Effects of Leptin Deficiency and Short-Term Repletion on Hepatic Gene Expression in Genetically Obese Mice

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 (Lep ob /Lep ob ) mouse, leading to hyperglycemia, steatosis, and hypercholesterolemia. Microarray expression profiles were used to identify transcriptional perturbations that underlie the altered hepatic physiology of Lep ob /Lep ob 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 Lep ob /Lep ob mice.

Genes for systemic vascular complications are differentially expressed in the livers of Type 2 diabetic patients

“…For example, up-regulation of Rad (a Ras-oncogene associated with diabetes), heat shock 70kD protein, and receptors for PDGF and endothelin, and down-regulation of general transcription and translation factors, and of cadherin and MHC have been observed in the skeletal muscle of insulin-resistant Pima Indians [7] and in Type 2 diabetic patients [8]. In addition, up-regulation of epidermal growth factor receptor and down-regulation of fatty acid-associated enzymes, fibronectin, VCAM1, MHC, plasminogen, SOD2, FMO5 and complement C3 have been observed in the liver of ob/ob mice [10,11,12].…”

“…More recently, microarray profiling of skeletal muscle tissue of Type 2 diabetic patients [7,8] and of healthy humans treated with insulin [9] has been reported. Although the liver is central for glucose homeostasis, microarray profiling of diabetic liver has been done only in Ob/Ob mice, a genetically obese rodent model of diabetes [10,11,12]. We have now used it to clarify the transcriptional alterations in the liver that are associated with the pathophysiology of Type 2 diabetes.…”

Reduced Expression of the Insulin Receptor in Mouse Insulinoma (MIN6) Cells Reveals Multiple Roles of Insulin Signaling in Gene Expression, Proliferation, Insulin Content, and Secretion

“…This criterion was selected after observing that the mean variance of all of the probes was 0.15, and the false positive rate was estimated to be 0.0032%. With similar multiple hybridizations and cDNA microarrays, the fold change of 1.3-1.4 was utilized to identify significant gene expression change in other studies (31)(32)(33). Additionally, significant fold changes required that the 95% CI of the fold change, two standard errors away from the fold change, excluded 1.…”

Decrease of plasma apolipoprotein A-IV during weight reduction in obese adolescents on a low fat diet

“…[12][13][14] In leptin receptor-deficient obese rats and in leptin-deficient obese mice, the expression of the apoA-IV gene is enhanced and its dietary regulation is altered. 15,16 Recently, Verges et al 17 reported that in obese patients fasting plasma apoA-IV is significantly elevated and postprandial plasma apoA-IV is markedly increased. There is little information, however, on the relation of plasma apoA-IV concentrations with the degree of obesity and it is unknown whether weight reduction alters plasma apoA-IV levels.…”