for 22 weeks. The results demonstrated that ZEA reduced body weight, fat weight, adipocyte hypertrophy, liver weight and lipid deposition, improved dyslipidemias, serum GPT, GOT, leptin and irisin levels, glucose intolerance, and insulin resistance in HFD-fed mice. Mechanistically, ZEA induced the expression of β3-AR and thermogenic factors such as PRDM16, PGC-1α, and UCP1 in inguinal WAT (iWAT) and brown adipose tissue. ZEA stimulated iWAT thermogenesis through the synergistic cooperation of key organelles, which manifested as increasing the expression of lipid droplet degradation factors: ATGL, CGI-58, pHSL, mitochondrial biogenesis factors: Sirt1, Nrf2, Tfam, Nampt, Cyt-C, peroxisomal biogenesis factors: Pex16, Pex19, Pmp70, and β-oxidation factors: Cpt1, Cpt2, Acadm, Acox1. The thermogenic effect of ZEA was proved to be dependent on β3-AR activation with SR59230A antagonist. Additionally, dietary supplementation of ZEA reversed gut microbiota dysbiosis by regulating the abundance of Firmicutes, Clostridia, Proteobacteria and Desulfovibrio, which were associated with the thermogenesis-, obesity-associated indexes by Spearman's correlation analysis. Gut microbiota functional analysis indicated that ZEA significantly enriched the lipid metabolism pathways. These results demonstrate that ZEA is a promising multi-target functional food for the treatment of obesity by activating β3-AR to stimulate iWAT thermogenesis and modulating gut microbiota.