Leptin gene Polymorphism and Leptin protein levels in Pediatric Autoimmune Hepatitis.

BACKGROUND: Leptin plays a role in regulating energy balance, immunity, and inflammation. Studies suggest higher leptin levels might be associated with various autoimmune diseases. Most of them were in adult. To our knowledge, our study is one of the few that describe serum leptin level and leptin gene polymorphism in children with autoimmune hepatitis (AIH). OBJECTIVE: Our study aims to explore the association between serum leptin level and genetic variations in leptin gene with the likelihood of AIH in children. PATIENTS AND METHODS: Thirty-one children with AIH and 29 healthy children serving as a control group were included. Serum leptin levels were measured by ELISA assays. Leptin rs2167270 genotyping was done using the real time-PCR. The relationship of serum leptin level and leptin gene polymorphism with patients' data was studied. Patients follow up to assess treatment response. RESULTS: Children with AIH had significantly higher levels of leptin compared to healthy controls. GG genotype was significantly more prevalent in the AIH group compared to controls. CONCLUSION: High serum leptin levels and leptin gene polymorphism may play a role in AIH development. It is worthy to recognize if leptin can serve as diagnostic and/or therapeutic target in AIH in children.

Association of leptin mRNA expression with meat quality trait in Tianfu black rabbits.

Leptin is a hormone synthesized and secreted primarily in adipocyte which can help to regulate energy balance. In this experiment, three tissue samples of Tianfu black rabbits at four growing periods were selected. The expression levels of leptin gene in different tissues were detected by real-time fluorescence quantitative PCR. The correlation analysis showed that the correlation coefficient between the expression levels of leptin gene in perirenal fat and intramuscular fat content in 84-day-old male rabbits was 0.73 (p < 0.05); the correlation coefficients between the expression levels of leptin gene in left biceps femoris and intramuscular fat and 24-hour pH in 84-day-old male rabbits were 0.95 (p < 0.01) and 0.85 (p < 0.05), respectively. Besides, the correlation coefficient between the expression levels of leptin gene in male left biceps femoris and cooked meat rate was 0.83 (p < 0.05). According to the analysis results, we inferred the expression levels of leptin gene in Tianfu black rabbits can influence meat quality and the meat quality of high expression levels of leptin gene in Tianfu black rabbits is better. These results revealed the leptin gene may be one of the important candidate genes for meat quality traits of molecular markers.

-2548G>A LEP Polymorphism Is Positively Associated with Increased Leptin and Glucose Levels in Obese Saudi Patients Irrespective of Blood Pressure Status

Background and Objectives: In this study, we aimed to investigate the link between common -2548G>A (rs7799039) promoter variant of the human leptin gene (LEP) with leptin and serum glucose leptin levels in obese Saudi patients. Materials and Methods: A total of 206 Saudi adults (80 obese normotensive nondiabetics, 76 obese hypertensive with Type 2 Diabetes and 50 normotensive nondiabetic controls) were genotyped for -2548G>A LEP polymorphism using the polymerase chain reaction-restriction fragment-length polymorphism technique. Results: Participants with minor AA genotype had significantly higher blood glucose levels (6.8 ± 0.55 mmol/L vs. 5.8 ± 0.30 mmol/L; p < 0.04) and HOMA-IR (4.1 ± 0.84 vs. 2.6 ± 0.67; p = 0.03) against those carrying major GG genotype. Participants with heterozygous GA genotype had significantly higher serum leptin levels against those carrying major GG genotype (40.0 ± 2.6 ng/mL vs. 29.6 ± 2.6 ng/mL; p = 0.04). Further investigation showed that individuals with AA, GA, GA + AA genotypes are at greater risk of developing hyperglycemia compared to those with GG genotype [OR 3.7(1.6−8.4), p = 0.001; 3.2 (1.2−8.6), p = 0.03; 3.5 (1.6−7.7), p = 0.001, respectively]. Additionally, the -2548AA allele was shown to be a risk factor for hyperglycemia [OR 1.9 (1.2−3.0), p = 0.006]. Our data revealed no relationship between this variant of the LEP gene with systolic and diastolic BP, signifying that this genetic variant is not a significant marker of obesity and hypertension in the Saudi population. Conclusions: AA and GA genotypes and LEP gene -2548AA alleles may signify potent risk factors predisposing healthy individuals to develop T2DM regardless of blood-pressure profile.

