Mutations In Leptin Gene Research Articles

Personalization of treatment based on obesity phenotypes

Introduction:
 Obesity is a significant clinical problem worldwide. The disease exhibits remarkable heterogeneity, leading to diverse pathogenesis among individuals. Despite a growing selection of weight-reducing medications and increased awareness of the importance of a healthy lifestyle, the effectiveness of obesity therapy often remains insufficient. This raises the question of whether tailoring obesity pharmacotherapy to specific phenotypes and individual patient characteristics results in improved treatment outcomes.
 Objective:
 To review literature on the effectiveness of obesity treatment based on the personalization of pharmacotherapy according to its underlying causes.
 Current Knowledge:
 Currently, the early outcome of weight loss is closely linked to the long-term effectiveness of obesity pharmacotherapy. However, due to the diversity of obesity pathogenesis, it is not helpful in selecting therapy at the initiation of treatment. Specific characteristics are sought to indicate the appropriate drug during therapy planning.
 In a U.S. study (Acosta et al., 2021) results showed that phenotype-guided obesity pharmacotherapy resulted in clinically more significant absolute weight loss than in the non-phenotyped group.
 Other studies demonstrated that for very rare types of obesity dependent on specific genetic mutations, targeted treatment addressing these defects yielded the best therapeutic outcomes (recombinant human leptin therapy for patients with leptin gene mutation – Farooqi et al., 2002; setmelanotide therapy for individuals with proopiomelanocortin deficiency – Clément et al., 2020).
 The impact of specific gene variants on therapeutic response should also be considered, leading to variability in treatment effects for different patients using the same drug.
 Conclusion:
 The concept of basing therapy on obesity phenotypes may currently serve as a guide for treatment selection, although it still requires confirmation in randomized clinical trials.

Defective autophagy contributes to bupivacaine-induced aggravation of painful diabetic neuropathy in db/db mice

Current evidence suggests that hyperactivated or impaired autophagy can lead to neuronal death. The effect of local anesthetics on painful diabetic neuropathy (PDN) and the role of autophagy in the above pathological process remain unclear, warranting further studies. So, PDN models were established by assessing the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in leptin gene-mutation (db/db) mice. Wild type (WT) and PDN mice received intrathecal 0.75% bupivacaine or/with intraperitoneal drug treatment (rapamycin or bafilomycin A1). Subsequently, the PWT and PWL were measured to assess hyperalgesia at 6 h, 24 h, 30 h, and 48 h after intrathecal bupivacaine. Also, sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity (MNCV) were measured before and 48 h after intrathecal bupivacaine treatment. The spinal cord tissue of L4-L6 segments and serum were harvested to evaluate the change of autophagy, oxidative stress, oxidative injury, and apoptosis. We found that bupivacaine induced the activation of autophagy but did not affect the pain threshold, SNCV and MNCV in WT mice at predefined time points. Conversely, bupivacaine lowered autophagosome generation and degradation, slowed SNCV and aggravated spinal dorsal horn neuron oxidative injury and hyperalgesia in PDN mice. The autophagy activator (rapamycin) could decrease spinal dorsal horn neuron oxidative injury, alleviate the alterations in SNCV and hyperalgesia in bupivacaine-treated PDN mice. Meanwhile, the autophagy inhibitor (bafilomycin A1) could exacerbate spinal dorsal horn neuron oxidative injury, the alterations in SNCV and hyperalgesia in bupivacaine-treated PDN mice. Our results showed that bupivacaine could induce defective autophagy, slowed SNCV and aggravate spinal dorsal horn neuron oxidative injury and hyperalgesia in PDN mice. Restoring autophagy may represent a potential therapeutic approach against nerve injury in PDN patients with local anesthesia and analgesia.

