Effects of dihydrotestosterone on differentiation and proliferation of human mesenchymal stem cells and preadipocytes.
The mechanisms by which androgens regulate fat mass are poorly understood. Although testosterone has been reported to increase lipolysis and inhibit lipid uptake, androgen effects on proliferation and differentiation of human mesenchymal stem cells (hMSCs) and preadipocytes have not been studied. Here, we investigated whether dihydrotestosterone (DHT) regulates proliferation, differentiation, or functional maturation of hMSCs and human preadipocytes from different fat depots. DHT (0-30 nM) dose-dependently inhibited lipid accumulation in adipocytes differentiated from hMSCs and downregulated expression of aP2, PPARgamma, leptin, and C/EBPalpha. Bicalutamide attenuated DHT's inhibitory effects on adipogenic differentiation of hMSCs. Adipocytes differentiated in presence of DHT accumulated smaller oil droplets suggesting reduced extent of maturation. DHT decreased the incorporation of labeled fatty acid into triglyceride, and downregulated acetyl CoA carboxylase and DGAT2 expression in adipocytes derived from hMSCs. DHT also inhibited lipid accumulation and downregulated aP2 and C/EBPalpha in human subcutaneous, mesenteric and omental preadipocytes. DHT stimulated forskolin-stimulated lipolysis in subcutaneous and mesenteric preadipocytes and inhibited incorporation of fatty acid into triglyceride in adipocytes differentiated from preadipocytes from all fat depots.


CONCLUSIONS
DHT inhibits adipogenic differentiation of hMSCs and human preadipocytes through an AR-mediated pathway, but it does not affect the proliferation of either hMSCs or preadipocytes. Androgen effects on fat mass represent the combined effect of decreased differentiation of fat cell precursors, increased lipolysis, and reduced lipid accumulation.
Gupta
Vandana
V
Department of Medicine, Boston University, School of Medicine, Boston Medical Center, Boston, MA 02118, USA.
Bhasin
Shalender
S
Guo
Wen
W
Singh
Rajan
R
Miki
Rika
R
Chauhan
Pratibha
P
Choong
Karen
K
Tchkonia
Tamara
T
Lebrasseur
Nathan K
NK
Flanagan
John N
JN
Hamilton
James A
JA
Viereck
Jason C
JC
Narula
Navjot S
NS
Kirkland
James L
JL
Jasuja
Ravi
R
D017667:Adipocytes / Q000187:drug effects* / Q000502:physiology; D050156:Adipogenesis / Q000187:drug effects; D000328:Adult; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004822:Epididymis; D006801:Humans; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D059630:Mesenchymal Stem Cells / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009919:Orchiectomy; D011944:Receptors, Androgen / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D011944:Receptors, Androgen; D013196:Dihydrotestosterone
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