Single nucleotide polymorphisms of leptin gene in five Ethiopian indigenous cattle breeds and the Korean Hanwoo breed.

Considering the escalating number of scientific reports on the association between the leptin gene and diverse physiological traits and performance of cattle populations, this study was directed towards identifying SNPs in the leptin gene among five indigenous cattle breeds of Ethiopia. DNA samples were extracted from the nasal swabs of the Ethiopian indigenous cattle breeds: Arsi (n = 18), Horro (n = 20), Begait (n = 21), Boran (n = 19), and Fogera (n = 17) and the Korean Hanwoo (a representative taurine breed) (n = 20), followed by PCR amplification of exon 2 and exon 3 regions of the leptin gene and sequence analysis of the PCR products. Five SNPs, two (generating missense mutations) on exon 2 and three (generating silent mutations) on exon 3 regions, were explicated in this study. Allele frequency and genotype frequency distribution pertaining to the SNPs were recorded for the studied cattle breeds besides the minor allele frequency and deviation from the Hardy-Weinberg equilibrium. Positive FIS index values were recorded for all the markers except SNP2, illustrative of heterozygote deficiency. MEGA X software-based evolutionary divergence analysis of the phylogenetic tree based on the SNP data revealed that the large-sized breeds, Hanwoo, Begait, Boran, and Fogera, were more closely clustered compared to the small-sized Arsi breed. Among the seven haplotypes documented from the various breeds, sequence analysis was suggestive of haplotypes 1 and 2 to be ancestral haplotypes for the leptin gene. This study is envisaged to accelerate molecular breeding programs for the genetic improvement of the Ethiopian cattle breeds.

Leptin gene polymorphism (rs7799039; G2548A) is associated with changes in serum lipid concentrations during pregnancy: a prospective cohort study.

PURPOSE: Little is known about the effects of leptin and leptin receptor polymorphisms on lipid changes during pregnancy. The aims of this study were to evaluate the associations between the single nucleotide polymorphisms (SNPs) of leptin and leptin receptor genes and the lipid concentrations during pregnancy; and to test whether dietary intake is a mediator in these associations. METHODS: A prospective cohort of 154 pregnant women was followed up in Rio de Janeiro, Brazil during the following gestational periods: 5-13th, 20-26th and 30-36th weeks. HDL-C, total cholesterol (TC) and triglyceride (TG) were measured by the enzymatic colorimetric method, and LDL-C was calculated. DNA was extracted by the phenol-chloroform method, and leptin (G2548A, rs7799039) and leptin receptor SNPs (Q223R; rs1137101 and K109R; rs1137100) were genotyped using real-time PCR. Statistical analyses included linear mixed-effect models. RESULTS: Women with the AA genotype of G2548A polymorphism reported a higher fat and total energy intake and had a higher increase in TG concentration during pregnancy than women with AG or GG genotype. The association between G2548A SNP and TG concentrations was not attenuated by adjusting for total lipid (g) and energy (kcal) intake. We did not observe significant associations between the Q223R and K109R SNPs and the lipid concentrations. CONCLUSIONS: Women homozygous for the A allele of the leptin SNP (G2548A) had a higher increase in TG concentrations per gestational week compared with women with the AG or GG genotype. This is an exploratory and hypothesis-generating study, and the results need confirmation in studies with larger sample sizes.'

Complex lipid globules in early-life nutrition improve long-term metabolic phenotype in intra-uterine growth-restricted rats.

Intra-uterine growth restriction (IUGR) is associated with adverse metabolic outcome later in life. Healthy mice challenged with a Western-style diet (WSD) accumulated less body fat when previously fed a diet containing large lipid globules (complex lipid matrix (CLM)). This study was designed to clarify whether an early-life CLM diet mitigates 'programmed' visceral adiposity and associated metabolic sequelae after IUGR. In rats, IUGR was induced either by bilateral uterine vessel ligation (LIG) or sham operation (i.e. intra-uterine stress) of the dam on gestational day 19. Offspring from non-operated (NOP) dams served as controls. Male offspring of all groups were either fed CLM or 'normal matrix' control diet (CTRL) from postnatal days (PND) 15 to 42. Thereafter, animals were challenged with a mild WSD until dissection (PND 98). Fat mass (micro computer-tomograph scan; weight of fat compartments), circulating metabolic markers and expression of 'metabolic' genes (quantitative real-time PCR) were assessed. CLM diet significantly reduced visceral fat mass in LIG at PND 40. At dissection, visceral fat mass, fasted blood glucose, TAG and leptin concentrations were significantly increased in LIG-CTRL v. NOP-CTRL, and significantly decreased in LIG-CLM v. LIG-CTRL. Gene expression levels of leptin (mesenteric fat) and insulin-like growth factor 1 (liver) were significantly reduced in LIG-CLM v. LIG-CTRL. In conclusion, early-life CLM diet mitigated the adverse metabolic phenotype after utero-placental insufficiency. The supramolecular structure of dietary lipids may be a novel aspect of nutrient quality that has to be considered in the context of primary prevention of obesity and metabolic disease in at-risk populations.

