title: Unsuppressed lipolysis in adipocytes is linked with enhanced gluconeogenesis and altered bile acid physiology in Insr(P1195L/+) mice fed high-fat-diet.
abstract: High-fat diet (HFD) triggers insulin resistance and diabetes mellitus, but their link remains unclear. Characterization of overt hyperglycemia in insulin receptor mutant (Insr(P1195L/+)) mice exposed to HFD (Insr(P1195L/+)/HFD mice) revealed increased glucose-6-phosphatase (G6pc) expression in liver and increased gluconeogenesis from glycerol. Lipolysis in white adipose tissues (WAT) and lipolysis-induced blood glucose rise were increased in Insr(P1195L/+)/HFD mice, while wild-type WAT transplantation ameliorated the hyperglycemia and the increased G6pc expression. We found that the expressions of genes involved in bile acid (BA) metabolism were altered in Insr(P1195L/+)/HFD liver. Among these, the expression of Cyp7a1, a BA synthesis enzyme, was insulin-dependent and was markedly decreased in Insr(P1195L/+)/HFD liver. Reduced Cyp7a1 expression in Insr(P1195L/+)/HFD liver was rescued by WAT transplantation, and the expression of Cyp7a1 was suppressed by glycerol administration in wild-type liver. These findings suggest that unsuppressed lipolysis in adipocytes elicited by HFD feeding is linked with enhanced gluconeogenesis from glycerol and with alterations in BA physiology in Insr(P1195L/+)/HFD liver.
authors.affiliation: Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670 Japan.
authors.forename: Eun Young
authors.initials: EY
authors.lastname: Lee
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University, Graduate School of Medicine, Chiba 260-8670 Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sakurai
authors.affiliation: Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670 Japan.
authors.forename: Xilin
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan.
authors.forename: Chitoku
authors.initials: C
authors.lastname: Toda
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University, Graduate School of Medicine, Chiba 260-8670 Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Genome Research and Clinical Application, Chiba University, Graduate School of Medicine, Chiba 260-8670 Japan.
authors.forename: Meizi
authors.initials: M
authors.lastname: Jiang
authors.affiliation: Department of Ageing Control, Juntendo University, Graduate School of Medicine. Bunkyo 113-0033, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Shirasawa
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University, Graduate School of Medicine, Chiba 260-8670 Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Tachibana
authors.affiliation: Department of Clinical Cell Biology and Medicine, Chiba University, Graduate School of Medicine, Chiba 260-8670 Japan.
authors.forename: Koutaro
authors.initials: K
authors.lastname: Yokote
authors.affiliation: Department of Clinical Biochemistry, Metabolic Research Laboratories, Addenbrooke's Treatment Centre, Institute of Metabolic Science, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: Antonio
authors.initials: A
authors.lastname: Vidal-Puig
authors.affiliation: Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Minokoshi
authors.affiliation: Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670 Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miki
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism / Q000637:transplantation; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001786:Blood Glucose; D001835:Body Weight; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005223:Fats / Q000378:metabolism; D005838:Genotype; D005943:Gluconeogenesis; D005990:Glycerol / Q000378:metabolism; D006943:Hyperglycemia / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008066:Lipolysis; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics*
chemical_list: D001647:Bile Acids and Salts; D001786:Blood Glucose; D005223:Fats; D007328:Insulin; D019289:Pyruvic Acid; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D005990:Glycerol