title: Effects of Estrogens on Adipokines and Glucose Homeostasis in Female Aromatase Knockout Mice.
abstract: The maintenance of glucose homeostasis within the body is crucial for constant and precise performance of energy balance and is sustained by a number of peripheral organs. Estrogens are known to play a role in the maintenance of glucose homeostasis. Aromatase knockout (ArKO) mice are estrogen-deficient and display symptoms of dysregulated glucose metabolism. We aim to investigate the effects of estrogen ablation and exogenous estrogen administration on glucose homeostasis regulation. Six month-old female wildtype, ArKO, and 17β-estradiol (E2) treated ArKO mice were subjected to whole body tolerance tests, serum examination of estrogen, glucose and insulin, ex-vivo muscle glucose uptake, and insulin signaling pathway analyses. Female ArKO mice display increased body weight, gonadal (omental) adiposity, hyperinsulinemia, and liver triglycerides, which were ameliorated upon estrogen treatment. Tolerance tests revealed that estrogen-deficient ArKO mice were pyruvate intolerant hence reflecting dysregulated hepatic gluconeogenesis. Analyses of skeletal muscle, liver, and adipose tissues supported a hepatic-based glucose dysregulation, with a down-regulation of Akt phosphorylation (a key insulin signaling pathway molecule) in the ArKO liver, which was improved with E2 treatment. Concurrently, estrogen treatment lowered ArKO serum leptin and adiponectin levels and increased inflammatory adipokines such as tumour necrosis factor alpha (TNFα) and interleukin 6 (IL6). Furthermore, estrogen deficiency resulted in the infiltration of CD45 macrophages into gonadal adipose tissues, which cannot be reversed by E2 treatment. This study describes the effects of estrogens on glucose homeostasis in female ArKO mice and highlights a primary phenotype of hepatic glucose dysregulation and a parallel estrogen modified adipokine profile.
authors: MIMR-PHI Institute of Medical Research, Clayton Vic 3180 Australia; Dept of Anatomy and Developmental Biology, Monash University, Clayton Vic 3800, Australia.
authors: Michelle L
authors: ML
authors: Van Sinderen
authors: St Vincent's Institute of Medical Research and Dept of Medicine, University of Melbourne, Fitzroy, Vic 3065, Australia.
authors: Gregory R
authors: GR
authors: Steinberg
authors: St Vincent's Institute of Medical Research and Dept of Medicine, University of Melbourne, Fitzroy, Vic 3065, Australia.
authors: Sebastian B
authors: SB
authors: Jørgensen
authors: St Vincent's Institute of Medical Research and Dept of Medicine, University of Melbourne, Fitzroy, Vic 3065, Australia.
authors: Jane
authors: J
authors: Honeyman
authors: MIMR-PHI Institute of Medical Research, Clayton Vic 3180 Australia; Dept of Anatomy and Developmental Biology, Monash University, Clayton Vic 3800, Australia.
authors: Jenny D
authors: JD
authors: Chow
authors: MIMR-PHI Institute of Medical Research, Clayton Vic 3180 Australia.
authors: Kerrie A
authors: KA
authors: Herridge
authors: MIMR-PHI Institute of Medical Research, Clayton Vic 3180 Australia.
authors: Amy L
authors: AL
authors: Winship
authors: MIMR-PHI Institute of Medical Research, Clayton Vic 3180 Australia.
authors: Evdokia
authors: E
authors: Dimitriadis
authors: MIMR-PHI Institute of Medical Research, Clayton Vic 3180 Australia; Dept of Anatomy and Developmental Biology, Monash University, Clayton Vic 3800, Australia.
authors: Margaret E E
authors: ME
authors: Jones
authors: MIMR-PHI Institute of Medical Research, Clayton Vic 3180 Australia.
authors: Evan R
authors: ER
authors: Simpson
authors: MIMR-PHI Institute of Medical Research, Clayton Vic 3180 Australia; The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville Vic 3000, Australia; Dept of Anatomy and Developmental Biology, Monash University, Clayton Vic 3800, Australia.
authors: Wah Chin
authors: WC
authors: Boon
mesh_terms: D054392:Adipokines / Q000097:blood*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001141:Aromatase / Q000235:genetics*; D004958:Estradiol / Q000097:blood* / Q000494:pharmacology; D004967:Estrogens / Q000097:blood* / Q000494:pharmacology; D005260:Female; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects*; D015850:Interleukin-6 / Q000097:blood; D020738:Leptin / Q000097:blood; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D054392:Adipokines; D004967:Estrogens; D015850:Interleukin-6; D020738:Leptin; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; D001141:Aromatase; D005947:Glucose