Evaluation of leptin and leptin receptor gene 3' UTR polymorphisms in essential hypertension.

INTRODUCTION: Leptin and leptin receptor gene polymorphisms have been associated with obesity; however, their association with blood pressure has not been fully elucidated. The aim of this study was to examine the effect of tetranucleotide repeat polymorphism in the 3' flanking region of the leptin and leptin receptor gene on blood pressure in hypertensives with obesity. METHODS: Two hundred and eighty hypertensives and 200 healthy controls were analyzed for a tetranucleotide repeat polymorphism of leptin and leptin receptor genes. Genotyping was done by amplifying DNA and determining the allele sizes using gel documentation system. Odds ratios were computed to predict the risk for hypertension caused by specific genotypes of leptin and leptin receptor genes and the effect of interaction between them on the development of hypertension was determined by MDR test. RESULTS: Significant preponderance in the incidence of male sex, obese individuals and those with positive family history was observed with significant elevation in the mean levels of SBP, DBP, BMI and reduction of HDL levels in hypertensives as compared to controls. Class I/I genotypes of leptin showed significantly high risk for developing hypertension irrespective of obesity. Genotypes of leptin receptor did not confer any risk for hypertension and cohorts studied. CONCLUSION: Homozygotes I/I were at greater risk for developing hypertension irrespective of obesity. When leptin and leptin receptor genes were considered together, synergistic interaction was observed between the two genes leading to hypertension, while the polymorphism at leptin gene and obesity was correlated.

Gene structure and expression of leptin in Chinese perch.

Leptin is an important hormone involved in regulation of food intake, energy expenditure and reproduction in mammals, but its role in acanthomorph fishes remains scant. In the present study, we characterized leptin gene structure and its tissue expression in Chinese perch (Siniperca chuatsi). In contrast to typical leptin gene organization of 3 exons and 2 introns in other vertebrates, Chinese perch leptin gene consisted of 2 exons and 1 intron. This is the first leptin gene characterized in Perciformes, and is also the first leptin gene lacking an intron reported in Perciformes. The unique gene structure, the conservation of both cysteines that form the single disulfide bridge in leptin, and stable clustering in phylogenetic analyses substantiate the unambiguous orthology of mammalian and fish leptins, despite low amino acid identity. Polymorphism of leptin gene was examined in wild and cultivated populations of Chinese perch by direct sequencing of 120 fish. No SNP was found in leptin gene. Leptin mRNA of Chinese perch was highly expressed in liver, and expressed at low levels in brain, visceral adipose tissue, intestine, spleen and muscle.

Intergenic lnc-LEP-2:6 and lnc-LEP-2:7 as novel biomarkers associated with type 2 diabetes mellitus.

CONTEXT: Type 2 diabetes mellitus (T2DM) has undeniably become a significant threat to public health in the modern world. OBJECTIVE: To identify molecules involved in the development of T2DM, the expression patterns of cis-lincRNAs-LEP were investigated in T2DM patients. MATERIALS AND METHODS: The expression levels of 11 lncRNAs-LEP and LEP mRNA in 71 diabetic patients and 32 controls were determined using qRT-PCR. The association between lncRNAs-LEP and T2DM was performed using ROC curve analysis. RESULTS: The expression analysis of lnc-LEP-2:6 and lnc-LEP-2:7 was significantly different (p≤ .0001) in diabetic patients compared to the controls. The ROC curve data showed that lnc-LEP-2:6 and lnc-LEP-2:7 have a high AUC, with 0.940 (95% CI: 0.875-0.977) and 0.958 (95% CI: 0.899-0.988), respectively. CONCLUSIONS: Our results revealed two novel biomarkers associated with the T2DM and suggest that the circulating intergenic, lnc-LEP-2:6 and lnc-LEP-2:7, might have a regulatory role in the disease pathogenesis.

