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

Insulin receptor substrate (IRS)-1 and IRS-2 have dominant roles in the action of insulin (1), but other substrates of the insulin receptor kinase, such as Gabl, c-Cbl, SH2-B and APS, are also of physiological relevance (2-5). Although the protein downstream of tyrosine kinases-1 (Dok1) is known to function as a multisite adapter molecule in insulin signaling (6-8), 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)-[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. These results indicate that Dok1 promotes adipocyte hypertrophy by counteracting the inhibitory effect of ERK on PPAR-[gamma] and may thus confer predisposition to diet-induced obesity.
We and others have shown that tyrosine-phosphorylated Dok1 binds and recruits p120 Ras GTPase-activating protein (rasGAP) as well as the adapter protein Nck, thereby regulating mitogenic signaling mediated by Ras [...]