Despite the fact that leptin has shown exciting results in the mouse models, the success rate of leptin for the reduction of body weight in humans is very low. This is due mainly to the fact that a very small fraction of the obese human population is leptin deficient, and the most common forms of obesity are associated with high leptin levels 
. In such cases, most obese patients are leptin resistant and fail to respond effectively to exogenous leptin 
. Several defects may contribute to the leptin resistant state, including defective leptin transport across the blood-brain barrier, reduced leptin receptor expression, defects in leptin signal transduction, or the induction of feedback inhibitors  
. However, if leptin resistance could be by-passed and genes/pathways which respond to leptin treatment could be regulated directly, new therapeutic strategies for the treatment of obesity may be possible. In this study, we determined the global hepatic gene expression profiles after peripheral and central leptin treatment. We found that the effect of central treatment on weight loss was significantly better than peripheral treatment; which confirms that leptin action on weight loss is primarily controlled by a central pathway via hypothalamic relay. We found 214 genes significantly correlated with leptin-mediated weight loss.
Obesity results from the imbalance of energy intake and energy utilization. When energy intake exceeds energy expenditure, excess energy is stored as triglycerides in lipid droplets. Conversely during nutrient deprivation, stored triglycerides are hydrolyzed into fatty acids and converted back to energy. Therefore, metabolic pathways are key regulators of energy balance. In this study, we found that genes which belong to metabolic, catabolic and biosynthetic pathways in mitochondria are highly expressed in ob/ob
mice when compared with the B6 baseline expression. However, leptin replacement results in the downregulation of these pathways back to normal. The Stearoyl-CoA Desaturase 1 (Scd1), which is a lipogenic enzyme involved in fatty acid synthesis and oxidation, is overexpressed in the livers of ob/ob
mice as compared to B6 and is downregulated after leptin replacement. This is consistent with the results of previous studies which have shown that Scd1 deficient mice are protected against obesity and insulin resistance 
. Also in humans, genetic variations in the Scd1 gene were found to be associated with body fat deposition and insulin sensitivity 
. Some recent studies have used pharmacological inhibition of Scd1 for treatment of obesity and insulin resistance 
. Glucokinase (GcK) phosphorylates glucose to produce glucose-6-phosphate and therefore regulates glucose metabolism. We found that expression of this gene is negatively correlated with leptin-mediated weight loss in ob/ob
mice. Long-term overexpression of Gck increases hepatic lipogenesis and circulating lipids, which leads to insulin resistance 
Weight loss also has been linked to GH-IGF1 axis in the literature, which has a critical role in the proliferation and differentiation of adipocytes 
. IGF-binding proteins (IGFBPs) modulate bioavailability of IGF. In this study we found that Igfbp2 was highly underexpressed in livers of ob/ob
mice but was normalized after leptin replacement. Recent studies have shown that overexpression of Igfbp2 protects against the development of obesity and improves insulin sensitivity 
. Treatment with recombinant Igfbp2 impairs 3T3-L1 differentiation and hence adipogenesis 
. Elevated insulin and body fat have been shown to be associated with decreased Igfbp1 and Igfbp2 levels cross-sectionally 
. A recent study observed markedly lower expression of Igfbp2 in liver from morbidly obese women 
. Such studies provide an impetus for investigating the effects of Igfbp2 for treatment of obesity. However, studies have also shown that Igfbp2 is overexpressed in a wide spectrum of cancers and IGF-independent effects of Igfbp2 are emerging 
. Igfbp2 expression was significantly higher in breast cancer tissue compared with benign breast tissue and Igfbp2 inhibition attenuated the associated aggressive phenotype of breast cancer cells both in vitro and in vivo 
. Overexpression of Igfbp2 has also been correlated with glioblastoma 
and lymph node metastasis in patients with invasive breast carcinomas 
. These findings suggest that further studies are required to evaluate IGF-dependent and -independent functions of Igfbp2 before choosing Igfbp2 as a therapeutic target for treatment of obesity.
We found that Cisd1, the mitochondrial gene which encodes for the MitoNEET protein, is upregulated in livers of ob/ob mice as compared to B6 and could be normalized by leptin. MitoNEET is an iron-containing outer mitochondrial membrane protein that regulates oxidative capacity and is involved in the control of maximal mitochondrial respiratory rates 
. This protein exists in low levels in preadipocytes, and its expression increases exponentially in differentiated adipocytes. Also, MitoNEET has been identified as a target for the thiazolidinedione class of diabetes drugs that may contribute to lipid lowering and/or antidiabetic actions 
Interestingly, the expression of five glutathione S-transferases (Gsta1, Gsta2, Gsta3, Gstt1, and Gstt3) were significantly downregulated after leptin administration. In an earlier study it was shown that Gsta3 expression is markedly induced during adipose conversion, which is virtually undetectable in confluent 3T3-L1 cells under basal conditions 
. Inhibition of the 3T3-L1 adipogenic program demonstrated that Gsta3 expression is associated specifically with acquisition of the adipocytic phenotype.
One important finding of this study was the upregulation of hepatic lysosomal pathways, including vesicles and vacuole, after leptin treatment. This finding is consistent with a recent study which has identified the previously unknown role of autophagy in regulating intracellular lipid stores 
. Starvation causes the induction of autophagy, which delivers intracellular proteins and organelles sequestered in double-membrane vesicles (autophagosomes) to lysosomes for degradation and use as an energy source. It was found that inhibition of autophagy in cultured hepatocytes and mouse liver increased triglyceride storage in lipid droplets.
In conclusion, this study identified key molecular pathways and downstream target genes involved in the leptin-mediated weight loss. Many of these genes have previously been shown to be associated with obesity; however, we also identified a number of novel target genes. Further detailed studies will be required to evaluate the possible use of these genes and the associated protein products as therapeutic targets for the treatment of obesity.