The corrective role of superparamagnetic iron oxide nanoparticles for the genes controlling hypothalamus-pituitary-testis-axis in male obesity-associated secondary hypogonadism.

Background: Obesity is one of the most prevalent and perilous health affairs. Male obesity-associated secondary hypogonadism (MOSH) is one of many of its complexities, which is mounting in parallel with the aggravation of obesity. Magnetic nanoparticles seem to be an advanced favorable trend in multiple biomedical fields. Aim: In this study, we explore the therapeutic effects of superparamagnetic iron oxide nanoparticles (SPIONs) coated with carboxymethyl cellulose (CMC) on an obese male rat model with MOSH syndrome, comparing their impacts with a well-known anti-obesity medication (Orlistat). Methods: 42 male albino rats split into 7 equal groups: 1-negative control: nonobese, untreated; 35 rats fed the high fat-high fructose (HFHF) diet for a period of 12 weeks. Obese rats splitted into 6 equal groups; 2-positive control: obese untreated; 3-obese given Orlistat (30 mg/kg); 4-obese given CMC-SPIONs (25 mgFe/kg); 5-obese given CMC-SPIONs (50 mgFe/kg); 6-obese given CMC-SPIONs(25 mgFe/kg) + Orlistat (30 mg/kg), 7-obese given CMC-SPIONs (50 mgFe/kg) + Orlistat (30 mg/kg); all treatments given orally for 4 weeks. During sacrifice, blood serum and sectioned hypothalamic, pituitary, testicular, and adipose tissues were collected for biochemical and biomolecular assessments. Results: The HFHF diet for 12 weeks resulted in a significant upsurge in body weight, body mass index, serum fasting glucose, insulin resistance, TAG, total cholesterol, and LDL-c; HDL-c was dropped. Serum FSH, LH, and testosterone values declined. A significant disorder in expression levels of genes regulating the hypothalamic-pituitary-testicular-axis pathway. Hypothalamic GnRH, Kisspeptin-1, Kisspeptin-r1, and Adipo-R1 values declined. GnIH and Leptin-R1 values raised up. Pituitary GnRH-R values declined. Testicular tissue STAR, HSD17B3, and CYP19A1 values declined. Adipose tissue adiponectin declined, while leptin raised up. CMC-SPIONs 25-50 mg could modulate the deranged biochemical parameters and correct the deranged expression levels of all previous genes. Co-treatments revealed highly synergistic effects on all parameters. Overall, CMC-SPIONs have significant efficiency whether alone or with Orlisat in limiting obesity and consequence subfertility. Conclusion: CMC-SPIONs act as an incoming promising contender for obesity and MOSH disorders management, and need more studies on their mechanisms.

Effects of Moringa Oleifera Leaf Extract Plus Rosiglitazone on Serum Leptin and Glucose and Lipid Metabolism in Type 2 Diabetic Rats.

Objective: To investigate the effects of Moringa Oleifera Leaf Extract (MOLE) plus rosiglitazone (RSG) on glucose and lipid metabolism, serum leptin, and the Akt/GSK3ß/ß-Catenin signaling pathway in type 2 diabetic (T2D) rats. Methods: Sixty male Sprague-Dawley (SD) rats were randomly divided into six groups: the normal group, the model group, the RSG group, the low- and high-dose MOLE group, and the MOLE+RSG group. The normal group was fed a standard rat diet, while the other groups were given a single intraperitoneal injection of low-dose streptozomycin (STZ) (35 mg/kg) and fed a high-sugar and high-fat diet. After 8 weeks, the treatment outcomes were evaluated by measuring key parameters of blood glucose and lipid metabolism and the protein kinase B (AKT) / Glycogen synthase kinase 3beta (GSK3ß) /ß-Catenin signaling pathway in the T2D rats. Results: Compared with the normal group, the model group showed significantly increased levels of blood glucose, blood lipids, serum leptin, free fatty acid (FFA), and tumor necrosis factor-α (TNF-α). Compared with the model group, the RSG, low-dose MOLE, and high-dose MOLE groups displayed effective control of blood glucose, blood lipids, serum leptin, FFA, and TNF-α. The MOLE+RSG group surpassed the RSG group in regulating glucose, lipid metabolism, and serum leptin levels in T2D rats. In addition, the MOLE+RSG group also had superiority over the RSG group in activating the AKT/GSK3ß/ß-Catenin pathway. Conclusion: MOLE plus RSG can effectively reduce blood glucose and blood lipids in T2DM rats.

