NAG‐1/GDF15 inhibits HFD‐induced obesity and inflammation by modulating gut microbiota

Abstract

Nonsteroidal anti‐inflammatory drug‐activated gene (NAG‐1) or growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor beta (TGF‐β) superfamily. Mice expressing NAG‐1/GDF15 have been shown to be resistant to high fat diet (HFD)‐induced obesity and inflammation. However, the exact mechanism underlying the anti‐obesity effects of NAG‐1/GDF15 remains unknown. The objective of this study was to examine whether the anti‐obesity effects of NAG‐1/GDF15 is associated with gut microbiota modulation and gut barrier function regulation. First, we confirmed that NAG‐1/GDF15 Tg mice are resistant to dietary induced obesity and inflammation. These mice also demonstrated improved insulin sensitivity compared to Wt littermates. We then found these phenotypic differences were correlated with differences in the composition of gut microbiota, gut barrier function and short chain fatty acids compositions in feces as determined by standard molecular biological methods. In addition, HFD reduced the expression of Cyp7a1, Cyp7b1, Cyp27a1, Ntcp, Mdr2, and Oatp that regulate bile acid metabolism in liver. However, the expression of these genes were increased in NAG‐1/GDF15 Tg mice. Furthermore, antibacterial peptide (Reg3g, Lyz‐1 and Defa) and MUC2 in small intestine were up‐regulated in NAG‐1/GDF15 Tg mice. We also found that NGA‐1/GDF15 down‐regulate the expression of TLR4 and its downstream signals in fat, liver and small intestines at both mRNA and protein levels as determined by Western blot and qRT‐PCR. Finally, we transplanted feces from NAG‐1/GDF15 mice into pseudo germ‐free mice and fed the mice with HFD and found that a shift in gut microbiota composition from NAG‐1/GDF15 mice could inhibit the development of obesity and inflammation. Taken together, our results indicate that the protection role of NAG‐1/GDF15 against HFD‐induced obesity and inflammation is mediated, at least in part, by the modulation of gut microbiota, function of gut barrier, and bile acid metabolism.Support or Funding InformationNational Natural Science Foundation of China Grant No. 81400822.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.