Tetra-Primer Amplification-Refractory Mutation System (ARMS)-PCR for Genotyping Mouse Leptin Gene Mutation.

Due to spontaneous deficiency in leptin, ob/ob mice are one of the most commonly used experimental animal models in diabetes research. In this study, we reported a quick and easy-to-conduct genotyping method using tetra-primer amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) to differentiate mice with a mutated allele from the wild-type genotype. The amplicon patterns of different genotypes are clearly visible and distinguishable on 1.5% agarose gel. This method can serve as a valuable tool to differentiate genotypes for breeding purposes, to maintain animal colonies, control the available space in the animal facility, and identify appropriate individuals for animal experiments.

A study of leptin and its gene 2548 G/A Rs7799039 single-nucleotide polymorphisms in Egyptian children: A single-center experience.

BACKGROUND/OBJECTIVES: The pathophysiology of obesity is multifactorial, including genetic and environmental factors. Previous studies had highlighted the association of the leptin gene/receptor with obesity. We aimed to study the leptin gene rs7799039 single nucleotide polymorphism (SNP) in children, and its association with the children's characteristics. METHODS: A cross-sectional analytic study that included 143 children with obesity (cases) and a comparable group of 86 lean children as controls. The anthropometric measures, blood pressure, and biochemical testing were done for all participants. The real-time polymerase chain reaction was used to detect rs7799039 SNP variant alleles and ELISA for leptin level assessment. RESULTS: The distribution of rs7799039 SNPs genotypes GG/GA/AA was comparable between both groups. Testing children regardless of their body mass index showed that the abnormalities in blood pressure, lipids values, insulin resistance, and hepatic insulin sensitivity were significantly associated with increased leptin levels. Among cases, the abnormal metabolic status was associated with higher leptin levels. CONCLUSIONS: The genotype' distribution of leptin gene rs7799039 SNP was similar in both children with obesity and those with normal-weight. The high blood pressure, abnormal lipid profile, and metabolic disturbances, were significantly associated with higher leptin levels and not with leptin gene rs7799039 SNP.

Severe Early Onset Obesity due to a Novel Missense Mutation in Exon 3 of the Leptin Gene in an Infant from Northwest India

Monogenic obesity, caused by mutations in one of the genes involved in the control of hunger and satiety, is a rare cause of early onset obesity (EOO). The most common of the single gene alterations affect the leptin gene (LEP), resulting in congenital leptin deficiency that manifests as intense hyperphagia, EOO and severe obesity associated with hormonal and metabolic alterations. Only eight mutations of (LEP associated with congenital leptin deficiency have been described in humans to date. In this study, we report a novel, homozygous, missense mutation in exon 3 of the (LEP gene (chr7:127894610;c.298G>A) resulting in the amino acid substitution of asparagine for aspartic acid at codon 100 (p.Asp100Asn) in a 10-month-old infant who presented to us with severe hyperphagia and EOO. She was subsequently found to have low serum leptin concentrations. Additionally, a homozygous missense variation of unknown significance in exon 11 of Bardet-Biedl syndrome-1 gene (chr11:66291279; G>A; Depth 168x) was detected. Significant abnormalities of lipid parameters were also present in our patient. Both parents were thin but there was a family history suggestive of EOO in a paternal uncle and a cousin. In conclusion, we report the second patient from India with a novel mutation of the (LEP gene associated with severe obesity.

Identification of g.170G>A and g.332G>A mutations in exon 3 of leptin gene (Bcnl and Cail) and their association with semen quality and testicular dimensions in Sanjabi rams.

The purpose of this study was to investigate leptin gene polymorphisms and their relationships with the characteristics of sperm quality and testicular dimensions. Semen samples were collected from 96 Sanjabi rams during autumn and spring seasons over two years. Simultaneously, the dimensions of length, width and scrotal circumference were measured. Blood samples were taken from the jugular vein to extract DNA. PCR was performed to amplify a 463bp fragment including exon 3 of leptin gene. PCR products were digested by Bcnl and Cail restriction enzymes to identify 170G>A and 332G>A mutations in exon 3, respectively. Leptin gene polymorphism in 170G>A locus had an effect on individual motility trait, water test and scrotal circumference (P<0.05) and animals with the AA genotype had the highest individual motility compared with the GG and GA genotypes (P<0.05). The AG genotypes had the highest water test compared with the GG and AA genotypes (P<0.05) but GG genotype had higher scrotal circumference than that of GA and AA genotypes (P<0.05). The results showed that polymorphism in 332G>A locus had a significant effect on viability trait, water test and scrotal circumference as GA genotypes had the highest amounts for these traits compared with GG genotypes (P<0.05). Based on our knowledge, the current study is the first report on the association of leptin gene polymorphisms with sperm fertility and testicular dimensions in sheep, which suggests leptin gene as a potential gene to be used in breeding programs in order to improve fertility in herds.