Effects of curcumin/turmeric supplementation on obesity indices and adipokines in adults: A grade-assessed systematic review and dose-response meta-analysis of randomized controlled trials.

In the present study, we explored the effect of curcumin/turmeric supplementation on anthropometric indices of obesity, leptin, and adiponectin. We searched PubMed, Scopus, Web of Science, Cochrane Library, and Google Scholar up to August 2022. Randomized clinical trials (RCTs) investigating the impact of curcumin/turmeric on obesity indices and adipokines were included. We applied the Cochrane quality assessment tool to evaluate the risk of bias. The registration number is CRD42022350946. Sixty eligible RCTs, with a total sample size of 3691 individuals were included for quantitative analysis. We found that supplementation with curcumin/turmeric significantly reduced body weight (WMD: -0.82 kg, 95% CI: -1.30, -0.35; p = 0.001), body mass index (WMD: -0.30 kg/m2 , 95% CI: -0.53, -0.06, p = 0.013), waist circumference (WMD: -1.31 cm, 95% CI: -1.94, -0.69, p < 0.001), body fat percentage (WMD: -0.88%, 95% CI: -1.51, -0.25, p = 0.007), leptin (WMD = -4.46 ng/mL; 95% CI: -6.70, -2.21, p < 0.001), and increased adiponectin (WMD = 2.48 µg/mL; 95% CI: 1.34, 3.62, p < 0.001). Overall, our study shows that supplementation with curcumin/turmeric significantly improves anthropometric indices of obesity and adiposity-related adipokines (leptin and adiponectin). However, due to high between-studies heterogeneity, we should interpret the results with caution.

Deoxyschizandrin ameliorates obesity and non-alcoholic fatty liver disease: Involvement of dual Farnesyl X receptor/G protein-coupled bile acid receptor 1 activation and leptin sensitization.

Natural dual farnesyl X receptor (FXR)/G protein-coupled bile acid receptor 1 (TGR5) activators have received little attention in the management of metabolic diseases. Deoxyschizandrin (DS), a natural lignan, occurs in S. chinensis fruit and has potent hepatoprotective effects, whereas its protective roles and mechanisms against obesity and non-alcoholic fatty liver disease (NAFLD) are largely elusive. Here, we identified DS as a dual FXR/TGR5 agonist using luciferase reporter and cyclic adenosine monophosphate (cAMP) assays. DS was orally or intracerebroventricularly administrated to high-fat diet-induced obesity (DIO) mice, and methionine and choline-deficient L-amino acid diet (MCD diet)-induced non-alcoholic steatohepatitis to evaluate its protective effects. Exogenous leptin treatment was employed to investigate the sensitization effect of DS on leptin. The molecular mechanism of DS was explored by Western blot, quantitative real-time PCR analysis, and ELISA. The results showed that DS activated FXR/TGR5 signaling and effectively reduced NAFLD in DIO and MCD diet-fed mice. DS countered obesity in DIO mice by promoting anorexia and energy expenditure and reversing leptin resistance, involving both peripheral and central TGR5 activation and leptin sensitization. Our findings indicate that DS may be a novel therapeutic approach for alleviating obesity and NAFLD through regulating FXR and TGR5 activities and leptin signaling.

Improved oral nutraceutical-based intervention for the management of obesity: pterostilbene-loaded chitosan nanoparticles.

Aim: To formulate and assess the oral anti-obesity effect of polymeric-based pterostilbene (PS)-loaded nanoparticles. Methods: Pterostilbene-hydroxypropyl ß-cyclodextrin inclusion complex loaded in chitosan nanoparticles (PS/HPßCD-NPs) were prepared and characterized in vitro. Cytotoxicity, pharmacokinetics and anti-obesity effects were assessed on Caco-2 cell line and high-fat-diet-induced obesity rat model, respectively. In vivo assessment included histological examination, protein and gene expression of obesity biomarkers in adipose tissues. Results: Safe PS/HPßCD-NPs were successfully prepared with improved bioavailability compared with free PS. PS/HPßCD-NPs showed an improved anti-obesity effect, as supported by histological examination, lipid profile, UCP1 gene expression and protein expression of SIRT1, COX2, IL-6 and leptin. Conclusion: Orally administered PS nanoparticles represent a new and promising anti-obesity strategy owing to the sustainable weight loss and minimal side effects; this may be of great socio-economic impact.