Single Nucleotide Polymorphism R25C and R25H on Leptin gene and their association with body weight and measurements of Pasundan cattle

Abstract. Hilmia N, Ramdani D, Hidayat R, Widyastuti R, Hernaman I, Dudi, Edianingsih P, Arifin J. 2023. Single Nucleotide Polymorphism R25C and R25H on Leptin gene and their association with body weight and measurements of Pasundan cattle. Biodiversitas 24: 6310-6315. The Leptin gene is a potential candidate for genetic selection in livestock. Nonsynonimous Single Nucleotide Polymorphisms (SNP) Arg25Cys/R25C in Leptin gene associated with fat deposition mainly. This study aimed to identify polymorphism of Leptin Gene based on SNPs of Pasundan cattle and their association with body weight and measurements. This research used 64 DNA samples along with the corresponding body weight and measurement data from Pasundan cattle. About 9 and 7 DNA samples from Bali and Ongole cross (PO) cattle respectively, were also collected as comparisons. The DNA along 620 bp was multiplied by PCR. The SNPs in the Leptin gene on exon two were identified, followed by direct sequencing of the PCR product. The sequencing results were analyzed by BioEdit and Molecular Evolutionary Genetic Analysis (MEGA) 4.0. The General Linear Model analyzed the association between SNPs and body weight and measurements. The results showed there were two nonsynonymous SNP in the Leptin gene on exon two, i.e. g.1047C>T/Arg25Cys/R25C (T allele) that changed amino acid Arginine to Cysteine and g.1048G>A/Arg25His/R25H (A allele) which changed Arginine to Histidine. The frequency of the C allele in the Leptin gene on Pasundan cattle (0.54) was higher than mutation alleles, i.e. T ( 0.29) and A allele (0.17). There were six genotypes: CC (0.266), CT (0.390), CA (0.156), TT, TA, and AA 0.063 respectively. The Leptin gene mutation at the 25th position of amino acids, which changed Arginin to Cystein or Histidin (R25C and R25H), did not affect body weight and measurement in Pasundan Cattle. Therefore, nonsynonymous SNP R25C and R25H could not be used as marker genetic selection in Pasundan cattle.

Chondroprotection of leptin deficiency demystified?

Using the unique preclinical model of lipodystrophy—a rare heterogeneous disorder characterized by the absence of subcutaneous adipose tissue—paracrine signaling from fat, rather than body weight, has been identified as a mediator of spontaneous and injury-induced joint degeneration1. Lipodystrophy is a leptin-deficient state that can be considered a lipid-partitioning disorder associated with severe insulin resistance, fatty liver, and hyperlipidemia (www.endotext.org). Other leptin-deficient states associated with extreme obesity are also chondroprotective, including deficiency due to a leptin gene mutation, as observed in ob/ob mice2, functional deficiency due to a leptin receptor gene mutation or silencing, as observed in db/db mice2, and lentiviral vector-mediated leptin receptor targeting3.

Association between IRS-1, PPAR-γ and LEP genes polymorphisms and growth traits in rabbits

Single nucleotide polymorphisms are commonly associated with changes in quantitative traits, and have been considered useful markers for improving different traits in livestock. The current study aimed to explore the effect of three SNPs located in Insulin receptor substrate (IRS-1), Peroxisome proliferator-activated receptor γ (PPAR-γ), and Leptin (LEP) genes on the growth traits of rabbits. Individuals from three rabbit breeds were genotyped using RFLP-PCR. The IRS-1 variant (c.189T > G) was associated with post-weaning body weight, and body weight gains, However, the effect on growth rates was insignificant in Baladi Red and V-line rabbits. The PPAR-γ variant (c.207A > C) was significantly associated with 8-wk body weights in V-line rabbits, 10-wk body weights, and growth rates from 8 to 10 weeks of age in New Zealand rabbits. However, the differences between genotypes were insignificant for body weight gains and average daily gain. The LEP gene mutation (g.16079636C > G) had significant effects on body weights at 6 and 8 weeks of age in New Zealand White rabbits and 8 weeks of age in Baladi Red rabbits were associated with the presence of the C allele. Concludingly, the results stressed the importance of the IRS-1 gene in post-weaning growth and suggested the existence of breed-specific effects for PPAR-γ and LEP.

Poly (ADP-ribose) polymerase 1-mediated defective mitophagy contributes to painful diabetic neuropathy in the db/db model.