Leptin gene tetranucleotide repeat polymorphism in obese individuals in Egypt.

BACKGROUND: Leptin is a peptide hormone secreted by the adipose tissue. Genetic mutations of the leptin gene were reported to cause severe obesity. OBJECTIVES: This study was undertaken to investigate the association of the polymorphic tetranucleotide repeat locus 3' UTR of leptin gene with obesity in Egyptian cases. SUBJECTS AND METHODS: This study has included 120 subjects affected with obesity 57 of them were consistent with the diagnosis of metabolic syndrome (MS) while the rest (63) had simple obesity. These cases were compared to 83 normal weight healthy controls. All participants were subjected to an estimation of their body mass index (BMI), waist hip ratio (WHR), serum as well as characterization of leptin gene tetranucleotide repeat (TTTC)n polymorphism by PCR technique. RESULTS: Thirteen different alleles were identified in all cases of obesity versus only 5 alleles in normal controls. The most frequent allele was the 154 bp allele (57.5% in all cases of obesity vs. 92.2% in controls). Total cases with obesity showed a significantly higher carriage rate of class II alleles (I/II + II/II genotypes) compared to healthy controls (48.3% vs. 6.0%, OR=14.6, 95% CI=5.5-38.6, p=<0.0001). This was more apparent in the group with simple obesity (52.3% vs. 6.0%, OR=17.2, 95% CI=6.1-48.1, p=<0.0001) than in MS cases (43.9 % vs. 6.0 %, OR =12.19, 95% CI=4.9-30.4, p=< 0.0001). Interestingly, cases with MS did not differ from those with simple obesity regarding their class I or II allele frequencies (p> 0.05). Although serum lipids were significantly higher in obese cases compared to controls, no difference was found among obese cases with different leptin gene class genotypes (p> 0.05). CONCLUSIONS: Tetranucleotide repeat (TTTC)n polymorphism in the 3' UTR of the human leptin gene was associated with obesity in Egyptian obese cases showing higher class II allele carriage rate. However, the lipoprotein levels were not affected by this polymorphism.

Lack of association between leptin levels and leptin gene polymorphism in obese women.

The aim of the present study was to evaluate the relationship between oligopolymorphism in the 25th codon of leptin gene and obesity. Eighty-seven obese women and 75 healthy women were constituted obese and control groups. Body fat percent, fat mass and lean body mass were determined by bioimpedance meter and leptin levels were determined. The presence of 25th codon oligopolymorphism in the leptin gene was done by PCR-RFLP technique. Mean leptin levels were 38.5±22.0 ng/ml, and 147.9±44.8 ng/ml in the control and obese groups, respectively. The correlations of serum leptin level to body fat percentage and fat mass in the control group were significant. The correlations in the obese group were not significant. This data implies that the difference of leptin levels between control and obese groups are more likely to be associated with alterations in the leptin gene other than 25th codon or alterations in the leptin receptor gene.

The role of leptin in the control of insulin-glucose axis.

Obesity and diabetes mellitus are great public health concerns throughout the world because of their increasing incidence and prevalence. Leptin, the adipocyte hormone, is well known for its role in the regulation of food intake and energy expenditure. In addition to the regulation of appetite and satiety that recently has attracted much attentions, insight has also been gained into the critical role of leptin in the control of the insulin-glucose axis, peripheral glucose and insulin responsiveness. Since the discovery of leptin, leptin has been taken for its therapeutic potential to obesity and diabetes. Recently, the therapeutic effects of central leptin gene therapy have been reported in insulin-deficient diabetes in obesity animal models such as ob/ob mise, diet-induced obese mice, and insulin-deficient type 1 diabetes mice, and also in patients with inactivating mutations in the leptin gene. Herein, we review the role of leptin in regulating feeding behavior and glucose metabolism and also the therapeutic potential of leptin in obesity and diabetes mellitus.

Association between Leptin gene polymorphisms and plasma leptin level in three consanguineous families with obesity.