Weight gain or obesity represents a major health risk and leads to diseases including cancer and heart disease. Most anti-obesity medications have significant side effects, and there are notable challenges concerning their availability in the body to produce an effect. Pterostilbene is a herbal drug with beneficial anti-obesity effects. However, it has problems such as poor solubility which restrict its use. The aim of the study was to formulate pterostilbene in a nano-based delivery system and fully characterize its anti-obesity effect when given orally. We evaluated the safety and anti-obesity effects of pterostilbene nanoparticles in cells and in obese rats fed on a high-fat diet. We also looked at how the body absorbs, distributes and gets rid of these nanoparticles. The prepared nanoparticles were nontoxic, with an improved anti-obesity effect; they decreased cholesterol levels and helped in changing white fat (which stores fat) to brown fat (which burns calories). We conclude that the developed pterostilbene nanoparticles, given orally, are a new and promising anti-obesity strategy given their long-lasting effect on weight loss and the minimal side effects. This may be of great economic and societal impact.

Effect of flavonoid intake on circulating levels of adiponectin and leptin: A systematic review and meta-analysis of randomized controlled clinical trials.

This meta-analysis of randomized controlled trials (RCTs) was conducted to explore the effects of flavonoid intake on adiponectin and leptin levels. The PubMed, EMBASE, and Cochrane Library databases were searched on March 1, 2021. Random-effects, subgroup, sensitivity, and meta-regression analyses were conducted on 40 publications. Flavonoid intake significantly increased circulating adiponectin (0.54 µg/ml, 95% CI [0.20, 0.88], p = .002; I2  = 86.4%) and significantly reduced leptin levels (weighted mean difference: -0.79 ng/ml, 95% CI [-1.33, -0.25], p = .004; I2  = 87.7%). Subgroup analysis demonstrated that flavonoid intervention produced a significant elevation in adiponectin levels only in studies that lasted more than 12 weeks, conducted in Asian regions, were parallel-designed, involved obese or overweight participants and participants with type 2 diabetes mellitus (T2DM) or cardiovascular diseases, used tea catechins, and used a dietary supplement intervention. A significantly negative effect on leptin levels was observed in studies conducted in Asian countries, with healthy participants and participants with T2DM, used whole food interventions, and involved participants with lower baseline leptin levels. In conclusion, flavonoid intake significantly increased circulating adiponectin and decreased leptin levels; however, study heterogeneity was very high. Future well-designed trials are required to address heterogeneous study designs and clarify the efficacy of plants in regulating adiponectin and leptin levels.

Leptin: an entry point for the treatment of peripheral tissue fibrosis and related diseases.

Leptin is a small peptide mainly secreted by adipocyte, which acts on the central nervous system of the hypothalamus to regulate the body's energy balance by inhibiting food intake, it also can directly act on specific cells through leptin receptors (for example, ObRa, which exists in the blood-brain barrier or kidneys), thereby affect cell metabolism. Excessive deposition of extracellular matrix (ECM) causes damage to normal tissues or destruction of organ structure, which will eventually lead to tissue or organ fibrosis. The sustainable development of fibrosis can lead to structural damage and functional decline of organs, and even exhaustion, which seriously threatens human health and life. In recent years, studies have found that leptin directly alleviates the fibrosis process of various tissues and organs in mammals. Therefore, we speculate that leptin may become a significant treatment for fibrosis of various tissues and organs in the future. So, the main purpose of this review is to explore the specific mechanism of leptin in the process of fibrosis in multiple tissues and organs, and to provide a theoretical basis for the treatment of various tissues and organs fibrosis and related diseases caused by it, which is of great significance in the future.

