Hepatic insulin signaling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expression.
Dissecting the role of insulin in the complex regulation of triglyceride metabolism is necessary for understanding dyslipidemia and steatosis. Liver insulin receptor knockout (LIRKO) mice show that in the physiological context of feeding, hepatic insulin signaling is not required for the induction of mTORC1, an upstream activator of the lipogenic regulator, SREBP-1c. Feeding induces SREBP-1c mRNA in LIRKO livers, though not to the extent observed in controls. A high fructose diet also partially induces SREBP-1c and lipogenic gene expression in LIRKO livers. Insulin signaling becomes more important in the pathological context of obesity, as knockdown of the insulin receptor in ob/ob mice, a model of Type 2 diabetes, using antisense oligonucleotides, abolishes the induction of SREBP-1c and its targets by obesity and ameliorates steatosis. Thus, insulin-independent signaling pathways can partially compensate for insulin in the induction of SREBP-1c by feeding but the further induction by obesity/Type 2 diabetes is entirely dependent upon insulin.
Department of Biochemistry and Biophysics, University of California-San Francisco, and Gladstone Institute of Cardiovascular Disease, San Francisco, CA 94158, USA.
Joel T
JT
Haas
Ji
J
Miao
Dipanjan
D
Chanda
Yanning
Y
Wang
Enpeng
E
Zhao
Mary E
ME
Haas
Matthew
M
Hirschey
B
B
Vaitheesvaran
Robert V
RV
Farese
Irwin J
IJ
Kurland
Mark
M
Graham
Rosanne
R
Crooke
Fabienne
F
Foufelle
Sudha B
SB
Biddinger
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004040:Dietary Carbohydrates / Q000008:administration & dosage; D005234:Fatty Liver / Q000378:metabolism; D005260:Female; D005632:Fructose / Q000008:administration & dosage; D015870:Gene Expression; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism; D007328:Insulin / Q000502:physiology*; D007659:Ketones / Q000097:blood; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D009765:Obesity / Q000378:metabolism*; D034622:RNA Interference; D011972:Receptor, Insulin / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
D004040:Dietary Carbohydrates; C506119:Insig1 protein, mouse; C506120:Insig2 protein, mouse; D007328:Insulin; D007659:Ketones; D008565:Membrane Proteins; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D005632:Fructose; D011972:Receptor, Insulin; D005947:Glucose