Studies have shown that poly (ADP-ribose) polymerase 1 (PARP1) is involved in the pathological process of diabetes. Mitophagy is widely acknowledged to be a key regulatory process in maintaining reactive oxygen species homeostasis via lysosome degradation of damaged mitochondria. However, the regulatory role of PARP1 in mitophagy-related mitochondrial oxidative injury and progression of painful diabetic neuropathy (PDN) is unclear. In this study, we studied the in vitro and in vivo mechanisms of PARP1-mediated mitophagy blockade in a leptin gene-mutation (db/db) mouse model of PDN. Db/db mice models of PDN were established by assessing the sciatic nerve conduction velocity (SNCV), mechanical withdrawal threshold (MWT), and thermal withdrawal latency (TWL). The results showed that PARP1 activity and mitochondrial injury of dorsal root ganglion (DRG) neurons were increased, and mitophagy was impaired in PDN mice. PARP1 was found to mediate the impairment of mitophagy in DRG neurons isolated from PDN mice. PARP1 inhibitors (PJ34 or AG14361) attenuated diabetes-induced peripheral nerve hyperalgesia, restored DRG neuron mitophagy function and decreased mitochondrial oxidative injury. Mitophagy impairment induced by lysosome deacidificant (DC661) aggravated diabetes-induced DRG neuron mitochondrial oxidative stress and injury. Taken together, our data revealed that PARP1-induced defective mitophagy of DRG neurons is a key mechanism in diabetes-induced peripheral neuropathic injury. Inhibition of PARP1 and restoration of mitophagy function are potential therapeutic targets for PDN.

When Leptin Is Not There: A Review of What Nonsyndromic Monogenic Obesity Cases Tell Us and the Benefits of Exogenous Leptin.

Obesity is a pandemic condition of complex etiology, resulting from the increasing exposition to obesogenic environmental factors combined with genetic susceptibility. In the past two decades, advances in genetic research identified variants of the leptin-melanocortin pathway coding for genes, which are related to the potentiation of satiety and hunger, immune system, and fertility. Here, we review cases of congenital leptin deficiency and the possible beneficial effects of leptin replacement therapy. In summary, the cases presented here show clinical phenotypes of disrupted bodily energy homeostasis, biochemical and hormonal disorders, and abnormal immune response. Some phenotypes can be partially reversed by exogenous administration of leptin. With this review, we aim to contribute to the understanding of leptin gene mutations as targets for obesity diagnostics and treatment strategies.

Leptin Gene and Receptor Mutations and its Association with Obesity and Overweight: A Mini Review

Overweight and obesity are considered a global epidemic in the twenty first century, it is a multifactorial disease due, in part, to a genetic component. The most common genetic alteration is one that affects the neuroregulatory pathway of Leptin, a fundamental hormone for appetite regulation. Mutations that affect the LEP gene are present in the different exons of this gene and have been described for many years. Although obesity due to a genetic mutation is not the most common cause, its diagnosis is of paramount importance since it can affect the quality of life and life expectancy of the patients suffering from this condition. The purpose of this mini review is to present up-to-date evidence regarding Leptin gene mutations, possible treatment strategies such as Leptin Replacement Therapy (LRT), leptin sensitizers and anti-inflammatory drugs, and discuss the importance of stablishing health policies worldwide to achieve a timely and successful approach to this disease.

Monogenic leptin deficiency in early childhood obesity.

Early childhood obesity is a public health problem worldwide. It affects different aspects of physical and mental child's health. Identifying the etiologies, especially treatable and preventable causes, can direct health professionals toward proper management. Analysis of serum leptin levels and leptin gene mutations is a rapid and easy step toward the diagnosis of congenital leptin deficiency that is considered an important cause in early childhood obesity. The aim of this study was to diagnose monogenic leptin deficiency in Egyptian children presenting with early onset obesity (EOO). The current cross-sectional study included 80 children who developed obesity during the first year of life with BMI > 2 SD (for age and sex). The studied population was subjected to history taking, auxological assessment, serum leptin assay, and leptin gene sequencing. Ten cases had leptin deficiency (12.5%), while 18 cases showed elevated leptin levels (22.5%). Leptin gene variants in the coding region were identified in 30% of the leptin-deficient group: two novel homozygous disease-causing variants (c.104 T > G and c.34 delC) and another previously reported homozygous pathogenic variant (c.313C > T). Leptin deficiency is considered a significant cause of monogenic obesity in Egyptian children with early-onset obesity as the diagnosis of these patients would be a perfect target for recombinant leptin therapy.