The effect of saffron supplementation on some inflammatory and oxidative markers, leptin, adiponectin, and body composition in patients with nonalcoholic fatty liver disease: A double-blind randomized clinical trial.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is characterized by oxidative stress and inflammation in the hepatocytes. Saffron and its constituents are reported to have several properties such as anti-inflammatory and anti-diabetic effects. MATERIALS AND METHODS: In a randomized double-blind placebo-controlled trial with two parallel groups including 76 eligible men and female patients with NAFLD aged 18-65, recruited from Hazrat Rasul Akram Hospital in Tehran, Iran. NAFLD was defined by a Gastroenterologist based on the American Gastrointestinal and Liver Association standards. Participants were randomly assigned to two groups receiving daily supplementation of either one tablet of 100 mg saffron (n = 38) or one placebo (n = 38) for 12 weeks. The primary outcome was high sensitive C-reactive protein (hs-CRP) and secondary outcomes were alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor alpha (TNF-α), malondialdehyde (MDA), total anti-oxidant capacity (TAC), leptin, adiponectin, anthropometric, and body composition Both groups were assigned similar diet and physical activity. RESULTS: In the treatment group, significant decreases in hs-CRP (-1.80 ng/ml, 95% CI = -2.97, -0.63, p = .032), leptin (-0.27 ng/ml, 95% CI = -0.65, -0.10, p = .040), MDA (-1.01 ng/ml, 95% CI = -1.89, -0.14, p = .023) and significant increase in TAC (0.34 µmol/L, 95% CI = 0.08, 0.61, p = .011) were observed compared to the placebo group. However, there were no significant changes in serum alanine aminotransferase, AST, TNF-α, body composition, and anthropometric indexes (p > .05). CONCLUSION: In the present study, 12 weeks of 100 mg of saffron supplementation indicated beneficial effects on serum levels of some inflammatory, oxidative stress, and adipokines biomarkers but it had no significant effect on serum concentrations of liver enzymes, anthropometric, and body composition measurements.

Synergistic effect of leptin and lipidized PrRP on metabolic pathways in ob/ob mice.

Lack of leptin production in ob/ob mice results in obesity and prediabetes that could be partly reversed by leptin supplementation. In the hypothalamus, leptin supports the production of prolactin-releasing peptide (PrRP), an anorexigenic neuropeptide synthesized and active in the brain. In our recent studies, the palmitoylated PrRP analog palm11-PrRP31 showed a central anorexigenic effect after peripheral administration. This study investigates whether PrRP could compensate for the deficient leptin in ob/ob mice. In two separate experiments, palm11-PrRP31 (5 mg/kg) and leptin (5 or 10 µg/kg) were administered subcutaneously twice daily for 2 or 8 weeks to 8- (younger) or 16-(older) week-old ob/ob mice, respectively, either separately or in combination. The body weight decreasing effect of palm11-PrRP31 in both younger and older ob/ob mice was significantly powered by a subthreshold leptin dose, the combined effect could be then considered synergistic. Leptin and palm11-PrRP31 also synergistically lowered liver weight and blood glucose in younger ob/ob mice. Reduced liver weight was linked to decreased mRNA expression of lipogenic enzymes. In the hypothalamus of older ob/ob mice, two main leptin anorexigenic signaling pathways, namely, Janus kinase, signal transducer and activator of transcription-3 activation and AMP-activated protein kinase de-activation, were induced by leptin, palm11-PrRP31, and their combination. Thus, palm11-PrRP31 could partially compensate for leptin deficiency in ob/ob mice. In conclusion, the results demonstrate a synergistic effect of leptin and our lipidized palm11-PrRP31 analog.

Leptin in depression: a potential therapeutic target.

Leptin, produced and secreted by white adipose tissue, plays a critical role in regulating body weight, food intake, and energy metabolism. Recently, several studies have identified an underlying role for leptin in regulation of mood and cognition via regulation of synaptic changes in the brain that have been associated with antidepressant-like actions. Brain neural plasticity occurs in response to a range of intrinsic and extrinsic stimuli, including those that may mediate the effects of antidepressants. Neural plasticity theories of depression are thought to explain multiple aspects of depression and the effects of antidepressants. It is also well documented that leptin has effects on neural plasticity. This review summarizes the recent literature on the role of leptin in neural plasticity in order to elaborate the possible mechanism of leptin's antidepressant-like effects. Recent findings provide new insights into the underlying mechanisms of neural plasticity in depression. Leptin may influence these mechanisms and consequently constitute a possible target for novel therapeutic approaches to the treatment of depression.

Defining the Transcriptional Targets of Leptin Reveals a Role for Atf3 in Leptin Action.

