Abstract
Insulin stimulates glucose uptake in adipose tissue and skeletal muscle by inducing plasma membrane translocation of the glucose transporter GLUT4. Although the small GTPase Rac1 is a key regulator downstream of phosphoinositide 3-kinase (PI3K) and the protein kinase Akt2 in skeletal muscle, it remains unclear whether Rac1 also regulates glucose uptake in white adipocytes. Herein, we investigated the physiological role of Rac1 in white adipocytes by employing adipocyte-specific rac1 knockout (adipo-rac1-KO) mice. Subcutaneous and epididymal white adipose tissues (WATs) in adipo-rac1-KO mice showed significant reductions in size and weight. Actually, white adipocytes lacking Rac1 were smaller than controls. Insulin-stimulated glucose uptake and GLUT4 translocation were abrogated in rac1-KO white adipocytes. On the other hand, GLUT4 translocation was augmented by constitutively activated PI3K or Akt2 in control, but not in rac1-KO, white adipocytes. Similarly, to skeletal muscle, the involvement of another small GTPase RalA downstream of Rac1 was demonstrated. In addition, mRNA levels of various lipogenic enzymes were down-regulated in rac1-KO white adipocytes. Collectively, these results suggest that Rac1 is implicated in insulin-dependent glucose uptake and lipogenesis in white adipocytes, and reduced insulin responsiveness due to the deficiency of Rac1 may be a likely explanation for atrophy of WATs.
Highlights
Two major types of adipose tissue, white adipose tissue (WAT) and brown adipose tissue (BAT), are known in mammals
Given that the signaling mechanisms mediated by phosphoinositide 3-kinase (PI3K) and Akt2 for insulin-stimulated glucose uptake are conserved between skeletal muscle and adipose tissue, it is possible that Rac1 serves as a molecular switch of insulin-stimulated glucose uptake downstream of PI3K and Akt2, in skeletal muscle and in adipose tissue
Consistent with this idea, we demonstrated that Rac1 was activated in a PI3K-dependent manner following in vitro insulin stimulation of primary cultured mouse adipocytes [23]
Summary
Two major types of adipose tissue, white adipose tissue (WAT) and brown adipose tissue (BAT), are known in mammals. The intracellular signaling mechanisms underlying insulin-stimulated GLUT4 translocation to the plasma membrane are thought to be conserved, at least in part, between skeletal muscle and adipose tissue [3,4,5,6]. Given that the signaling mechanisms mediated by PI3K and Akt for insulin-stimulated glucose uptake are conserved between skeletal muscle and adipose tissue, it is possible that Rac serves as a molecular switch of insulin-stimulated glucose uptake downstream of PI3K and Akt, in skeletal muscle and in adipose tissue Consistent with this idea, we demonstrated that Rac was activated in a PI3K-dependent manner following in vitro insulin stimulation of primary cultured mouse adipocytes [23]. To resolve this controversy about whether Rac is implicated in adipocyte insulin signaling for glucose uptake, we further investigated the role of Rac, employing rac1-KO mouse white adipocytes in this study
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