title: Nonreceptor tyrosine phosphatase Shp2 promotes adipogenesis through inhibition of p38 MAP kinase.
abstract: The molecular mechanism underlying adipogenesis and the physiological functions of adipose tissue are not fully understood. We describe here a unique mouse model of severe lipodystrophy. Ablation of Ptpn11/Shp2 in adipocytes, mediated by aP2-Cre, led to premature death, lack of white fat, low blood pressure, compensatory erythrocytosis, and hepatic steatosis in Shp2(fat-/-) mice. Fat transplantation partially rescued the lifespan and blood pressure in Shp2(fat-/-) mice, and administration of leptin also restored partially the blood pressure of mutant animals with endogenous leptin deficiency. Consistently, homozygous deletion of Shp2 inhibited adipocyte differentiation from embryonic stem (ES) cells. Biochemical analyses suggest a Shp2-TAO2-p38-p300-PPARγ pathway in adipogenesis, in which Shp2 suppresses p38 activation, leading to stabilization of p300 and enhanced PPARγ expression. Inhibition of p38 restored adipocyte differentiation from Shp2(-/-) ES cells, and p38 signaling is also suppressed in obese patients and obese animals. These results illustrate an essential role of adipose tissue in mammalian survival and physiology and also suggest a common signaling mechanism involved in adipogenesis and obesity development.
authors.affiliation: Department of Pathology and Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093-0864, USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: He
authors.forename: Helen H
authors.initials: HH
authors.lastname: Zhu
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Bauler
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Theodore
authors.initials: T
authors.lastname: Ciaraldi
authors.forename: Nazilla
authors.initials: N
authors.lastname: Alderson
authors.forename: Shuangwei
authors.initials: S
authors.lastname: Li
authors.forename: Marie-Astrid
authors.initials: MA
authors.lastname: Raquil
authors.forename: Kaihong
authors.initials: K
authors.lastname: Ji
authors.forename: Shufen
authors.initials: S
authors.lastname: Wang
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shao
authors.forename: Robert R
authors.initials: RR
authors.lastname: Henry
authors.forename: Philip D
authors.initials: PD
authors.lastname: King
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
mesh_terms: D050156:Adipogenesis / Q000502:physiology*; D000273:Adipose Tissue / Q000637:transplantation; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D017353:Gene Deletion; D020738:Leptin / Q000008:administration & dosage / Q000172:deficiency / Q000494:pharmacology; D008060:Lipodystrophy / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D017931:DNA Primers; D020738:Leptin; D047495:PPAR gamma; D050881:E1A-Associated p300 Protein; C494361:Ep300 protein, mouse; D011494:Protein Kinases; C404957:TAOK2 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11