Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance.

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 epsilon 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.
Authors	Takashi Matsuzaka, Hitoshi Shimano, Naoya Yahagi, Toyonori Kato, Ayaka Atsumi, Takashi Yamamoto, Noriyuki Inoue, Mayumi Ishikawa, Sumiyo Okada, Naomi Ishigaki, Hitoshi Iwasaki, Yuko Iwasaki, Tadayoshi Karasawa, Shin Kumadaki, Toshiyuki Matsui, Motohiro Sekiya, Ken Ohashi, Alyssa H Hasty, Yoshimi Nakagawa, Akimitsu Takahashi, Hiroaki Suzuki, Sigeru Yatoh, Hirohito Sone, Hideo Toyoshima, Jun-ichi Osuga, Nobuhiro Yamada
Journal	Nature medicine (Nat Med) Vol. 13 Issue 10 Pg. 1193-202 (Oct 2007) ISSN: 1078-8956 [Print] United States
PMID	17906635 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Dietary Fats Elovl6 protein, mouse Insulin Insulin Receptor Substrate Proteins Intracellular Signaling Peptides and Proteins Irs2 protein, mouse Phosphoproteins RNA, Messenger Acetyltransferases Fatty Acid Elongases Proto-Oncogene Proteins c-akt Protein Kinase C-epsilon
Topics	Acetyltransferases (deficiency, genetics, metabolism) Animals Body Weight (drug effects) Carcinoma, Hepatocellular (pathology) Cell Line, Tumor Diet, Atherogenic Dietary Fats (administration & dosage, pharmacology) Fatty Acid Elongases Gene Deletion Insulin (metabolism) Insulin Receptor Substrate Proteins Insulin Resistance Intracellular Signaling Peptides and Proteins (physiology) Liver Neoplasms (pathology) Male Mice Mice, Knockout Obesity (chemically induced, genetics, metabolism) Phosphoproteins (physiology) Phosphorylation Protein Kinase C-epsilon (antagonists & inhibitors) Proto-Oncogene Proteins c-akt (metabolism) RNA, Messenger (metabolism) Signal Transduction Time Factors

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