TFE3 transcriptionally activates hepatic IRS-2, participates in insulin signaling and ameliorates diabetes

Yoshimi Nakagawa^1, 2, Hitoshi Shimano^1, 2, Tomohiro Yoshikawa¹, Tomohiro Ide¹, Mariko Tamura¹, Mika Furusawa¹, Takashi Yamamoto¹, Noriyuki Inoue¹, Takashi Matsuzaka^1, 2, Akimitsu Takahashi^1, 2, Alyssa H Hasty³, Hiroaki Suzuki¹, Hirohito Sone^1, 2, Hideo Toyoshima¹, Naoya Yahagi² & Nobuhiro Yamada¹

¹  Department of Internal Medicine, Metabolism and Endocrinology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan, 305-8575.

²  Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, Japan, 305-8575.

³  Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, 21^st Avenue South and Garland Avenue, Nashville, Tennessee 37232, USA.

Using an expression cloning strategy, we have identified TFE3, a basic helix-loop-helix protein, as a transactivator of metabolic genes that are regulated through an E-box in their promoters. Adenovirus-mediated expression of TFE3 in hepatocytes in culture and in vivo strongly activated expression of IRS-2 and Akt and enhanced phosphorylation of insulin-signaling kinases such as Akt, glycogen synthase kinase 3 and p70S6 kinase. TFE3 also induced hexokinase II (HK2) and insulin-induced gene 1 (INSIG1). These changes led to metabolic consequences, such as activation of glycogen and protein synthesis, but not lipogenesis, in liver. Collectively, plasma glucose levels were markedly reduced both in normal mice and in different mouse models of diabetes, including streptozotocin-treated, db/db and KK mice. Promoter analyses showed that IRS2, HK2 and INSIG1 are direct targets of TFE3. Activation of insulin signals in both insulin depletion and resistance suggests that TFE3 could be a therapeutic target for diabetes.

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