Letter abstract
Nature Medicine 14, 188 - 193 (2008)
Published online: 20 January 2008 | Corrected online: 23 January 2008 | doi:10.1038/nm1706
Dok1 mediates high-fat diet–induced adipocyte hypertrophy and obesity through modulation of PPAR-
phosphorylation
Tetsuya Hosooka1, Tetsuya Noguchi1, Ko Kotani1, Takehiro Nakamura1, Hiroshi Sakaue1, Hiroshi Inoue1,5, Wataru Ogawa1, Kazutoshi Tobimatsu1, Kazuo Takazawa1, Mashito Sakai1, Yasushi Matsuki2, Ryuji Hiramatsu2, Tomoharu Yasuda3,5, Mitchell A Lazar4, Yuji Yamanashi3 & Masato Kasuga1
Insulin receptor substrate (IRS)-1 and IRS-2 have dominant roles in the action of insulin1, but other substrates of the insulin receptor kinase, such as Gab1, c-Cbl, SH2-B and APS, are also of physiological relevance2, 3, 4, 5. Although the protein downstream of tyrosine kinases-1 (Dok1) is known to function as a multisite adapter molecule in insulin signaling6, 7, 8, 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)-
on Ser112. Mutation of this negative regulatory site for the transactivation activity of PPAR- blocked development of the lean phenotype caused by Dok1 ablation. These results indicate that Dok1 promotes adipocyte hypertrophy by counteracting the inhibitory effect of ERK on PPAR- and may thus confer predisposition to diet-induced obesity.
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
- Genomic Science Laboratories, DainipponSumitomo Pharma, 4-2-1 Takatsukasa, Takarazuka 665-8555, Japan.
- Department of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8510, Japan.
- Division of Endocrinology, Diabetes and Metabolism; Departments of Medicine, Genetics and Pharmacology; and Institute for Diabetes, Obesity and Metabolism; University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6149, USA.
- Present addresses: Frontier Science Organization, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan (H.I.); Laboratory for Lymphocyte Differentiation, RIKEN Research Center for Allergy and Immunology, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan (T.Y.).
Correspondence to: Masato Kasuga1 e-mail: kasuga@med.kobe-u.ac.jp
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
NEWS AND VIEWS
Turning WAT into BAT gets rid of fatNature Medicine News and Views (01 Oct 2001)
Retinaldehyde: more than meets the eyeNature Medicine News and Views (01 Jun 2007)
RESEARCH
Combined therapeutic strategy using erythropoietin and mesenchymal stem cells potentiates neurogenesis after transient focal cerebral ischemia in ratsJournal of Cerebral Blood Flow & Metabolism Original Article
AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiencyNature Medicine Article (01 Feb 2009)
See all 60 matches for Research