INTRODUCTION: Leptin (LEP) gene is one of the most promising candidate genes for obesity. Previous studies have tested the association of polymorphisms in LEP gene with obesity and obesity-related metabolic biomarkers (anthropometric variables, glucose, insulin level, leptin level and lipid profile). However, the results of these studies were still controversial. To determine whether LEP gene is associated with obesity in Tunisian population, we performed a family-based association study between LEP polymorphisms and obesity and obesity-related metabolic biomarkers. METHODS: Seven single nucleotide polymorphisms (SNPs) in 5' region of LEP gene were genotyped in three consanguineous families including 33 individuals. The previously reported LEP SNPs (H1328084, H1328082, rs10487506, H1328081, H1328080, G-2548A and A19G) were evaluated by PCR-RFLP and direct sequencing methods. Single SNP association and haplotype association analyses were performed using the family-based association test (FBAT). To determine allele frequencies of these SNPs in general population, 52 unrelated individuals from the general Tunisian population were also analyzed. RESULTS: Two SNPs showed significant associations with plasma leptin level (H1328084: A>G, Z=2.058, p=0.039; A19G: G>A, Z=2.058, p=0.039). When haplotypes were constructed with these two-markers, the risk AA haplotype (frequency 57.1%) was positively associated with plasma leptin level (Z=2.058, p=0.039). Moreover, SNPs H1328084 and A19G are predicted to modify transcription-factor binding sites. CONCLUSIONS: Our study provided that two functional variants in 5' regulatory region of LEP gene are associated with plasma leptin level as a quantitative trait. It suggested that H1328084 and A19G have an important role in regulating plasma leptin level.

Genetic polymorphisms and protein structures in growth hormone, growth hormone receptor, ghrelin, insulin-like growth factor 1 and leptin in Mehraban sheep.

The somatotropic axis, the control system for growth hormone (GH) secretion and its endogenous factors involved in the regulation of metabolism and energy partitioning, has promising potentials for producing economically valuable traits in farm animals. Here we investigated single nucleotide polymorphisms (SNPs) of the genes of factors involved in the somatotropic axis for growth hormone (GH1), growth hormone receptor (GHR), ghrelin (GHRL), insulin-like growth factor 1 (IGF-I) and leptin (LEP), using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and DNA sequencing methods in 452 individual Mehraban sheep. A nonradioactive method to allow SSCP detection was used for genomic DNA and PCR amplification of six fragments: exons 4 and 5 of GH1; exon 10 of GH receptor (GHR); exon 1 of ghrelin (GHRL); exon 1 of insulin-like growth factor-I (IGF-I), and exon 3 of leptin (LEP). Polymorphisms were detected in five of the six PCR products. Two electrophoretic patterns were detected for GH1 exon 4. Five conformational patterns were detected for GH1 exon 5 and LEP exon 3, and three for IGF-I exon 1. Only GHR and GHRL were monomorphic. Changes in protein structures due to variable SNPs were also analyzed. The results suggest that Mehraban sheep, a major breed that is important for the animal industry in Middle East countries, has high genetic variability, opening interesting prospects for future selection programs and preservation strategies.

Long-term correction of type 1 and 2 diabetes by central leptin gene therapy independent of effects on appetite and energy expenditure.

Adipocyte-derived leptin is a hormone associated with the regulation of energy homeostasis, including glucose metabolism. Hyperleptinemia, induced by the consumption of energy-enriched diets, inhibits leptin transport across the blood-brain barrier, and thereby produces leptin insufficiency in the hypothalamus. As a result of sustained leptin insufficiency, the hypothalamic restraint on pancreatic insulin secretion is lost. Additionally, both glucose metabolism and energy expenditure are also diminished, and both type 1 and type 2 diabetes are induced. A replication-deficient recombinant adeno-associated virus vector engineered to encode the leptin gene (rAVV-LEP) has been used in models of diabetes as a novel therapeutic approach. After rAVV-LEP injection in ob/ob mice, hypothalamic leptin expression was increased, body weight was suppressed, and hyperinsulinemia was ameliorated. Additionally injection of rAVV-LEP into the hypothalamus suppressed the expression of orexigenic neuropeptide Y (NPY) and enhanced anorexigenic pro-opiomelanocortin (POMC) in the arcuate nucleus (ARC) in rats. It is proposed that central leptin gene therapy should be tested clinically to reduce the worldwide epidemic of obesity, diabetes, and shortened life span. In this article, the information has been assembled from published review articles on this topic.