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Wdnm1-like, a new adipokine with a role in MMP-2 activation

Department of Biochemistry and Cancer Biology and Center for Diabetes and Endocrine Research, University of Toledo Health Science Campus, Toledo, Ohio

Submitted 27 March 2008 ; accepted in final form 13 May 2008

White adipose tissue functions in energy storage and as an endocrine organ. DNA microarray analysis led us to identify Wdnm1-like, a distant member of the whey acidic protein/four-disulfide core (WAP/4-DSC) family, as a differentiation-dependent gene in white and brown adipogenesis. Wdnm1-like is a novel 6.8-kDa protein, and Western blot analysis reveals secretion into culture media. Wdnm1-like transcript is selectively expressed in adipose tissue and liver and is enriched 500-fold in white adipose depots vs. brown. Cellular fractionation of WAT demonstrates Wdnm1-like transcript expression is restricted to the adipocyte population. Studies in 3T3-L1 preadipocytes, an in vitro model of white adipogenesis, indicate Wdnm1-like transcript increases within 6 h of adipogenic induction with an 17,000-fold increase by day 7. Dramatic upregulation of Wdnm1-like also accompanies white adipogenesis of ScAP-23 preadipocytes and primary preadipocytes. TNF- treatment of 3T3-L1 adipocytes increased Wdnm1-like transcript level 2.4-fold and was attenuated by pretreatment with the p38 MAP kinase inhibitor SB203580. A number of WAP/4-DSC family proteins function as protease inhibitors. This, taken with the role of extracellular remodeling in adipogenesis, led us to address effects of Wdnm1-like on matrix metalloproteinase (MMP) activity. Gelatin zymography of HT1080 fibrosarcoma cells transfected with a Wdnm1-like expression construct revealed markedly increased levels of active MMP-2. Our findings identify a new member of the adipocyte "secretome" that functions to enhance MMP-2 activity. We postulate that Wdnm1-like may play roles in remodeling of the extracellular milieu in adipogenesis, as well as in tumor microenvironments where adipocytes are key stromal components.

adipocyte; adipogenesis; four-disulfide core; secreted factor; adipose tissue; extracellular matrix; matrix metalloproteinase-2

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