Secreted frizzled-related protein 5 suppresses adipocyte mitochondrial metabolism through WNT inhibition.
Preadipocytes secrete several WNT family proteins that act through autocrine/paracrine mechanisms to inhibit adipogenesis. The activity of WNT ligands is often decreased by secreted frizzled-related proteins (SFRPs). Sfrp5 is strongly induced during adipocyte differentiation and increases in adipocytes during obesity, presumably to counteract WNT signaling. We tested the hypothesis that obesity-induced Sfrp5 expression promotes the development of new adipocytes by inhibiting endogenous suppressors of adipogenesis. As predicted, mice that lack functional SFRP5 were resistant to diet-induced obesity. However, counter to our hypothesis, we found that adipose tissue of SFRP5-deficient mice had similar numbers of adipocytes, but a reduction in large adipocytes. Transplantation of adipose tissue from SFRP5-deficient mice into leptin receptor-deficient mice indicated that the effects of SFRP5 deficiency are tissue-autonomous. Mitochondrial gene expression was increased in adipose tissue and cultured adipocytes from SFRP5-deficient mice. In adipocytes, lack of SFRP5 stimulated oxidative capacity through increased mitochondrial activity, which was mediated in part by PGC1α and mitochondrial transcription factor A. WNT3a also increased oxygen consumption and the expression of mitochondrial genes. Thus, our findings support a model of adipogenesis in which SFRP5 inhibits WNT signaling to suppress oxidative metabolism and stimulate adipocyte growth during obesity.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Hiroyuki
H
Mori
Tyler C
TC
Prestwich
Michael A
MA
Reid
Kenneth A
KA
Longo
Isabelle
I
Gerin
William P
WP
Cawthorn
Vedrana S
VS
Susulic
Venkatesh
V
Krishnan
Andy
A
Greenfield
Ormond A
OA
Macdougald
D041721:3T3-L1 Cells; D048868:Adaptor Proteins, Signal Transducing; D017667:Adipocytes / Q000378:metabolism*; D050156:Adipogenesis; D052436:Adipose Tissue, White / Q000473:pathology; D000818:Animals; D049108:Cell Enlargement; D002478:Cells, Cultured; D004431:Ear, External / Q000473:pathology; D004734:Energy Metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000378:metabolism; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020738:Leptin / Q000097:blood; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D009765:Obesity / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D010101:Oxygen Consumption; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D060449:Wnt Signaling Pathway; D060509:Wnt3A Protein / Q000378:metabolism / Q000502:physiology; D000094742:Secreted Frizzled-Related Proteins
D048868:Adaptor Proteins, Signal Transducing; D005947:Glucose; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D012333:RNA, Messenger; D060509:Wnt3A Protein; C487972:Sfrp5 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C555511:Wnt3a protein, mouse