Obesity and Diabetes Affects Growth Plate Cartilage Histomorphometry

Childhood obesity and diabetes are strongly associated with decreased stature and poor bone health in adulthood. Similarly, ob/ob mice that have a leptin gene mutation causing it to overeat and develop the type 2 diabetes mellitus phenotype exhibit significantly reduced limb bone length and fracture resistance. In previous studies, we found decreased growth plate cartilage thickness in conjunction with increased bone fracture risk in obese diabetic mice in comparison with lean counterparts. Here, we use confocal laser scanning microscopy with post‐capture thresholding to assess 3D histological differences in z‐stacks of proximal tibia growth plate cartilage 80–100 μm in depth in juvenile lean and ob/ob mice. We find lean mice have significantly greater numbers of chondrocyte columns in growth plate cartilage with greater chondrocyte cell volumes in comparison with obese diabetic mice (P < 0.05). These data explicate the role of growth plate cartilage in bone health of obese diabetic juveniles. Our findings suggest obesity and diabetes may impair growth plate cartilage development by adversely affecting chondrocyte proliferation and hypertrophy.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Screening of Madgyal Sheep for Leptin Gene Using PCR-SSCP

Leptin is a candidate gene for growth rate in mammals. The worldwide studies on various livestock species have identified various point mutations in Leptin gene, which are found to be influencing important economic traits including growth rate. The main objective of present study was to determine Leptin gene polymorphism and its association with body weights in Madgyal sheep using PCR-SSCP technique. PCR-SSCP is a reproducible, rapid and quite simple method for the detection of mutations through electrophoretic mobility differences in PCR amplified DNA. We have successfully amplified 180 bp and 275bp amplicons representing exon 1/2 and exon 3 of LEP gene, respectively. The PCR-SSCP analysis of these amplicons revealed a uniform band pattern in all 100 Madgyal sheep. The occurrence of monomorphic nature of Leptin gene in the present study indicates the lack of Leptin gene mutation in Madgyal sheep.

Mutations in Leptin (LEP) Gene Are Associated with Carcass and Meat Quality Traits in Crossbreed Rabbits

ABSTRACTLeptin is a hormone synthesized and secreted primarily in adipose cells that help to regulate energy balance. This study examined the associations of single nucleotide polymorphisms in the rabbit leptin gene with growth traits, slaughter traits and physicochemical parameters of New Zealand White (NZW) and Belgian Giant Grey (BGG) crossbreed rabbits. In total, 320 crossbreed animals were genotyped for polymorphisms within exon 2—g.16081633T>C, intron 1_2—g.16081420C>T, and within UTR—g.16079636C>G for association analysis. Identified polymorphisms within rabbits leptin gene showed significant differences for dissectible fat percentage in carcass and dissectible fat weight in intermediate part (g.16081633T>C). Moreover, meat traits like protein content (g.16081633T>C; g.16079636C>G), intramuscular fat content (g.16081633T>C; g.16079636C>G, g.16081420C>T), dry matter (g.16081420C>T), ash (g.16081420C>T), water (g.16081420C>T), and cohesiveness (g.16081420C>T, g.16079636C>G) were affected by polymorphisms in leptin gene. We conclude that polymorphism in the rabbit leptin gene influences important carcass and meat traits of NZW × BGG crossbreeds. Therefore, polymorphisms identified in this study may be used in selection as a meat trait markers.

Concordance of bioactive vs. total immunoreactive serum leptin levels in children with severe early onset obesity.

