title: Sex differences in sympathetic innervation and browning of white adipose tissue of mice.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  Effects 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.
  
  
  RESULTS
  We 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.
  
  
  CONCLUSIONS
  Collectively, 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.
authors.affiliation: College of Pharmacy, Yonsei University, 310 Veritas Hall D, 85 Songdogwahak-ro, Yeonsu-gu Incheon, 21983 South Korea.
authors.forename: Sang-Nam
authors.initials: SN
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Pusan National University, Busan, 46241 South Korea.
authors.forename: Young-Suk
authors.initials: YS
authors.lastname: Jung
authors.affiliation: College of Pharmacy, Yonsei University, 310 Veritas Hall D, 85 Songdogwahak-ro, Yeonsu-gu Incheon, 21983 South Korea.
authors.forename: Hyun-Jung
authors.initials: HJ
authors.lastname: Kwon
authors.affiliation: BK21 PLUS Program for Creative Veterinary Science Research, Research Institute for Veterinary Science, and Korea Mouse Phenotyping Center, Seoul National University, Seoul, 08826 South Korea.
authors.forename: Je Kyung
authors.initials: JK
authors.lastname: Seong
authors.affiliation: School of Medicine, Wayne State University, Detroit, MI 48201 USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Granneman
authors.affiliation: College of Pharmacy, Yonsei University, 310 Veritas Hall D, 85 Songdogwahak-ro, Yeonsu-gu Incheon, 21983 South Korea.
authors.forename: Yun-Hee
authors.identifier: 0000-0003-2776-3203
authors.initials: YH
authors.lastname: Lee
keywords: Brown adipocytes; Sex differences; Sympathetic innervation; UCP1; White adipose tissue