Estradiol modulates gut microbiota in femaleob/obmice fed a high fat diet

Abstract

0Estrogens protect against diet-induced obesity in women and female rodents. In support of these 2 1 anorectic effects, lack of estrogens in postmenopausal women is associated with weight gain, 2 2 increasing their risk for cardiovascular diseases and cancer. Estrogens act with leptin, a satiety 2 3 2 hormone encoded by the ob gene, to regulate energy homeostasis in females. Leptin-deficient 1 mice (ob/ob) exhibit morbid obesity and insulin resistance. In addition to estrogens and leptin, 2 the gut microbiome (gut microbes and their metabolites), is critical in regulating energy 3 metabolism. The present study investigates whether estrogens and leptin modulate gut 4 microbiota in ovariectomized ob/ob (obese) or heterozygote (lean) control mice fed a high-fat 5 diet (HFD) that received either 17β-Estradiol (E2) or vehicle implants. E2 attenuated weight gain 6 in both genotypes compared to vehicle counterparts. Moreover, both obesity (ob/ob mice) and 7 E2 reduced gut microbial diversity. ob/ob mice exhibited lower species richness than control 8 mice, while E2-treated mice had reduced evenness compared to vehicle mice. Regarding taxa, 9 E2 treatment was associated with higher abundances of the family S24-7. Leptin was associated targeting the gut microbiome for hormone-dependent metabolic disorders in women. 1 6 1 7 1 8 1 9 2 1and behavior [4][5][6]. Estrogens reduce food intake, attenuate body weight gain and adiposity, and 2 2 increase physical activity in both humans and rodents [1, 2]. Postmenopausal women have lower 2 3 3 levels of circulating estrogens and an increased tendency to gain fat weight, which increases their 1 risk for obesity, cardiovascular disease, stroke, and type 2 diabetes [7][8][9]. Similarly, in mice on a 2 high-fat diet (HFD), ovariectomy increases energy intake and the development of obesity, while 3 estradiol (E2) treatment prevents weight gain [2,[10][11][12][13], indicating that estrogens protect against 4 HFD-induced obesity. 6Leptin is a peptide hormone secreted primarily by adipocytes, which acts in the brain to stimulate 7 metabolism, promote satiety, and regulate fat storage [14][15][16]. A mutation in the ob gene that 8 encodes leptin results in mice lacking the hormone (ob/ob) [17]. While phenotypically normal at 9 birth, ob/ob mice quickly develop obesity and diabetes [18]. Additionally, ob/ob mice exhibit 1 0 increased food intake and decreased physical activity, energy metabolism, and body temperature 1 1 compared to lean controls, making ob/ob mice an excellent genetic model of obesity [19][20][21]. 2Administering leptin to adult ob/ob mice reverses these effects by decreasing food intake, 1 3 increasing energy output and decreasing circulating levels of glucose and insulin [22, 23]. 1 4 1 5Leptin and estrogen signaling pathways interact to influence reproduction and energy 1 6 metabolism. High levels of E2 are associated with increased leptin sensitivity in both male and 1 7 female rodents [24]. In mice, ovariectomy decreases leptin sensitivity, but can be restored by E2 1 ...