Enhanced insulin sensitivity, energy expenditure and thermogenesis in adipose-specific pten suppression in mice

ABSTRACT Pten is an important phosphatase, suppressing the phosphatidylinositol-3 kinase/Akt pathway. Here, we generated adipose-specific Pten-deficient (AdipoPten-KO) mice, using newly

generated _Acdc_ promoter–driven _Cre_ transgenic mice. AdipoPten-KO mice showed lower body and adipose tissue weights despite hyperphagia and enhanced insulin sensitivity with induced

phosphorylation of Akt in adipose tissue. AdipoPten-KO mice also showed marked hyperthermia and increased energy expenditure with induced mitochondriagenesis in adipose tissue, associated

with marked reduction of p53, inactivation of Rb, phosphorylation of cyclic AMP response element binding protein (CREB) and increased expression of _Ppargc1a_, the gene that encodes

peroxisome proliferative activated receptor gamma coactivator 1 alpha. Physiologically, adipose _Pten_ mRNA decreased with exposure to cold and increased with obesity, which were linked to

the mRNA alterations of mitochondriagenesis. Our results suggest that altered expression of adipose _Pten_ could regulate insulin sensitivity and energy expenditure. Suppression of adipose

_Pten_ may become a beneficial strategy to treat type 2 diabetes and obesity. Access through your institution Buy or subscribe This is a preview of subscription content, access via your

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Y. Matsuzawa and K. Sugihara for their encouragement, and K. Nishida, K. Oiki and S. Mizuno for technical assistance. This work was supported in part by grants from the Suzuken Memorial

Foundation, The Nakajima Foundation, Kanae Foundation for Life and Socio-Medical Science, The Tokyo Biochemical Research Foundation, Takeda Medical Research Foundation, Uehara Memorial

Foundation, Takeda Science Foundation, Novartis Foundation (Japan) for the Promotion of Science, The Cell Science Research Foundation, The Mochida Memorial Foundation for Medical and

Pharmaceutical Research, a Grant-in-Aid from the Japan Medical Association, The Naito Foundation, a grant from the Japan Heart Foundation Research, Kato Memorial Bioscience Foundation, Japan

Research Foundation for Clinical Pharmacology, a grant from the Ministry of Health, Labor and Welfare, Japan, and Grants-in-Aid from COE Research and Scientific Research on Priority Areas

from the Ministry of Education, Culture, Sports, Science and Technology, Japan. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Social and Environmental Medicine, Graduate School

of Frontier Bioscience, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka Nobuyasu Komazawa, Gen Kondoh & Junji Takeda * Department of Medicine and Pathophysiology, Graduate

School of Frontier Bioscience, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka Morihiro Matsuda, Masanori Iwaki, Toshiyuki Takagi & Iichiro Shimomura * Division of Food Science

and Biotechnology, Laboratory of Nutrition Chemistry, Graduate School of Agriculture, Kyoto University, Kitashirakawa, Sakyo-ku, 606-8502, Kyoto Wataru Mizunoya, Kazuo Inoue & Tohru

Fushiki * Department of Dermatology, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka Yasuyuki Sumikawa * Department of Biochemistry, Akita University, 1-1 Hondou, Akita, 010-8543,

Akita, Japan Akira Suzuki * Advanced Medical Discovery Institute, University of Toronto, Toronto, M5G 2Cl, Ontario, Canada Tak Wah Mak * Department of Pathology, Graduate School of Medicine,

Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka Toru Nakano * Center for Advanced Science and Innovation, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka Junji Takeda *

Department of Internal Medicine and Molecular Science, Osaka University, 2-2 Yamadaoka, Suita, 565-0871, Osaka Iichiro Shimomura * PREST, Japan Science and Technology Agency, 4-1-8 Honcho,

Kawaguchi, 332-0012, Saitama, Japan Iichiro Shimomura Authors * Nobuyasu Komazawa View author publications You can also search for this author inPubMed Google Scholar * Morihiro Matsuda View

author publications You can also search for this author inPubMed Google Scholar * Gen Kondoh View author publications You can also search for this author inPubMed Google Scholar * Wataru

Mizunoya View author publications You can also search for this author inPubMed Google Scholar * Masanori Iwaki View author publications You can also search for this author inPubMed Google

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Correspondence to Iichiro Shimomura. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY FIG. 1 Expression

analyses of _Cre_ in _Adiponectin_ promoter-driven _Cre_ transgenic mice. (PDF 34 kb) SUPPLEMENTARY FIG. 2 Supplemental data of Fig. 4b, 5b, 5d and 5e. (PDF 286 kb) SUPPLEMENTARY TABLE 1

Primers used in mRNA analyses (PDF 20 kb) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Komazawa, N., Matsuda, M., Kondoh, G. _et al._ Enhanced insulin

sensitivity, energy expenditure and thermogenesis in adipose-specific Pten suppression in mice. _Nat Med_ 10, 1208–1215 (2004). https://doi.org/10.1038/nm1117 Download citation * Received:

24 June 2004 * Accepted: 08 September 2004 * Published: 17 October 2004 * Issue Date: 01 November 2004 * DOI: https://doi.org/10.1038/nm1117 SHARE THIS ARTICLE Anyone you share the following

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