Effects of Leptin Deficiency and Short-Term Repletion on Hepatic Gene Expression in Genetically Obese Mice
- 1Medicine and
- 2Pediatrics, Naomi Berrie Diabetes Center, Columbia University College of Physicians & Surgeons, New York, New York
Abstract
By supplying most organs of the body with metabolic substrates, the liver plays a central role in maintaining energy balance. Hepatic metabolism of glucose, fatty acids, and lipoproteins is disrupted in the leptin-deficient obese (Lepob/Lepob) mouse, leading to hyperglycemia, steatosis, and hypercholesterolemia. Microarray expression profiles were used to identify transcriptional perturbations that underlie the altered hepatic physiology of Lepob/Lepob mice. A wide variety of genes involved in fatty acid metabolism are altered in expression, which suggests that both fatty acid synthesis and oxidation programs are activated in obese mice. The expression of a small subset of genes is upregulated by leptin deficiency, not modulated by caloric restriction, and markedly suppressed by short-term leptin treatment. Among these leptin-regulated genes, apolipoprotein A-IV is a strong candidate for mediating the atherogenic-resistant phenotype of Lepob/Lepob mice.
Footnotes
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Address correspondence and reprint requests to Rudolph L. Leibel, MD, Division of Molecular Genetics, Russ Berrie Research Building, Columbia University College of Physicians & Surgeons, 1150 St. Nicholas Avenue, New York, NY 10032. E-mail: rl232{at}columbia.edu.
Received for publication 2 April 2001 and accepted in revised form 19 June 2001.
Apo A-IV, apolipoprotein A-IV; dNTP, deoxynucleotide triphosphates; dUTP; deoxyuridine-triphosphate; HMG, hydroxymethylglutaryl; IIP2, insulin-induced protein 2; PCR, polymerase chain reaction; SSC, sodium chloride–sodium citrate; SREBP-1, sterol regulatory element-binding protein 1.
