Castration influences intestinal microflora and induces abdominal obesity in high-fat diet-fed mice

Abstract

Late-onset hypogonadism (i.e. androgen deficiency) raises the risk for abdominal obesity in men. The mechanism for this obesity is unclear. Here, we demonstrated that hypogonadism after castration caused abdominal obesity in high-fat diet (HFD)-fed, but not in standard diet (SD)-fed, C57BL/6J mice. Furthermore, the phenotype was not induced in mice treated with antibiotics that disrupt the intestinal microflora. In HFD-fed mice, castration increased feed efficiency and decreased fecal weight per food intake. Castration also induced in an increase of visceral fat mass only in the absence of antibiotics in HFD-fed mice, whereas subcutaneous fat mass was increased by castration irrespective of antibiotics. Castration reduced the expression in the mesenteric fat of both adipose triglyceride lipase and hormonesensitive lipase in HFD-fed mice, which was not observed in the presence of antibiotics. Castration decreased thigh muscle (i.e. quadriceps and hamstrings) mass, elevated fasting blood glucose levels, and increased liver triglyceride levels in a HFD-dependent manner, whereas these changes were not observed in castrated mice treated with antibiotics. The Firmicutes/Bacteroidetes ratio and Lactobacillus species increased in the feces of HFD-fed castrated mice. These results show that androgen (e.g. testosterone) deficiency can alter the intestinal microbiome and induce abdominal obesity in a dietdependent manner.Obesity is a global epidemic problem due to its strong association with an increased risk of cardiovascular diseases 1,2 . The excess accumulation of abdominal visceral fat, a diagnostic criterion of the metabolic syndrome 2 , increases the disorder in lipid metabolism, including an elevation of hepatic triglyceride levels 3 . In contrast, subcutaneous fat reduces the incidence of cardiovascular diseases, indicating the importance of body fat distribution 1,2 . Recent results show that the changes in intestinal microbiota are related to the development of obesity and to the increase of visceral fat mass [4][5][6][7] . Testosterone is a male sexual hormone (viz. androgen) that exerts a broad range of male physiological functions, such as the development of reproductive organs and the emergence of sexual behaviors 8,9 . Hypogonadism (i.e. low testosterone level) increases in men the risk of obesity, cardiovascular diseases, and even mortality [10][11][12][13] through the increase of body fat, in particular visceral fat 14,15 ; and testosterone treatment reduces the amount of visceral fat 16 . Androgen deprivation therapies, such as either castration or an leteinizing hormone-releasing hormone analog for prostate cancer patients, also promote the development of obesity [17][18][19] . Because the blood bioactive testosterone level steadily drops approximately 2% per year after around the age of 20 to 30 in men 20 , the age-dependent decline of testosterone is a risk factor for the age-related prevalence of abdominal obesity and its related diseases in men 14,20 . Despite increasing evidence in both clinical an...

Hypogonadism alters cecal and fecal microbiota in male mice

“…, castration or luteinizing hormone-releasing hormone analog) had not been reported to induce obesity in mice or rats 18-20 . However, our recent study showed that castration-induced obesity in C57BL/6J mice occurred in a diet-dependent manner, despite decreased food intake 16 . In general, decreased body temperature secondary to lower heat production is considered a risk for the development of obesity because of the decreased energy expenditure.…”

“…In accordance with our recent paper, 16 C57BL/6J mice were castrated at 8-weeks-old and fed the AIN93G-based standard-diet (SD, containing 7% corn oil), or the HFD (containing 14% beef tallow, 14% lard, and 2% corn oil substituted for cornstarch). Castrated mice (sacrificed at 13-weeks-old) exhibited smaller cecal content weight than sham-operated mice in the HFD-dependent manner (Fig.…”

“…Although sex differences are also observed in the prevalence of metabolic diseases, 15 the involvement of sex hormones in the gut microbiota in sex-biased metabolic changes remains poorly understood. Our recent study showed that androgen deprivation by castration changes the composition of fecal microbiota in a high-fat diet (HFD)-dependent manner 16 . In addition, castrated male mice fed an HFD also exhibited obesity, impaired fasting glucose, excess accumulation of liver triglyceride, and thigh muscle loss.…”

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Figure 1.Effects of castration and diet on cecal weight and cecal microbiota. Mice were castrated or sham operated at 8-weeks-old and grown to 13 weeks with either a standard diet (SD) or high-fat diet (HFD), as described previously 16 (A) Cecal content was weighed. (B) DNA was extracted from cecal microbiota and analyzed by real-time PCR using specific primers 16 .

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Agaro-Oligosaccharides Regulate Gut Microbiota and Adipose Tissue Accumulation in Mice

“…Accumulating evidence demonstrates that the gut microbiota and its metabolites affect body weight and energy homeostasis (2)(3)(4). The current use of genomicsbased molecular techniques such as metabolomics and metagenomics has boosted studies aimed at clarifying the precise relation between gut microbiota and obesity (5).…”