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Hepatic CCAAT/Enhancer Binding Protein Mediates Induction of Lipogenesis and Regulation of Glucose Homeostasis in Leptin-Deficient Mice

Laboratory of Metabolism, National Cancer Institute (K.M., Y.I., F.J.G.), and Comparative Medicine Branch, National Institutes of Allergy and Infectious Diseases (J.M.W.), Molecular Disease Branch, National Heart, Lung, and Blood Institute (H.B.B.) and Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases (D.L.), National Institutes of Health, Bethesda, Maryland 20892; and Institut National de la Santé et de la Recherche Médicale, Unité 539 (G.L.), Hotel Dieu, 44000 Nantes, France

Address all correspondence and requests for reprints to: Frank J. Gonzalez, Building 37, Room 3106, National Institutes of Health, Bethesda, Maryland 20892. E-mail: fjgonz{at}helix.nih.gov.

CCAAT/enhancer binding protein (C/EBP) is a critical factor in glucose metabolism in the neonate as revealed by conventional C/EBP-null mice that do not survive beyond the first day after birth because of severe hypoglycemia and a deficiency in hepatic glycogen accumulation. To elucidate the function of C/EBP in leptin-deficient mouse (ob/ob) liver, a C/EBP-liver null mouse on an ob/ob background (ob/ob-C/EBP/Cre⁺) was produced using a floxed C/EBP allele and Cre recombinase under control of the albumin promoter (AlbCre). The C/EBP-deficient liver in ob/ob mice had significantly decreased triglyceride content compared with equivalent mice lacking the AlbCre transgene (ob/ob-C/EBP/Cre^–). Expression of genes involved in lipogenesis including fatty acid synthase, acetyl-coenzyme A carboxylase, stearoyl-coenzyme A desaturase 1 and ATP-citrate lyase dramatically decreased in ob/ob-C/EBP/Cre⁺ mouse liver. Induction of these lipogenic genes by a high-carbohydrate diet caused an exacerbation in the development of fatty liver and an increase in liver size, hepatic triglyceride, and cholesterol contents in ob/ob-C/EBP/Cre^– mice but not in ob/ob-C/EBP/Cre⁺ mice. Deficiency in hepatic C/EBP expression caused an exacerbation of hyperglycemia because of decreased insulin secretion. Taken together, these results indicate that hepatic C/EBP plays a critical role in the acceleration of lipogenesis in ob/ob mice and in glucose homeostasis by the indirect regulation of insulin secretion.

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