Pref-1 (Preadipocyte factor-1) is expressed in adipose precursor cells, downregulated during differentiation and is absent in mature adipocytes. Thus, Pref-1 is widely used as a preadipocyte marker. We have shown Pref-1 Inhibition of adipogenesis by gain- and loss- of function studies in vitro as well as in vivo. Pref-1 is synthesized as a plasma membrane glycoprotein with 6 EGF-repeats in its extracellular domain;the Pref-1 ectodomain is cleaved by TACE at the juxtamembrane region to generate the biologically active soluble Pref-1. Pref-1 inhibits adipocyte differentiation by activating MEK/ERK and we recently detected an interaction of Pref-1 with fibronectin. The goal of this research is to further elucidate the molecular mechanisms underlying the Pref-1 function in adipose tissue development. First, we will examine the Pref-1 interaction with fibronectin and the specific integrin receptor that mediates Pref-1 inhibition of adipocyte differentiation. We will also study the fibronectin/integrin signaling pathway that is dependent on the Pref-1/fibronectin interaction in inhibiting adipocyte differentiation. Downstream signaling molecules including FAK and Rac will be examined. Next, to mark and characterize Pref-1 expressing adipose precursor cells, we will generate Pref-1- reporter mice that express GFP and RFP in an inducible manner. Using these reporter mice, we will monitor and examine Pref-1 expressing adipose precursor cells. We will also define the signature of these cells by genome-wide microarray analysis. Furthermore, comparison of the expression patterns as affected by Pref-1 null and Pref- 1 overexpression will help us to understand the Pref-1 function in adipose precursor cells.

Public Health Relevance

Obesity is a major health problem causing metabolic syndrome and type II diabetes, and the control of adiposity is a top priority in managing these diseases. This research is directed toward understanding adipocyte differentiation and adipose tissue development, the process that contributes to the development of obesity. Elucidating the mechanisms of Pref-1 function and regulation will allow us to begin to develop strategies to control obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK050828-16
Application #
8444573
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
1995-05-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
16
Fiscal Year
2013
Total Cost
$301,180
Indirect Cost
$100,795
Name
University of California Berkeley
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Hudak, Carolyn S; Gulyaeva, Olga; Wang, Yuhui et al. (2014) Pref-1 marks very early mesenchymal precursors required for adipose tissue development and expansion. Cell Rep 8:678-87
Wang, Yuhui; Hudak, Carolyn; Sul, Hei Sook (2010) Role of preadipocyte factor 1 in adipocyte differentiation. Clin Lipidol 5:109-115
Jacobs, Frank M J; van der Linden, Annemarie J A; Wang, Yuhui et al. (2009) Identification of Dlk1, Ptpru and Klhl1 as novel Nurr1 target genes in meso-diencephalic dopamine neurons. Development 136:2363-73
Wang, Yuhui; Sul, Hei Sook (2009) Pref-1 regulates mesenchymal cell commitment and differentiation through Sox9. Cell Metab 9:287-302
Ahmadian, Maryam; Duncan, Robin E; Sul, Hei Sook (2009) The skinny on fat: lipolysis and fatty acid utilization in adipocytes. Trends Endocrinol Metab 20:424-8
Sul, Hei Sook (2009) Minireview: Pref-1: role in adipogenesis and mesenchymal cell fate. Mol Endocrinol 23:1717-25
Villena, Josep A; Choi, Cheol Soo; Wang, Yuhui et al. (2008) Resistance to high-fat diet-induced obesity but exacerbated insulin resistance in mice overexpressing preadipocyte factor-1 (Pref-1): a new model of partial lipodystrophy. Diabetes 57:3258-66
Kim, Kyung-Ah; Kim, Jung-Hyun; Wang, Yuhui et al. (2007) Pref-1 (preadipocyte factor 1) activates the MEK/extracellular signal-regulated kinase pathway to inhibit adipocyte differentiation. Mol Cell Biol 27:2294-308
Wang, Yuhui; Sul, Hei Sook (2006) Ectodomain shedding of preadipocyte factor 1 (Pref-1) by tumor necrosis factor alpha converting enzyme (TACE) and inhibition of adipocyte differentiation. Mol Cell Biol 26:5421-35
Wang, Yuhui; Kim, Kyung-Ah; Kim, Jung-Hyun et al. (2006) Pref-1, a preadipocyte secreted factor that inhibits adipogenesis. J Nutr 136:2953-6

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