Effects Of EGCG On Brown Adipose Tissue Activation And Hypothalamic Inflammatory Pathway In Obese Mice Fed A High-Fat Diet

Obesity is an escalating global epidemic caused by an imbalance between energy intake and expenditure.(-)-Epigallocatechin-3-gallate(EGCG),the major polyphenol in green tea,has been reported to be conducive to preventing obesity and alleviating obesity-related chronic diseases.However,the role of EGCG in energy metabolism disorders and central nervous system dysfunction induced by a high-fat diet(HFD)remains to be elucidated.The aim of this study is to evaluate the effects of EGCG on brown adipose tissue thermogenesis and microglia-mediated hypothalamic inflammation in HFD-induced obesity.Related cell model and mice model have been built and investigations have been carried out including obesity-related metabolic metabolism,brown adipose tissue(BAT)activity,energy consumption,mRNA expression of major inflammatory cytokines,phosphorylation of critical proteins in NF-κB and JAK2/STAT3 signaling pathways,and immunofluorescence staining of microglial marker Iba-1 in hypothalamic arcuate nucleus.Experimental results demonstrated that dietary supplementation of EGCG sigrificantly inhibited HFD-induced obesity by enhancing BAT thermogenesis,attenuating the hypothalamic inflammation and microglia overactivation.This study attempts to offer additional evidence for the potential application of EGCG in combating obesity and maintaining the energy balance regulation in hypothalamus.The main results are as follows:(1)C57BL/6J mice were randomly divided into six groups with different diets:normal chow diet(NCD),normal chow diet supplemented with 0.5%EGCG(NCD + 0.5%EGCG),normal chow diet supplemented with 1%EGCG(NCD + EGCG),high-fat diet(HFD),high-fat diet supplemented with 0.5%EGCG(HFD + 0.5%EGCG),and high-fat diet supplemented with 1%EGCG(HFD + EGCG).After four weeks’treatment,the HFD induced a rmarked increase in body weight,adipose tissue weight,the size of adipose cells,and levels of serum glucose and total triglyceride,which could be dramatically alleviated by EGCG supplementation.Supplementation with 0.5%EGCG and 1%EGCG reduced the body weights by 32.4%and 46.5%respectively,compared with the HFD group.In addition,there was no significant difference in energy intake between different groups,indicating that dietary supplementation of EGCG could significantly reduce the food calorne utilization rate of mice fed high-fat diet,thereby reducing weight gain.(2)It was speculated that EGCG played an important role in energy expenditure through promoting BAT activity.Indeed,mRNA expressions of genes related to thermogenesis and mitochondrial biogenesis in BAT,such as UCP1,PGC-1α,and PRDM16,were dramatically increased in HFD + EGCG group.Previous studies have shown that BAT activation induced by excessive energy intake is similar to that induced by cold exposure.Therefore,a cold tolerance test was implemented to evaluate adaptive thermogenesis among the four groups of mice.Data showed that EGCG treatment increased energy expenditure owing to enhanced BAT thermogenesis and resisted obesity induced by HFD.(3)The influence of EGCG on SFA-mediated lipid accumulation and inflammatory responses in palmitic acid-stimulated BV-2 cells were tested.Results showed less lipid accumulation and lower levels of TNFa,IL-6,and IL-1β in groups with EGCG pretreatment than the palmitic acid group,which intensifies with the increase of EGCG concentration.Moreover,EGCG inhibited the palmitic acid-induced activation of NF-κB and JAK2/STAT3 pathway by suppressing phosphorylation of IκB-a,NF-κB,JAK2 and STAT3.(4)In HFD-induced obese mice model,EGCG-treated mice presented a marked decline of inflammatory cytokine levels and microglia activation in the hypothalamus,as compared to those of the HFD group.Consistently,the phosphorylation of IκB-a,NF-κB,JAK2 and STAT3 was also noticeably upregulated by HFD,which could be mitigated by EGCG,suggesting that EGCG attenuates HFD-induced neuroinflammation through the suppression of NF-κB and JAK2/STAT3 signal pathways,providing a neurological insight into the anti-obesity mechanism of EGCG.