title: 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: Department of Internal Medicine (Endocrinology and Metabolism) Graduate School of Comprehensive Human Sciences, 1-1-1 Tennodai, Tsukuba Ibaraki 305-8575, Japan.
authors: Takashi
authors: T
authors: Matsuzaka
authors: Hitoshi
authors: H
authors: Shimano
authors: Naoya
authors: N
authors: Yahagi
authors: Toyonori
authors: T
authors: Kato
authors: Ayaka
authors: A
authors: Atsumi
authors: Takashi
authors: T
authors: Yamamoto
authors: Noriyuki
authors: N
authors: Inoue
authors: Mayumi
authors: M
authors: Ishikawa
authors: Sumiyo
authors: S
authors: Okada
authors: Naomi
authors: N
authors: Ishigaki
authors: Hitoshi
authors: H
authors: Iwasaki
authors: Yuko
authors: Y
authors: Iwasaki
authors: Tadayoshi
authors: T
authors: Karasawa
authors: Shin
authors: S
authors: Kumadaki
authors: Toshiyuki
authors: T
authors: Matsui
authors: Motohiro
authors: M
authors: Sekiya
authors: Ken
authors: K
authors: Ohashi
authors: Alyssa H
authors: AH
authors: Hasty
authors: Yoshimi
authors: Y
authors: Nakagawa
authors: Akimitsu
authors: A
authors: Takahashi
authors: Hiroaki
authors: H
authors: Suzuki
authors: Sigeru
authors: S
authors: Yatoh
authors: Hirohito
authors: H
authors: Sone
authors: Hideo
authors: H
authors: Toyoshima
authors: Jun-ichi
authors: J
authors: Osuga
authors: Nobuhiro
authors: N
authors: Yamada
mesh_terms: D000123:Acetyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000473:pathology; D045744:Cell Line, Tumor; D004036:Diet, Atherogenic; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology*; D000081031:Fatty Acid Elongases; D017353:Gene Deletion; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008113:Liver Neoplasms / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000502:physiology; D010766:Phosphorylation; D051744:Protein Kinase C-epsilon / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D004041:Dietary Fats; C000630968:Elovl6 protein, mouse; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases; D051057:Proto-Oncogene Proteins c-akt; D051744:Protein Kinase C-epsilon