Leptin acts via its receptor (LepRb) to modulate gene expression in hypothalamic LepRb-expressing neurons, thereby controlling energy balance and glucose homeostasis. Despite the importance of the control of gene expression in hypothalamic LepRb neurons for leptin action, the transcriptional targets of LepRb signaling have remained undefined because LepRb cells contribute a small fraction to the aggregate transcriptome of the brain regions in which they reside. We thus employed translating ribosome affinity purification followed by RNA sequencing to isolate and analyze mRNA from the hypothalamic LepRb neurons of wild-type or leptin-deficient (Lepob/ob) mice treated with vehicle or exogenous leptin. Although the expression of most of the genes encoding the neuropeptides commonly considered to represent the main targets of leptin action were altered only following chronic leptin deprivation, our analysis revealed other transcripts that were coordinately regulated by leptin under multiple treatment conditions. Among these, acute leptin treatment increased expression of the transcription factor Atf3 in LepRb neurons. Furthermore, ablation of Atf3 from LepRb neurons (Atf3LepRbKO mice) decreased leptin efficacy and promoted positive energy balance in mice. Thus, this analysis revealed the gene targets of leptin action, including Atf3, which represents a cellular mediator of leptin action.

Leptin Involvement in Primary Brain and Pituitary Tumors: Therapeutic Potential, Prognostic Value, and Proposed Diagnostic Application.

Brain tumors are associated with increased mortality and morbidity and are the most common cancer type in children and young adults. The present review focuses on the interplay between leptin, the most extensively studied adipokine, and the onset, development, and treatment of primary brain and intracranial tumors. The two main mechanisms for increased leptin levels in intracranial tumor survivors, leptin resistance caused by hypothalamic damage, or secondary to obesity, are discussed. The contradicting mechanistic observations on leptin being able to both promote tumorinogenesis (e.g., in gliomas) as well as inhibit it (e.g., in adenomas) are also reported. Additionally, the relevant current and future clinical applications, including most notably the proposed use of serum leptin measurements for non-invasive brain tumor diagnostics, are also reported.

Leptin Replacement Reestablishes Brain Insulin Action in the Hypothalamus in Congenital Leptin Deficiency.

OBJECTIVE: Human obesity is associated with impaired central insulin signaling, and in very rare cases, severe obesity can be caused by congenital leptin deficiency. In such patients, leptin replacement results in substantial weight loss and improvement in peripheral metabolism. RESEARCH DESIGN AND METHODS: In a leptin-deficient patient, we investigated the impact of leptin substitution on central insulin action, as quantified by changes in neuronal activity after intranasal insulin application. This was assessed before and during the first year of metreleptin substitution. RESULTS: After only 1 year, treatment with metreleptin reestablishes brain insulin sensitivity, particularly in the hypothalamus and, to a lesser degree, in the prefrontal cortex. Results are depicted in comparison with a control group. In our patient, brain activation changes were accompanied by substantial weight loss, reduced visceral adipose tissue, reduced intrahepatic lipid content, and improved whole-body insulin sensitivity. CONCLUSIONS: Leptin replacement and weight loss improved homeostatic insulin action in the patient in question.

Association of metreleptin treatment and dietary intervention with neurological outcomes in Celia's encephalopathy.

Celia's encephalopathy (progressive encephalopathy with/without lipodystrophy, PELD) is a recessive neurodegenerative disease that is fatal in childhood. It is caused by a c.985C>T variant in the BSCL2/seipin gene that results in an aberrant seipin protein. We evaluated neurological development before and during treatment with human recombinant leptin (metreleptin) plus a dietary intervention rich in polyunsaturated fatty acids (PUFA) in the only living patient. A 7 years and 10 months old girl affected by PELD was treated at age 3 years with metreleptin, adding at age 6 omega-3 fatty acid supplementation. Her mental age was evaluated using the Battelle Developmental Inventory Screening Test (BDI), and brain PET/MRI was performed before treatment and at age 5, 6.5, and 7.5 years. At age 7.5 years, the girl remains alive and leads a normal life for her mental age of 30 months, which increased by 4 months over the last 18 months according to BDI. PET images showed improved glucose uptake in the thalami, cerebellum, and brainstem. This patient showed a clear slowdown in neurological regression during leptin replacement plus a high PUFA diet. The aberrant BSCL2 transcript was overexpressed in SH-SY5Y cells and was treated with docosahexaenoic acid (200 µM) plus leptin (0.001 mg/ml) for 24 h. The relative expression of aberrant BSCL2 transcript was measured by qPCR. In vitro studies showed significant reduction (32%) in aberrant transcript expression. This therapeutic approach should be further studied in this devastating disease.

