Transcriptional Profiling Reveals Global Defects in Energy Metabolism, Lipoprotein, and Bile Acid Synthesis and Transport with Reversal by Leptin Treatment in Ob/ob Mouse Liver

Abstract

Leptin, a hormone secreted by adipose tissue, has been shown to have a major influence on hepatic lipid and lipoprotein metabolism. To characterize changes in lipid and lipoprotein gene expression in mouse liver, suppression subtractive hybridization and cDNA microarray analysis were used to identify mRNAs differentially expressed after leptin treatment of ob/ob mice. Ob/ob mice showed a profound decrease in mRNAs encoding genes controlling bile acid synthesis and transport as well as a variety of apolipoprotein genes and hepatic lipase with reversal upon leptin administration, suggesting that leptin coordinately regulates high density lipoprotein and bile salt metabolism. Leptin administration also resulted in decreased expression of genes involved in fatty acid and cholesterol synthesis, glycolysis, gluconeogenesis, and urea synthesis, and increased expression of genes mediating fatty acid oxidation, ATP synthesis, and oxidant defenses. The changes in mRNA expression are consistent with a switch in energy metabolism from glucose utilization and fatty acid synthesis to fatty acid oxidation and increased respiration. The latter changes may produce oxidant stress, explaining the unexpected finding that leptin induces a battery of genes involved in antioxidant defenses. Expression cluster analysis revealed responses of several sets of genes that were kinetically linked. Thus, the mRNA levels of genes involved in fatty acid and cholesterol synthesis are rapidly (<1 h) repressed by leptin administration, in association with an acute decrease in plasma insulin levels and decreased sterol regulator element-binding protein-1 expression. In contrast, genes participating in fatty acid oxidation and ketogenesis were induced more slowly (24 h), following an increase in expression of their common regulatory factor, peroxisome proliferator-activated receptor ␣. However, the regulation of genes involved in high density lipoprotein and bile salt metabolism shows complex kinetics and is likely to be mediated by novel transcription factors.Leptin, a 16-kDa circulating protein synthesized primarily by white adipose tissue, has diverse regulatory roles in animal physiology, influencing energy metabolism, neuroendocrine, immune, and reproductive functions (1, 2). While various isoforms of the leptin receptor are widely expressed, leptin actions on appetite and energy metabolism are thought to be mediated mainly through the receptor with a long intracellular domain present in the central nervous system (1). The binding of leptin to its receptor in the brain leads to the activation of Janus kinases and signal transducers and activators of transcription, thereby altering the expression and release of a number of neuropeptide effectors known to be involved in the control of feeding behavior and energy balance (1, 2).Mice with genetic defects in the leptin signaling pathway (e.g. ob/ob and db/db mice) are obese and infertile, and show reduced activity and body temperature (3). They also exhibit hyperlipidemia, hyperinsulinemia, hypergly...

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

“…Increases in reactive oxygen species are prevented by SOD2 [28]. Impaired expression of SOD2 or other genes associated with a stress defence system, including FMO5, as observed here and in ob/ob mice [11], could increase oxidative stress in the diabetic state. Similar alterations in gene expression in blood vessels may increase the risk of atherosclerosis.…”

“…The down-regulation of plasminogen observed by us in the diabetic liver could thus result in reduced fibrinolysis, leading to thrombosis and atherosclerosis. Down-regulation of plasminogen has also been reported in the livers of ob/ob mice [11].…”

“…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.…”

Genome‐wide analysis of changes in early gene expression induced by oestrogen

“…Thus, it was suggested that oestrogen down-regulates ketogenesis and activates sterol synthesis. This effect of oestrogen is the reverse of the effect of leptin (Liang & Tall 2001), and the overall gene expression changes by oestrogen contrasted significantly with the gene expression changes caused by leptin. Although not all gene expression profiles are consistent with an oestrogen effect (for example, urea metabolism was not affected in our study though it was affected by leptin), the behaviour of the selected genes in our study showed the reverse effect following leptin treatment.…”