Dok1 mediates high-fat diet-induced adipocyte hypertrophy and obesity through modulation of PPAR-gamma phosphorylation

Nature Medicine
Tetsuya HosookaMasato Kasuga

Abstract

Insulin receptor substrate (IRS)-1 and IRS-2 have dominant roles in the action of insulin, but other substrates of the insulin receptor kinase, such as Gab1, c-Cbl, SH2-B and APS, are also of physiological relevance. Although the protein downstream of tyrosine kinases-1 (Dok1) is known to function as a multisite adapter molecule in insulin signaling, its role in energy homeostasis has remained unclear. Here we show that Dok1 regulates adiposity. Expression of Dok1 in white adipose tissue was markedly increased in mice fed a high-fat diet, whereas adipocytes lacking this adapter were smaller and showed a reduced hypertrophic response to this dietary manipulation. Dok1-deficient mice were leaner and showed improved glucose tolerance and insulin sensitivity compared with wild-type mice. Embryonic fibroblasts from Dok1-deficient mice were impaired in adipogenic differentiation, and this defect was accompanied by an increased activity of the protein kinase ERK and a consequent increase in the phosphorylation of peroxisome proliferator-activated receptor (PPAR)-gamma on Ser112. Mutation of this negative regulatory site for the transactivation activity of PPAR-gamma blocked development of the lean phenotype caused by Dok1 ablation. Th...Continue Reading

References

May 1, 1997·Endocrinology·J W LeitnerB Draznin
Feb 17, 2000·The Journal of Clinical Investigation·P D MilesJ M Olefsky
Oct 14, 2000·Annual Review of Cell and Developmental Biology·E D Rosen, B M Spiegelman
Oct 11, 2003·Developmental Cell·Shamina M RangwalaMitchell A Lazar
Oct 28, 2003·Diabetes·Asako MinamiYousuke Ebina
Nov 7, 2003·Proceedings of the National Academy of Sciences of the United States of America·Hana KoutnikovaJohan Auwerx
Dec 6, 2003·Science·Morris F White
Dec 9, 2003·Proceedings of the National Academy of Sciences of the United States of America·Weimin HeRonald M Evans
Aug 18, 2004·Molecular and Cellular Biology·Chaojun DuanLiangyou Rui
Nov 3, 2004·The Journal of Clinical Investigation·Juan C MoleroGregory J Cooney
Feb 9, 2005·The Journal of Experimental Medicine·Hisaaki ShinoharaYuji Yamanashi
Apr 19, 2005·Proceedings of the National Academy of Sciences of the United States of America·Julie R JonesMark A Magnuson
Apr 8, 2006·Physiological Reviews·Béatrice DesvergneWalter Wahli
Nov 4, 2006·The Journal of Biological Chemistry·Tamon SakaiMasato Kasuga

❮ Previous
Next ❯

Citations

Feb 27, 2010·Pflügers Archiv : European journal of physiology·Kunitoshi UchidaMakoto Tominaga
Sep 8, 2010·Nature Reviews. Endocrinology·Masanobu Kawai, Clifford J Rosen
Jan 15, 2009·The Journal of Biological Chemistry·Frédéric TremblayRuth E Gimeno
May 4, 2013·Carcinogenesis·Teresa FriedrichElke Burgermeister
Dec 2, 2008·PPAR Research·Dorina VeliceasaOlga V Volpert
Jul 4, 2008·PPAR Research·Elke Burgermeister, Rony Seger
Jun 16, 2012·Cellular and Molecular Life Sciences : CMLS·Feng ZhangShizhong Zheng
Mar 2, 2016·European Journal of Obstetrics, Gynecology, and Reproductive Biology·Tiego A DinizIsmael F Freitas-Junior
Mar 1, 2011·Lung Cancer : Journal of the International Association for the Study of Lung Cancer·Ajaya Kumar RekaVenkateshwar G Keshamouni
Aug 4, 2011·Journal of Lipids·M V DodsonW G Bergen
Nov 17, 2009·Immunological Reviews·Ryuichi MashimaYuji Yamanashi
Dec 5, 2012·Genes to Cells : Devoted to Molecular & Cellular Mechanisms·Ryuichi MashimaYuji Yamanashi
Dec 15, 2010·Nutrition Research·Chikako AraiShigeharu Fukuda
Jul 29, 2016·PLoS Computational Biology·Chuan GaoBarbara E Engelhardt
Oct 26, 2016·Scientific Reports·Wensi TaoXiang-Xi Xu
Jul 29, 2008·Biochemical and Biophysical Research Communications·Jianping Ye
Dec 17, 2009·Obesity Reviews : an Official Journal of the International Association for the Study of Obesity·A L HevenerUNKNOWN Stock Conference Working Group
Feb 22, 2012·Nature·Atsuhiko IchimuraPhilippe Froguel
May 6, 2011·The Journal of Biological Chemistry·Le-nan ZhuangGang Pei
Jul 7, 2019·Nature Communications·Vahid KheirollahiElie El Agha
Oct 28, 2019·Oncoimmunology·Tong LiElke Burgermeister
Jul 29, 2020·International Journal of Obesity : Journal of the International Association for the Study of Obesity·Edward T WargentClaire J Stocker
Sep 1, 2013·Hormone Molecular Biology and Clinical Investigation·Masanobu Kawai
Oct 19, 2017·The Journal of Endocrinology·Jin-Bong LeeYoung-Jun Park
May 1, 2020·Frontiers in Cell and Developmental Biology·Tingliang WangMing Pei
Jun 15, 2011·Biological Research for Nursing·Takeo MinematsuHiromi Sanada

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cardiomyopathy

Cardiomyopathy is a disease of the heart muscle, that can lead to muscular or electrical dysfunction of the heart. It is often an irreversible disease that is associated with a poor prognosis. There are different causes and classifications of cardiomyopathies. Here are the latest discoveries pertaining to this disease.