Hepatic gene expression profiling reveals key pathways involved in leptin-mediated weight loss in ob/ob mice.
BACKGROUND
Leptin, a cytokine-like protein, plays an important role in the regulation of body weight through inhibition of food intake and stimulation of energy expenditure. Leptin circulates in blood and acts on the brain, which sends downstream signals to regulate body weight. Leptin therapy has been successful in treating leptin deficient obese patients. However, high levels of leptin have been observed in more common forms of obesity indicating a state of leptin resistance which limits the application of leptin in the treatment of obesity. If the central effect of leptin could be by-passed and genes which respond to leptin treatment could be regulated directly, new therapeutic targets for the treatment of obesity may be possible. The purpose of this study was to identify genes and subsequent pathways correlated with leptin-mediated weight loss.


RESULTS
WE UTILIZED MICROARRAY TECHNOLOGY TO COMPARE HEPATIC GENE EXPRESSION CHANGES AFTER TWO TYPES OF LEPTIN ADMINISTRATION: one involving a direct stimulatory effect when administered peripherally (subcutaneous: SQ) and another that is indirect, involving a hypothalamic relay that suppresses food intake when leptin is administered centrally (intracerebroventricular: ICV). We identified 214 genes that correlate with leptin mediated weight loss. Several biological processes such as mitochondrial metabolic pathways, lipid metabolic and catabolic processes, lipid biosynthetic processes, carboxylic acid metabolic processes, iron ion binding and glutathione S-transferases were downregulated after leptin administration. In contrast, genes involved in the immune system inflammatory response and lysosomal activity were found to be upregulated. Among the cellular compartments mitochondrion (32 genes), endoplasmic reticulum (22 genes) and vacuole (8 genes) were significantly over represented.


CONCLUSIONS
In this study we have identified key molecular pathways and downstream genes which respond to leptin treatment and are involved in leptin-mediated weight loss. Many of these genes have previously been shown to be associated with obesity; however, we have also identified a number of other novel target genes. Further investigation will be required to assess the possible use of these genes and their associated protein products as therapeutic targets for the treatment of obesity.
Sharma
Ashok
A
Center for Biotechnology and Genomic Medicine, School of Medicine, Medical College of Georgia, Augusta, Georgia, United States of America.
Bartell
Shoshana M
SM
Baile
Clifton A
CA
Chen
Bo
B
Podolsky
Robert H
RH
McIndoe
Richard A
RA
She
Jin-Xiong
JX
D017667:Adipocytes / Q000187:drug effects / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002264:Carboxylic Acids / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016000:Cluster Analysis; D015536:Down-Regulation / Q000187:drug effects; D004333:Drug Administration Routes; D004435:Eating / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D005982:Glutathione Transferase / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007501:Iron / Q000378:metabolism; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D020411:Oligonucleotide Array Sequence Analysis; D015431:Weight Loss / Q000187:drug effects* / Q000235:genetics
D002264:Carboxylic Acids; D007328:Insulin; D020738:Leptin; D007501:Iron; D005982:Glutathione Transferase
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