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 relevance^{2, 3, 4, 5}. Although the protein downstream of tyrosine kinases-1 (Dok1) is known to function as a multisite adapter molecule in insulin signaling^{6, 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.

1. 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.
2. Genomic Science Laboratories, DainipponSumitomo Pharma, 4-2-1 Takatsukasa, Takarazuka 665-8555, Japan.
3. Department of Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, Tokyo 113-8510, Japan.
4. 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.
5. 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

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