Leptin Gene Transfer Improves Symptoms of Type 2 Diabetic Mice by Regulating Leptin Signaling Pathway and Insulin Resistance of Peripheral Tissues.

The leptin gene was transferred into the liver of streptozocin- and high fat diet-induced type 2 diabetic (T2D) mice by hydrodynamic-based gene delivery. The food intake, water consumption, glucose concentration, and triglyceride and total cholesterol levels of T2D mice were significantly decreased. Meanwhile, plasma leptin was remarkably increased after gene transfer for 2, 3, 5, and 7 days, while plasma adiponectin was also significantly increased at day 2. To understand the mechanism of action of leptin on T2D mice, gene expressions related to glycometabolism and energy metabolism in the liver, epididymal adipose tissue, hypothalamus, and muscle were measured. The mRNA expression levels of adiponectin receptor 1 (ADR1), glucose transporter 4 (GLUT4), glucose-6-phosphase, and peroxisome proliferator-activated receptor γ in the liver, leptin, adiponectin, and hormone-sensitive lipase in adipose tissue, leptin, leptin-receptor, ADR1 in the hypothalamus, and ADR1, GLUT4, and insulin 1 in the gastrocnemius significantly increased. Moreover, the hepatic glycogen of the leptin-gene-treated group was significantly increased in comparison to the control group. Meanwhile, the significant decrease of forkhead box O1, adiponectin receptor 2, and peroxisome proliferator-activated receptor α in the liver, and agouti-related protein and proopiomelanocortin genes in the hypothalamus were also observed. In fat tissue and hypothalamus, leptin and adiponectin protein levels were also significantly increased, whereas the neuropeptide Y protein level was significantly decreased. These results indicated that the leptin gene transfer could improve the symptoms of T2D mice by regulating the leptin-hypothalamus signaling pathway and improving the insulin resistance of the peripheral tissues of T2D mice.

The long road to leptin.

Leptin is an adipose tissue hormone that functions as an afferent signal in a negative feedback loop that maintains homeostatic control of adipose tissue mass. This endocrine system thus serves a critical evolutionary function by protecting individuals from the risks associated with being too thin (starvation) or too obese (predation and temperature dysregulation). Mutations in leptin or its receptor cause massive obesity in mice and humans, and leptin can effectively treat obesity in leptin-deficient patients. Leptin acts on neurons in the hypothalamus and elsewhere to elicit its effects, and mutations that affect the function of this neural circuit cause Mendelian forms of obesity. Leptin levels fall during starvation and elicit adaptive responses in many other physiologic systems, the net effect of which is to reduce energy expenditure. These effects include cessation of menstruation, insulin resistance, alterations of immune function, and neuroendocrine dysfunction, among others. Some or all of these effects are also seen in patients with constitutively low leptin levels, such as occur in lipodystrophy. Leptin is an approved treatment for generalized lipodystrophy, a condition associated with severe metabolic disease, and has also shown potential for the treatment of other types of diabetes. In addition, leptin restores reproductive capacity and increases bone mineral density in patients with hypothalamic amenorrhea, an infertility syndrome in females. Most obese patients have high endogenous levels of leptin, in some instances as a result of mutations in the neural circuit on which leptin acts, though in most cases, the pathogenesis of leptin resistance is not known. Obese patients with leptin resistance show a variable response to exogenous leptin but may respond to a combination of leptin plus amylin. Overall, the identification of leptin has provided a framework for studying the pathogenesis of obesity in the general population, clarified the nature of the biologic response to starvation, and helped to advance our understanding of the neural mechanisms that control feeding.

Modeling the impact of growth and leptin deficits on the neuronal regulation of blood pressure.

