Comparative Study Of Ovariectomy And Adrenalectomy On Adipose Tissue Remodeling In Female Mice

In addition to function as a passive “energy reservoir”,adipose tissue can actively communicate with other organ by secreting hormones,adipokines and exosomal mi RNAs to regulate whole-body metabolism and energy homeostasis.Thus,maintaining adipose tissue homeostasis itself is pivotal for whole-body homeostasis.Increasing studies on model animals,menopausal women and patients with Addison’s disease and Cushing’s syndrome have found that both dysfunction of ovary and adrenal gland can cause adipose tissue remodeling and related metabolic disorders by affecting endocrine hormones and other factors,but their distinct and common roles are poorly understood.Moreover,although subcutaneous adipose tissue(SAT)and visceral adipose tissue(VAT)are both belong to white adipose tissue(WAT),they are significantly heterogeneous in several aspects,including progenitors,anatomical position and metabolic function,and their response to ovarian versus adrenal gland failure has not been reported yet.In this study,through biochemical,histological and RNA-seq analyses,we comprehensively explored the mechanisms underpinning subcutaneous and visceral adipose tissue remodeling in response to ovariectomy versus adrenalectomy in female C57BL/6J mice.And through integrative analysis of our data with other published omics data,we further identified the distinct and common roles of ovariectomy(OVX)versus adrenalectomy(ADX)in regulating the adipose tissue remodeling,as well as the resultant metabolic disorders.The main results of this study are as follows:(1)Compared to the sham control mice,the body weight,SAT and VAT weight and adipocytes size were markedly increased in OVX mice;ADX had no effect on body weight but decreased weight of both SAT and VAT.(2)4171 differentially expressed gene(DEGs)were identified between SAT and VAT of sham mice.The highly activated Wnt signaling seemed to be a major SAT intrinsic trait and limited it adipogenic potential.SAT was more sensitive in response to both OVX and ADX stimuli(The number of DEGs in SAT was 9.17 and 4.34 times more than visceral adipose tissue,respectively)and ADX bur not OVX,exerted great effects on the intrinsic difference between SAT and VAT.(3)Disfunction of ovary promoted adipogenesis and lipogenesis in both SAT and VAT by activating PPARG signaling.Irs1,Myc,Gpd1 and Mrap as direct target genes of PPARG,played a pivotal role in adipose tissue expansion and related metabolic disorder.(4)Disfunction of adrenal gland caused adipose tissue atrophy mainly by inhibiting NR3C1 signaling and affecting adipocyte structure rather than inhibiting lipid metabolism.Meanwhile,activation of 12 key transcription factors(e.g.,SP140,IRF8 and SCML4),cellular senescence and B cell infiltration may be responsible for ADX-caused strong inflammatory response in the subcutaneous adipose tissue of female mice.(5)Both failure of ovary and adrenal gland function may enhance circadian rhythmicity in VAT,and impaired cell proliferation,neurogenesis,tissue morphogenesis,as well as extracellular matrix organization in SAT,thus causing dysfunction of adipose tissues and concomitant metabolic disorders.In this study,we comparatively investigated the effects of ovariectomy and adrenalectomy on SAT and VAT remolding,our findings will not only improve the understanding of adipose tissue remodeling,but also provide new clues and ideas for the prevention and treatment of human metabolic diseases such as Addison’s disease,Cushing’s syndrome and menopausal obesity.