Sex differences in sympathetic innervation and browning of white adipose tissue of mice

Abstract

BackgroundThe higher prevalence of obesity-related metabolic disease in males suggests that female sex hormones provide protective mechanisms against the pathogenesis of metabolic syndrome. Because browning of white adipose tissue (WAT) is protective against obesity-related metabolic disease, we examined sex differences in β3-adrenergic remodeling of WAT in mice.MethodsEffects of the β3-adrenergic receptor agonist CL316,243 (CL) on browning of white adipose tissue were investigated in male and female C57BL mice. The role of ovarian hormones in female-specific browning was studied in control female C57BL mice and mice with ovarian failure induced by 4-vinylcyclohexene diepoxide treatment for 15 days.ResultsWe found that treatment with CL-induced upregulation of brown adipocyte markers and mitochondrial respiratory chain proteins in gonadal WAT (gWAT) of female mice, but was without effect in males. In contrast, CL treatment was equally effective in males and females in inducing brown adipocyte phenotypes in inguinal WAT. The tissue- and sex-specific differences in brown adipocyte recruitment were correlated with differences in sympathetic innervation, as determined by tyrosine hydroxylase immunostaining and western blotting. Levels of the neurotrophins NGF and BDNF were significantly higher in gWAT of female mice. CL treatment significantly increased NGF levels in gWAT of female mice but did not affect BDNF expression. In contrast, estradiol treatment doubled BDNF expression in female adipocytes differentiated in vitro. Ovarian failure induced by 4-vinylcyclohexene diepoxide treatment dramatically reduced BDNF and TH expression in gWAT, eliminated induction of UCP1 by CL, and reduced tissue metabolic rate.ConclusionsCollectively, these data demonstrate that female mice are more responsive than males to the recruitment of brown adipocytes in gonadal WAT and this difference corresponds to greater levels of estrogen-dependent sympathetic innervation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13293-016-0121-7) contains supplementary material, which is available to authorized users.

Gender and Sex Differences in Adipose Tissue

“…In addition to inflammation-induced remodeling, a sex difference in sympathetic activity results in female-specific induction of brown adipocytes in GWAT, which could be involved in the protection of female mice against metabolic disease [77]. Estrogen can also influence brown adipose tissue (BAT) activity by upregulating thermogenesis.…”

Estrogen Receptor beta (ERβ) Regulation of Lipid Homeostasis—Does Sex Matter?

“…These differences could be the consequence of the different genetic basis of fat distribution between the sexes [29]. In addition, female mice are more responsive to recruitment of brown adipocytes in VAT than male mice, probably due to the higher level of estrogen-dependent sympathetic innervation [30]. One possible mechanism that could be behind the actions of ERβ in lipid homeostasis is the cross-talk between ERβ and PPARγ, where ERβ inhibits the ligand-mediated PPARγ activity that leads to reduced adipogenesis [8,11].…”

Cited4 is a sex‐biased mediator of the antidiabetic glitazone response in adipocyte progenitors

“…Estrogen signaling has been implicated in the regulation of thermogenic adipose tissue expression with both central nervous system and local effects in adipocyte progenitor cells (Lapid et al, 2014;Martinez de Morentin et al, 2014). For instance, it was shown that the induction of Ucp1 by CL-316,243 in mouse gWAT was compromised by experimental ovarian failure (Kim et al, 2016). Interestingly, the estrogen receptor is able to interfere with the activity of PPARg and thereby influence PPARgdependent metabolic processes (Foryst-Ludwig et al, 2008;Benz et al, 2012).…”