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

Yoshimi Nakagawa; Hitoshi Shimano; Tomohiro Yoshikawa; Tomohiro Ide; Mariko Tamura; Mika Furusawa; Takashi Yamamoto; Noriyuki Inoue; Takashi Matsuzaka; Akimitsu Takahashi; Alyssa H Hasty; Hiroaki Suzuki; Hirohito Sone; Hideo Toyoshima; Naoya Yahagi; Nobuhiro Yamada

doi:10.1038/nm1334

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

Nat Med. 2006 Jan;12(1):107-13. doi: 10.1038/nm1334. Epub 2005 Dec 4.

Authors

Yoshimi Nakagawa¹, Hitoshi Shimano, Tomohiro Yoshikawa, Tomohiro Ide, Mariko Tamura, Mika Furusawa, Takashi Yamamoto, Noriyuki Inoue, Takashi Matsuzaka, Akimitsu Takahashi, Alyssa H Hasty, Hiroaki Suzuki, Hirohito Sone, Hideo Toyoshima, Naoya Yahagi, Nobuhiro Yamada

Affiliation

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.

PMID: 16327801
DOI: 10.1038/nm1334

Abstract

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 3beta 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenoviridae / genetics
Adenoviridae / metabolism
Animals
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / physiology*
Blood Glucose / metabolism
Blotting, Northern
Cells, Cultured
Chromatin Immunoprecipitation
Cloning, Molecular
Diabetes Mellitus / therapy*
Diabetes Mellitus, Experimental
Dose-Response Relationship, Drug
Glycogen / metabolism
Glycogen Synthase Kinase 3 / metabolism
Glycogen Synthase Kinase 3 beta
Green Fluorescent Proteins / metabolism
Hepatocytes / metabolism
Hexokinase / metabolism
Humans
Immunoblotting
Immunoprecipitation
Insulin / metabolism*
Insulin Receptor Substrate Proteins
Intracellular Signaling Peptides and Proteins
Male
Membrane Proteins / metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Models, Biological
Phosphoproteins / metabolism*
Phosphorylation
Plasmids / metabolism
Promoter Regions, Genetic
Protein Structure, Tertiary
Proto-Oncogene Proteins c-akt / metabolism
Rats
Ribosomal Protein S6 Kinases, 70-kDa / metabolism
Signal Transduction
Streptozocin / pharmacology
Time Factors
Transcriptional Activation

Substances

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Blood Glucose
INSIG1 protein, human
IRS2 protein, human
Insulin
Insulin Receptor Substrate Proteins
Intracellular Signaling Peptides and Proteins
Irs2 protein, mouse
Irs2 protein, rat
Membrane Proteins
Phosphoproteins
TFE3 protein, human
Green Fluorescent Proteins
Streptozocin
Glycogen
Hexokinase
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Gsk3b protein, mouse
Gsk3b protein, rat
Proto-Oncogene Proteins c-akt
Ribosomal Protein S6 Kinases, 70-kDa
Glycogen Synthase Kinase 3