17β-Estradiol suppresses visceral adipogenesis and activates brown adipose tissue-specific gene expression.
Both functional ovaries and estrogen replacement therapy (ERT) reduce the risk of type 2 diabetes (T2D). Understanding the mechanisms underlying the antidiabetic effects of 17β-estradiol (E2) may permit the development of a molecular targeting strategy for the treatment of metabolic disease. This study examines how the promotion of insulin sensitivity and weight loss by E2 treatment in high-fat-diet (HFD)-fed mice involve several anti-adipogenic processes in the visceral adipose tissue. Magnetic resonance imaging (MRI) revealed specific reductions in visceral adipose tissue volume in HFD+E2 mice, compared with HFD mice. This loss of adiposity was associated with diminished visceral adipocyte size and reductions in expression of lipogenic genes, adipokines and of the nuclear receptor nr2c2/tr4. Meanwhile, expression levels of adipose triglyceride lipase/pnpla2 and leptin receptor were increased. As mRNA levels of stat3, a transcription factor involved in brown adipose tissue differentiation, were also increased in visceral adipose, the expression of other brown adipose-specific markers was assessed. Both expression and immunohistochemical staining of ucp-1 were increased, and mRNA levels of dio-2, and of adrβ3, a regulator of ucp-1 expression during the thermogenic response, were increased. Furthermore, expression of cpt-1b, a brown adipose-specific gene involved in fatty acid utilization, was also increased. Methylation studies demonstrated that the methylation status of both dio-2 and adrβ3 was significantly reduced. These results show that improved glycemic control and weight loss due to E2 involve anti-adipogenic mechanisms which include suppressed lipogenesis and augmented fatty acid utilization, and in addition, the activation of brown adipose tissue-specific gene expression in association with E2-dependent epigenetic modifications in these genes.
Saad Misfer
SM
Al-Qahtani
Galyna
G
Bryzgalova
Ismael
I
Valladolid-Acebes
Marion
M
Korach-André
Karin
K
Dahlman-Wright
Suad
S
Efendić
Per-Olof
PO
Berggren
Neil
N
Portwood
D050156:Adipogenesis / Q000187:drug effects*; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D015153:Blotting, Western; D019175:DNA Methylation; D059305:Diet, High-Fat / Q000009:adverse effects; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015415:Biomarkers; D012333:RNA, Messenger; D004958:Estradiol