ContextLeptin secreted from adipose tissue signals peripheral energy status to the brain. Monogenic leptin deficiency results in severe early onset obesity with hyperphagia. Recently, a similar phenotype of inactivating leptin mutations but with preserved immunoreactivity and hence normal circulating immunoreactive leptin has been reported.ObjectiveWe aimed to evaluate the proportion of bioactive leptin serum levels (compared to immunoreactive leptin) as a biomarker for the screening of leptin gene mutations causing monogenic obesity. Furthermore, we aimed to compare the immunoreactive and bioactive leptin levels associations with parameters of insulin resistance and insulin secretion in obese children and adolescents.Patients and methodsWe measured bioactive and immunoreactive leptin levels by enzyme-linked immunosorbent assays in fasting serum samples of 70 children with severe (BMI SDS >3) non-syndromic obesity with onset <3 years of life from our Leipzig childhood obesity cohort (n = 1204). Sanger sequencing of the leptin gene was performed in probands with proportion of bioactive/immunoreactive leptin <90%.ResultsThe mean levels of bioactive and immunoreactive leptin were almost identical (41.1±25.2 vs. 41.1±25.4ng/mL). In three probands with the lowest bioactive leptin proportion (<90%) we did not identify mutations in the leptin gene. Compared to immunoreactive leptin, bioactive leptin showed similar and slightly better statistical associations with indices of insulin resistance in correlation and multivariate analyses.ConclusionIn our sample selected for severe early onset childhood obesity, we did not identify leptin gene mutations leading to decreased proportion of bioactive leptin.Nevertheless, the bioactive leptin levels were stronger associated with selected insulin secretion/resistance indices than the immunoreactive leptin levels.

Effects of Recombinant Human Leptin (Metreleptin) on Nocturnal Luteinizing Hormone Secretion in Lipodystrophy Patients

Background: Leptin replacement in patients with leptin gene mutations improves hypogonadotropic hypogonadism. The effects of leptin replacement on luteinizing hormone (LH) secretion in patients with lipodystrophy are unknown. Aim: We examined nocturnal LH secretory dynamics on and off exogenous leptin therapy using a 2-period, nonrandomized study that included leptin-naïve and leptin-treated subjects with lipodystrophy. Methods: In period 1 (5 days) the leptin-treated group (n = 4) continued leptin; leptin was then withdrawn for the next 14 days (period 2). Leptin-naïve subjects (n = 8) were studied without leptin in period 1 and with leptin replacement in period 2. LH secretory dynamics were assessed (23:00-07:00 h, sampling every 10 min, analyzed by multiparameter deconvolution algorithm) at the end of each period. Results: Mean (on vs. off: 5.0 ± 3.1 vs. 3.2 ± 1.3 IU/l, p = 0.04) and integrated LH concentrations (2,403 ± 1,495 vs. 1,534 ± 642 IU × l^-1 × min^-1, p = 0.04) were higher on leptin therapy. Leptin treatment increased burst mass (9.7± 15.4 vs. 7.0 ± 11.2 IU/l, p = 0.03) and tended to nonsignificantly increase LH burst frequency (0.77 ± 0.26 vs. 0.67 ± 0.24 h^-1, p = 0.08). Consequently, leptin therapy increased the pulsatile production rate (64 ± 101 vs. 57 ± 73 IU × l^-1 × 8 h^-1, p = 0.01). On leptin, testosterone (507 ± 286 vs. 360 ± 174 ng/dl, p = 0.09) and estradiol levels (74 ± 36 vs. 29 ± 24 pg/ml, p = 0.01) were higher in males and females, respectively. Conclusions: Leptin increases spontaneous nocturnal LH secretion in patients with lipodystrophy. This is consistent with rodent and in vitro studies showing a direct stimulatory effect (hypothalamic, pituitary or both) of leptin on LH secretion. These novel findings may explicate some of the salutary effects of leptin therapy on the hypothalamic-pituitary-gonadal axis in lipodystrophy.

Obesity and Leanness Caused by Mutations in the Leptin Gene: Already 6 Pathogenic Mutations Reported in this Gene

Obesity and leanness are the medical conditions in which excess and deficient body fat present respectively. It may have an adverse effect on health, leading to reduced life expectancy and increased health problems. Environmental factors, especially increased consumption of high caloric diet, are considered responsible for the obesity epidemic, although genetic factors also contribute dysregulation of food consumption. Leptin gene may have an effect on the obesity and leanness because six pathogenic mutations already reported in leptin gene. Leptin gene mutations have a vital role to cause different types of cancers.

