Abstract
BackgroundLeptin, 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.Methodology/Principal FindingsWe 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/SignificanceIn 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.
Highlights
Leptin, a cytokine-like protein containing 167 amino acids that is predominantly expressed in adipocytes, was discovered in 1994 by positional cloning of the obese gene [1]
The four animals with negligible weight loss after leptin-ICV treatment animals were removed from the analyses while evaluating effects of leptin administration on body weight, food intake and insulin levels
We profiled these animals for gene expression, and the data were included for Identification of genes correlated with weight loss
Summary
A cytokine-like protein containing 167 amino acids that is predominantly expressed in adipocytes, was discovered in 1994 by positional cloning of the obese (ob) gene [1]. Leptin plays a very important role in regulation of body weight and fat deposition through the inhibition of food intake and stimulation of energy expenditure [2]. Leptin-deficient (ob/ob) mice and leptin receptordeficient (db/db) mice are severely obese, infertile and insulin resistant, have increased food intake, reduced body temperature and decreased energy expenditure, immune function and bone formation [3,4,5]. A cytokine-like protein, plays an important role in the regulation of body weight through inhibition of food intake and stimulation of energy expenditure. 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
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