A microarray analysis of sexual dimorphism of adipose tissues in high-fat-diet-induced obese mice

Abstract

Objective A sexual dimorphism exists in body fat distribution; females deposit relatively more fat in subcutaneous/inguinal depots whereas males deposit more fat in the intra-abdominal/gonadal depot. Our objective was to systematically document depot- and sex-related differences in the accumulation of adipose tissue and gene expression, comparing differentially expressed genes in diet-induced obese mice with mice maintained on a chow diet. Research Design and Methods We used a microarray approach to determine whether there are sexual dimorphisms in gene expression in age-matched male, female or ovariectomized female (OVX) C57/BL6 mice maintained on a high-fat (HF) diet. We then compared expression of validated genes between the sexes on a chow diet. Results After exposure to a high fat diet for 12 weeks, females gained less weight than males. The microarray analyses indicate in intra-abdominal/gonadal adipose tissue in females 1642 genes differ by at least twofold between the depots, whereas 706 genes differ in subcutaneous/inguinal adipose tissue when compared with males. Only 138 genes are commonly regulated in both sexes and adipose tissue depots. Inflammatory genes (cytokine–cytokine receptor interactions and acute-phase protein synthesis) are upregulated in males when compared with females, and there is a partial reversal after OVX, where OVX adipose tissue gene expression is more ′male-like′. This pattern is not observed in mice maintained on chow. Histology of male gonadal white adipose tissue (GWAT) shows more crown-like structures than females, indicative of inflammation and adipose tissue remodeling. In addition, genes related to insulin signaling and lipid synthesis are higher in females than males, regardless of dietary exposure. Conclusions These data suggest that male and female adipose tissue differ between the sexes regardless of diet. Moreover, HF diet exposure elicits a much greater inflammatory response in males when compared with females. This data set underscores the importance of analyzing depot-, sex- and steroid-dependent regulation of adipose tissue distribution and function.

Sex differences during the course of diet-induced obesity in mice: adipose tissue expandability and glycemic control

“…We verified the hypothesis (see Introduction) that the capacity for enlargement is increased in adipocytes of female compared with male mice in response to a long-term HF feeding, possibly reflecting the higher insulin sensitivity of the female adipocytes. In contrast to similar studies performed previously, 6,7,19 the sex-dependent metabolic phenotypes observed in this mouse model of dietary obesity could not be attributed to a lower body weight gain, adiposity and/or smaller fat cells in females. Most of the results were confirmed by an independent experiment on a separate cohort of animals (not shown).…”

“…Most of the results were confirmed by an independent experiment on a separate cohort of animals (not shown). Study of Grove et al, 19 published recently in this journal, showed less inflamed gWAT in female than in male C57BL/6 mice fed HF diet for 12 weeks after weaning, with female mice having lower fat mass. Moreover, in female mice, the size of adipocytes tended to be smaller in gWAT, whereas it was significantly smaller in scWAT.…”

“…16 Moreover, larger fat cells are associated with a low-grade adipose tissue inflammation, another key factor linking obesity with insulin resistance. 13,14,[17][18][19] Enhanced secretion of chemoattractants in obese state, like monocyte chemoattractant protein-1 (MCP-1), is believed to promote migration of macrophages 20,21 as well as other immune cells 22 into the tissue accompanied by the phenotypic switch of macrophages to proinflammatory state. 23,24 Higher release of proinflammatory cytokines, like tumor necrosis factor a (TNFa) and interleukin 6, into circulation may disrupt insulin signaling in other tissues.…”

“…23,24 Higher release of proinflammatory cytokines, like tumor necrosis factor a (TNFa) and interleukin 6, into circulation may disrupt insulin signaling in other tissues. [25][26][27] Recent studies in mice 19,28 showed that high-fat (HF) diet-induced obesity is associated with increased macrophage infiltration and inflammation in gonadal fat (gWAT) and to a lower extent also in subcutaneous fat (scWAT). Inflammatory state in gWAT is correlated with systemic insulin resistance 28 and with hepatic triglyceride (TAG) content in rodents.…”

“…[34][35][36][37] Most of the above studies were performed on male subjects. However, studies in humans [38][39][40] as well as in mice 19 suggest that lower adipose tissue macrophage infiltration 19 and/or smaller fat cell size 19,40 in female subjects could contribute to the sex differences in propensity to the disorders of the metabolic syndrome. In this study performed in mice, we tested a hypothesis that because of a higher stimulation of lipogenesis and a stronger antilipolytic effect of insulin in female adipocytes, especially those in gWAT, 4,7 (1) prolonged HF feeding may eventually result in larger fat cells in female than in male animals, and that (2) glycemic control may be less affected by excessive adiposity in female than in male mice, even in the presence of larger adipocytes in the females.…”