Effects of leptin deficiency and short-term repletion on hepatic gene expression in genetically obese mice

By supplying most organs of the body with metabolic substrates, the liver p lays a central role in maintaining energy balance. Hepatic metabolism of gl ucose, fatty acids, and lipoproteins is disrupted in the leptin-deficient o bese (Lep(ob)/Lep(ob)) mouse, leading to hyperglycemia, steatosis, and hype rcholesterolemia. Microarray expression profiles were used to identify tran scriptional perturbations that underlie the altered hepatic physiology of L ep(ob)/Lep(ob) mice. A wide variety of genes involved in fatty acid metabol ism are altered in expression, which suggests that both fatty acid synthesi s and oxidation programs are activated in obese mice. The expression of a s mall 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 candi date for mediating the atherogenic-resistant phenotype of Lep(ob)/Lep(ob) m ice.