Leptin Gene Mutations in Morbidly Obese and Severely Lean Individuals from Punjab, Pakistan

Obesity has become an epidemic of modern world. Although 6 mutations in the leptin gene have been found to be associated with congenital leptin deficiency, leptin gene polymorphism has not been studied in adult morbidly obese and severely lean individuals. This study involves comparison of obese and lean individuals. In this research leptin gene mutations were studied in both morbidly obese and severely lean adults. Studied individuals belong to Punjab, region of Pakistan. Present study included 25 consenting morbidly obese (BMI>30 kg/m2) and 25 severely lean (BMI<18 kg/m2) individuals from Punjab, Pakistan. By using organic method DNA extracted and PCR was done to amplify leptin gene with the help of specific primers. The sequence of leptin gene was analyzed by using SSCP, heteroduplex analysis and automated Sanger sequencing. No genetic mutation was detected in leptin gene in studied morbidly obese and severely lean individuals. The result suggested that in Pakistani population leptin gene may not be a major cause for obesity and leanness. Other genetics as well as environmental factors may be involved.

Generation of leptin-deficient Lepmkyo/Lepmkyo rats and identification of leptin-responsive genes in the liver

Leptin is one of the key molecules in maintaining energy homeostasis. Although genetically leptin-deficient Lep(ob)/Lep(ob) mice have greatly contributed to elucidating leptin physiology, the use of more than one species can improve the accuracy of analysis results. Using the N-ethyl-N-nitrosourea mutagenesis method, we generated a leptin-deficient Lep(mkyo)/Lep(mkyo) rat that had a nonsense mutation (Q92X) in leptin gene. Lep(mkyo)/Lep(mkyo) rats showed obese phenotypes including severe fatty liver, which were comparable to Lep(ob)/Lep(ob) mice. To identify genes that respond to leptin in the liver, we performed microarray analysis with Lep(mkyo)/Lep(mkyo) rats and Lep(ob)/Lep(ob) mice. We sorted out genes whose expression levels in the liver of Lep(mkyo)/Lep(mkyo) rats were changed from wild-type (WT) rats and were reversed toward WT rats by leptin administration. In this analysis, livers were sampled for 6 h, a relatively short time after leptin administration to avoid the secondary effect of metabolic changes such as improvement of fatty liver. We did the same procedure in Lep(ob)/Lep(ob) mice and selected genes whose expression patterns were common in rat and mouse. We verified their gene expressions by real-time quantitative PCR. Finally, we identified eight genes that primarily respond to leptin in the liver commonly in rat and mouse. These genes might be important for the effect of leptin in the liver.

