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

Tetsuya Hosooka, Tetsuya Noguchi, Ko Kotani, Takehiro Nakamura, Hiroshi Sakaue, Hiroshi Inoue, Wataru Ogawa, Kazutoshi Tobimatsu, Kazuo Takazawa, Mashito Sakai, Yasushi Matsuki, Ryuji Hiramatsu, Tomoharu Yasuda, Mitchell A. Lazar, Yuji Yamanashi, Masato Kasuga

研究成果: ジャーナルへの寄稿学術誌査読

84 被引用数 (Scopus)


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)-γ on Ser112. Mutation of this negative regulatory site for the transactivation activity of PPAR-γ 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-γ and may thus confer predisposition to diet-induced obesity.

ジャーナルNature medicine
出版ステータス出版済み - 2月 1 2008

!!!All Science Journal Classification (ASJC) codes

  • 生化学、遺伝学、分子生物学(全般)


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