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...

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Muscle atrophy increases the production of reactive oxygen species and the expression of atrophy-related genes, which are involved in the ubiquitin -proteasome system. In the present study, we investigated the effects of b-carotene on oxidative stress (100 mM-H 2 O 2 )-induced muscle atrophy in murine C2C12 myotubes. b-Carotene (10 mM) restored the H 2 O 2 -induced decreased levels of myosin heavy chain and tropomyosin (P,0·05, n 3) and decreased the H 2 O 2 -induced increased levels of ubiquitin conjugates. b-Carotene reduced the H 2 O 2 -induced increased expression levels of E3 ubiquitin ligases (Atrogin-1 and MuRF1) and deubiquitinating enzymes (USP14 and USP19) (P,0·05, n 3) and attenuated the H 2 O 2 -induced nuclear localisation of FOXO3a. Furthermore, we determined the effects of b-carotene on denervation-induced muscle atrophy. Male ddY mice (8 weeks old, n 30) were divided into two groups and orally pre-administered micelle with or without b-carotene (0·5 mg once daily) for 2 weeks, followed by denervation in the right hindlimb. b-Carotene was further administered once daily until the end of the experiment. At day 3 after denervation, the ratio of soleus muscle mass in the denervated leg to that in the sham leg was significantly higher in b-carotene-administered mice than in control vehicle-administered ones (P,0·05, n 5). In the denervated soleus muscle, b-carotene administration significantly decreased the expression levels of Atrogin-1, MuRF1, USP14 and USP19 (P,0·05, n 5) and the levels of ubiquitin conjugates. These results indicate that b-carotene attenuates soleus muscle loss, perhaps by repressing the expressions of Atrogin-1, MuRF1, USP14 and USP19, at the early stage of soleus muscle atrophy.

Quercetin and its glycosides possess various health beneficial functions, but comparative study of them on energy metabolism in different tissues are not well studied. In this study, we investigated AMP-activated protein kinase regulated glucose metabolism in the skeletal muscle and lipid metabolism in the white adipose tissue and liver to compare the effectiveness of quercetin and its glycosides, namely isoquercitrin, rutin, and enzymatically modified isoquercitrin, in male ICR mice. The mice were fed a standard or high-fat diet supplemented with 0.1% quercetin and its glycosides for 13 weeks. Quercetin glycosides, but not quercetin, decreased body weight gain and fat accumulation in the mesenteric adipose tissue in high-fat groups. All compounds decreased high-fat diet-increased plasma glucose and insulin levels. Moreover, all compounds significantly increased AMP-activated protein kinase phosphorylation in either standard or high-fat diet-fed mice in all tissues tested. As its downstream events, all compounds induced glucose transporter 4 translocation in the muscle. In the white adipose tissue and liver, all compounds increased lipogenesis while decreased lipolysis. Moreover, all compounds increased browning markers and decreased differentiation markers in adipose tissue. Therefore, quercetin and its glycosides are promising food components for prevention of adiposity and hyperglycemia through modulating AMP-activated protein kinase-driven pathways.

Summary Supplements and naturally occurring nutraceuticals effective for maintenance or enhancement of skeletal muscle mass are expected to contribute to prevention of decreased mobility and increased risk of developing metabolic diseases. However, information about available food components remains widely unavailable. In the present study, we investigated the effects of dietary b-carotene on the quantity and quality of skeletal muscle under physiological conditions. Male ddY mice (8 wk old) were orally administered b-carotene (0.5 mg once daily) for 14 d. Dietary b-carotene had no influence on body weight, but increased the soleus muscle/body weight ratio. The cross-sectional area (CSA) in muscle fibers of the soleus muscle was increased, indicating that administration of b-carotene induces muscle hypertrophy. In the soleus muscle of the b-carotene-administered mice, twitch force tended to be increased (p50.06) and tetanic force was significantly increased, whereas specific force (force per CSA) remained unchanged. Dietary b-carotene increased the mRNA level of insulin-like growth factor 1 (Igf-1) as its splicing variant Igf-1ea, but had no influence on the liver Igf-1 mRNA level or serum IGF-1 level. b-Carotene promoted protein synthesis in the soleus muscle and reduced levels of ubiquitin conjugates, but had no influence on the mRNA levels of two atrogenes, Atrogin-1 and Murf1. On the other hand, b-carotene had no influence on the processing of the autophagy marker protein light chain 3. These results indicate that in mice, administration of b-carotene increases mass and induces functional hypertrophy in the soleus muscle, perhaps by promoting IGF-1-mediated protein synthesis and by reducing ubiquitin-mediated protein degradation.