Article abstract
Nature Medicine 13, 1193 - 1202 (2007)
Published online: 30 September 2007 | doi:10.1038/nm1662
Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance
Takashi Matsuzaka1,2, Hitoshi Shimano1,2, Naoya Yahagi2,3, Toyonori Kato1, Ayaka Atsumi1, Takashi Yamamoto1, Noriyuki Inoue1, Mayumi Ishikawa1, Sumiyo Okada1, Naomi Ishigaki1, Hitoshi Iwasaki1, Yuko Iwasaki1, Tadayoshi Karasawa1, Shin Kumadaki1, Toshiyuki Matsui1, Motohiro Sekiya3, Ken Ohashi3, Alyssa H Hasty4, Yoshimi Nakagawa1,2, Akimitsu Takahashi1, Hiroaki Suzuki1, Sigeru Yatoh1, Hirohito Sone1, Hideo Toyoshima1, Jun-ichi Osuga3 & Nobuhiro Yamada1
Abstract
Insulin resistance is often associated with obesity and can precipitate type 2 diabetes. To date, most known approaches that improve insulin resistance must be preceded by the amelioration of obesity and hepatosteatosis. Here, we show that this provision is not mandatory; insulin resistance and hyperglycemia are improved by the modification of hepatic fatty acid composition, even in the presence of persistent obesity and hepatosteatosis. Mice deficient for Elovl6, the gene encoding the elongase that catalyzes the conversion of palmitate to stearate, were generated and shown to become obese and develop hepatosteatosis when fed a high-fat diet or mated to leptin-deficient ob/ob mice. However, they showed marked protection from hyperinsulinemia, hyperglycemia and hyperleptinemia. Amelioration of insulin resistance was associated with restoration of hepatic insulin receptor substrate-2 and suppression of hepatic protein kinase C 
activity resulting in restoration of Akt phosphorylation. Collectively, these data show that hepatic fatty acid composition is a new determinant for insulin sensitivity that acts independently of cellular energy balance and stress. Inhibition of this elongase could be a new therapeutic approach for ameliorating insulin resistance, diabetes and cardiovascular risks, even in the presence of a continuing state of obesity.
- Department of Internal Medicine (Endocrinology and Metabolism) Graduate School of Comprehensive Human Sciences, 1-1-1 Tennodai, Tsukuba Ibaraki 305-8575, Japan.
- Center for Tsukuba Advanced Research Alliance University of Tsukuba, 1-1-1 Tennodai, Tsukuba Ibaraki 305-8575, Japan.
- Department of Metabolic Disease, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
- Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Correspondence to: Hitoshi Shimano1,2 e-mail: shimano-tky@umin.ac.jp
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