Hormone level and dopamine tells the value of food

Ideal food should be delicious and nutritious. But sometimes, the food you eat is delicious but not nutritious, or nutritious but not delicious. To let animals know which to be delicious or nutritious is an important or valuable question. In a recent article published in Nature Neuroscience1, Friedman JM et al addressed this question and showed that the level of hormone leptin and dopamine system co-regulated the reward value of food in mice. Leptin, a 16 kDa protein encoded by the Ob (Obese) gene, is a hormone that has a central role in regulation of fat metabolism, appetite and the balance between energy intake and consumption2. Leptin was identified and its role in fat metabolism was firstly revealed by Friedman JM et al in 1994. In mouse genetic screen study, they found that mutation in the genes encoding either leptin itself or leptin's receptor caused massively obese in mice, and this could be rescued by injections of leptin. These findings in mice coincided with the observations that humans carrying homozygous mutations in leptin gene suffered severe obesity. These results indicated that leptin signals are important in regulating fat metabolism. Later studies revealed that instead of a signal to consume the surfeit of fat, leptin is a signal informing the brain of enough nutrients in the body. Thus, when an animal is full up, its leptin level goes high that in turn sends a satiety signal to the brain and stop the animal from eating more. On the contrary, when an animal is in hunger, its leptin level drops, thus sends less satiety signal to the brain; and this drive the animal to looking for nutritious food. Dopamine is a neurotransmitter involved in modulating many important brain functions. Dopamine is released by the dopaminegic neurons in hypothalamus, substantia nigra and especially ventral tegmental area (VTA) — a brain region tightly linked with rewarding process. Many studies showed that rewarding process is highly related to the activation of the dopaminegic neurons in the VTA of the middle brain3. A trick that the authors used in their research is to mimic the rewarding process by specifically activating of the dopaminegic neurons in VTA. The technique that Friedman JM et al used in this article is optogentectics, a recently developed tool, in which light-activatable cation channel (eg, Channelrhodopsin II, ChR2) or light-activatable chloride pump (eg, Halorhodopsin from Natromonas, NPHR) are used to activate or silent the function of the interested neurons4. They generated a kind of genetically engineered mice, in which ChR2 protein was specifically expressed in the dopaminegic neuron in VTA. An optic fiber was then introduced to the VTA of the mice. When laser pulses were delivered to VTA through the optic fiber, the dopaminegic neurons were activated, mimicking a rewarding process. Next, they measured the preference index of the mice to two kinds of “sugar”, sucrose and sucralose. Sucrose is a kind of natural sugar with nutrient, which sucralose is a synthetic sweetener with very low calories. They found that the mice naturally prefer the nutritious sucrose to the low-calorie sucralose, suggesting that nutrient of sucrose confer it a higher rewarding value, and sucralose has a lower rewarding value. Interestingly, this could be reversed when sucralose was paired with activation of the dopaminegic neurons. When the sucralose solution was applied to the mice, laser pulses were simultaneously delivered to activate the dopaminegic neurons in VTA. In this scenario, the mice switched to prefer sucralose. These results suggest that preference to a food not only depends on the sensation on the tongue, but also the brain judgment of its reward value of the food. Furthermore, the authors investigated whether the leptin level affects the judgment of food reward value. When the mice were deprived for food for 24 h, the dropping of leptin level coincided with that the value of sucrose increased. Upregulation of leptin by injection can reverse this effect. These results indicated that leptin could regulate the reward value of nutrient. The findings made by the authors are not only important to our fundamental understanding of the regulatory mechanisms of appetite and fat metabolism, but also provide important clues for weight control and therapeutics for metabolism-related disorders, such as obesity and nervosa. If the leptin level in people with obesity or nervosa can be modulated, their appetite or desire for food, and their body weight can be controlled.

Leptin deficiency andleptingene mutations in obese children from Pakistan

Congenital leptin deficiency is a rare human genetic condition clinically characterized by hyperphagia and acute weight gain usually during the first postnatal year. The worldwide data on this disorder includes only 14 cases and four pathogenic mutations have been reported in the leptin gene. The objectives of this study were to measure serum leptin levels in obese children and to detect leptin gene mutations in those found to be leptin deficient. A total of 25 obese children were recruited for the study. Leptin deficiency was detected in nine of them. Leptin gene sequencing identified mutations in homozygous state in all the leptin deficient children. Two cases carried novel mutations (c.481_482delCT and c.104_106delTCA) and each of the remaining seven the previously reported frameshift mutation (c.398delG). The results suggest that leptin deficiency caused by mutations in the leptin gene may frequently be seen in obese Pakistani children from Central Punjab.

Congenital leptin deficiency: diagnosis and effects of leptin replacement therapy

To describe our 10-year experience in treating leptin-deficient humans. Three adults and one boy presented with childhood-onset morbid obesity, hypogonadism and family history of obesity and early death. Serum leptin was inappropriately low. A recessive C105T leptin gene mutation was identified. Metabolic and endocrine assessments were conducted, before and while on and off leptin. The adults' body mass index decreased from 51.2 ± 2.5 to 29.5 ± 2.8 kg/m(2). Serum lipids normalized, insulin resistance decreased, and one of the initially diabetic females became normoglycemic. Hypogonadotropic hypogonadism was reversed, and other changes were observed in the adrenal, sympathetic, somatotropic and thyroid functions. Leptin replacement therapy reverses endocrine and metabolic alterations associated with leptin deficiency. Some of these results may be extrapolated to other diseases.