The risk of hypertension is increased by intrauterine growth restriction (IUGR) and preterm birth. In the search for modifiable etiologies for this life-threatening cardiovascular morbidity, a number of pathways have been investigated, including excessive glucocorticoid exposure, nutritional deficiency and aberration in sex hormone levels. As a neurotrophic hormone that is intimately involved in the cardiovascular regulation and whose levels are influenced by glucocorticoids, nutritional status and sex hormones, leptin has emerged as a putative etiologic and thus a therapeutic agent. As a product of maternal and late fetal adipocytes and the placenta, circulating leptin typically surges late in gestation and declines after delivery until the infant consumes sufficient leptin-containing breast milk or accrues sufficient leptin-secreting adipose tissue to reestablish the circulating levels. The leptin deficiency seen in IUGR infants is a multifactorial manifestation of placental insufficiency, exaggerated glucocorticoid exposure and fetal adipose deficit. The preterm infant suffers from the same cascade of events, including separation from the placenta, antenatal steroid exposure and persistently underdeveloped adipose depots. Preterm infants remain leptin deficient beyond term gestation, rendering them susceptible to neurodevelopmental impairment and subsequent cardiovascular dysregulation. This pathologic pathway is efficiently modeled by placing neonatal mice into atypically large litters, thereby recapitulating the perinatal growth restriction-adult hypertension phenotype. In this model, neonatal leptin supplementation restores the physiologic leptin surge, attenuates the leptin-triggered sympathetic activation in adulthood and prevents leptin- or stress-evoked hypertension. Further pathway interrogation and clinical translation are needed to fully test the therapeutic potential of perinatal leptin supplementation.

Treatment of diet-induced lipodystrophic C57BL/6J mice with long-acting PASylated leptin normalises insulin sensitivity and hepatic steatosis by promoting lipid utilisation.

AIMS/HYPOTHESIS: Recombinant leptin offers a viable treatment for lipodystrophy (LD) syndromes. However, due to its short plasma half-life, leptin replacement therapy requires at least daily subcutaneous (s.c.) injections. Here, we optimised this treatment strategy in LD mice by using a novel leptin version with extended plasma half-life using PASylation technology. METHODS: A long-acting leptin version was prepared by genetic fusion with a 600 residue polypeptide made of Pro, Ala and Ser (PASylation), which enlarges the hydrodynamic volume and, thus, retards renal filtration, allowing less frequent injection. LD was induced in C57BL/6J mice by feeding a diet supplemented with conjugated linoleic acid (CLA). Chronic and acute effects of leptin treatment were assessed by evaluating plasma insulin levels, insulin tolerance, histological liver sections, energy expenditure, energy intake and body composition. RESULTS: In a cohort of female mice, 4 nmol PAS-leptin (applied via four s.c. injections every 3 days) successfully alleviated the CLA-induced LD phenotype, which was characterised by hyperinsulinaemia, insulin intolerance and hepatosteatosis. The same injection regimen had no measurable effect when unmodified recombinant leptin was administered at an equivalent dose. In a cohort of LD males, a single s.c. injection of PAS-leptin did not affect energy expenditure but inhibited food intake and promoted a shift in fuel selection towards preferential fat oxidation, which mechanistically substantiates the metabolic improvements. CONCLUSIONS/INTERPRETATION: The excellent pharmacological properties render PASylated leptin an agent of choice for refining both animal studies and therapeutic strategies in the context of LD syndromes and beyond.

The Effects of Leptin Replacement on Neural Plasticity.

Leptin, an adipokine synthesized and secreted mainly by the adipose tissue, has multiple effects on the regulation of food intake, energy expenditure, and metabolism. Its recently-approved analogue, metreleptin, has been evaluated in clinical trials for the treatment of patients with leptin deficiency due to mutations in the leptin gene, lipodystrophy syndromes, and hypothalamic amenorrhea. In such patients, leptin replacement therapy has led to changes in brain structure and function in intra- and extrahypothalamic areas, including the hippocampus. Furthermore, in one of those patients, improvements in neurocognitive development have been observed. In addition to this evidence linking leptin to neural plasticity and function, observational studies evaluating leptin-sufficient humans have also demonstrated direct correlation between blood leptin levels and brain volume and inverse associations between circulating leptin and risk for the development of dementia. This review summarizes the evidence in the literature on the role of leptin in neural plasticity (in leptin-deficient and in leptin-sufficient individuals) and its effects on synaptic activity, glutamate receptor trafficking, neuronal morphology, neuronal development and survival, and microglial function.