Sexual dimorphism in glucose metabolism is shaped by androgen-driven gut microbiome

• Published in: Nature communications Vol. 12; no. 1; pp. 7080 - 14
• Main Authors: Gao, Aibo, Su, Junlei, Liu, Ruixin, Zhao, Shaoqian, Li, Wen, Xu, Xiaoqiang, Li, Danjie, Shi, Juan, Gu, Bin, Zhang, Juan, Li, Qi, Wang, Xiaolin, Zhang, Yifei, Xu, Yu, Lu, Jieli, Ning, Guang, Hong, Jie, Bi, Yufang, Gu, Weiqiong, Wang, Jiqiu, Wang, Weiqing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.12.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 38/23; 3T3-L1 Cells; 631/326/2565/2134; 64/60; 692/163/2743; 692/699/317; 82/1; Androgens; Androgens - pharmacology; Animals; Anti-Bacterial Agents - pharmacology; Antibiotics; Castration; Cell Line; Depletion; Diabetes; Diabetes mellitus (non-insulin dependent); Digestive system; Dihydrotestosterone; Dihydrotestosterone - pharmacology; Fecal Microbiota Transplantation; Female; Females; Gastrointestinal Microbiome - drug effects; Gastrointestinal Microbiome - genetics; Gastrointestinal Microbiome - physiology; Glucose; Glucose - metabolism; Glutamic Acid - blood; Glutamine; Glutamine - blood; Gut microbiota; Hep G2 Cells; Homeostasis; Homeostasis - drug effects; Humanities and Social Sciences; Humans; Insulin; Insulin resistance; Insulin Resistance - physiology; Intestinal microflora; Male; Males; Metabolism; Mice; Mice, Inbred C57BL; Microbiomes; Microbiota; multidisciplinary; Orchiectomy; Risk analysis; Risk factors; Science; Science (multidisciplinary); Sex Factors; Sexual dimorphism; Supplements
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-27187-7

Males are generally more susceptible to impaired glucose metabolism and type 2 diabetes (T2D) than females. However, the underlying mechanisms remain to be determined. Here, we revealed that gut microbiome depletion abolished sexual dimorphism in glucose metabolism. The transfer of male donor microbiota into antibiotics-treated female mice led the recipients to be more insulin resistant. Depleting androgen via castration changed the gut microbiome of male mice to be more similar to that of females and improved glucose metabolism, while reintroducing dihydrotestosterone (DHT) reversed these alterations. More importantly, the effects of androgen on glucose metabolism were largely abolished when the gut microbiome was depleted. Next, we demonstrated that androgen modulated circulating glutamine and glutamine/glutamate (Gln/Glu) ratio partially depending on the gut microbiome, and glutamine supplementation increases insulin sensitivity in vitro. Our study identifies the effects of androgen in deteriorating glucose homeostasis partially by modulating the gut microbiome and circulating glutamine and Gln/Glu ratio, thereby contributing to the difference in glucose metabolism between the two sexes. Male sex is a risk factor for impaired glucose metabolism and type 2 diabetes. Here the authors identify that androgen modulates the gut microbiome, which drives insulin resistance and contributes to sexual dimorphism in glucose metabolism in mice.