Crucial role of a long-chain fatty acid elongase, Elovl6, in obesity-induced insulin resistance.
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.
Matsuzaka
Takashi
T
Department of Internal Medicine (Endocrinology and Metabolism) Graduate School of Comprehensive Human Sciences, 1-1-1 Tennodai, Tsukuba Ibaraki 305-8575, Japan.
Shimano
Hitoshi
H
Yahagi
Naoya
N
Kato
Toyonori
T
Atsumi
Ayaka
A
Yamamoto
Takashi
T
Inoue
Noriyuki
N
Ishikawa
Mayumi
M
Okada
Sumiyo
S
Ishigaki
Naomi
N
Iwasaki
Hitoshi
H
Iwasaki
Yuko
Y
Karasawa
Tadayoshi
T
Kumadaki
Shin
S
Matsui
Toshiyuki
T
Sekiya
Motohiro
M
Ohashi
Ken
K
Hasty
Alyssa H
AH
Nakagawa
Yoshimi
Y
Takahashi
Akimitsu
A
Suzuki
Hiroaki
H
Yatoh
Sigeru
S
Sone
Hirohito
H
Toyoshima
Hideo
H
Osuga
Jun-ichi
J
Yamada
Nobuhiro
N
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
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