Leptin Signaling Research Articles

0040 Leptin Signaling in the Dorsomedial Hypothalamus Couples Metabolism and Breathing in Obesity

Abstract Introduction Individuals with obesity hypoventilation syndrome (OHS) are unable to increase ventilation to match increased CO2 production (VCO2). Obstructive sleep apnea (OSA), defined by the closure of the upper airway during sleep, is present in 90% of OHS patients. Leptin, an adipocyte-produced hormone, acts in leptin receptor (LEPRb) positive neurons and was implicated in the pathophysiology of OSA and OHS. Diet-induced obese (DIO) C57BL/6J mice shows features of OHS and OSA. Leptin-mediated neural pathways may link metabolism and breathing in obesity. We hypothesized that LEPRb-positive neurons in the dorsomedial hypothalamus (DMH) are necessary and sufficient to match control of breathing to VCO2 and that the stimulation of these neurons relieves OHS in DIO mice. Methods We expressed designer receptors exclusively activated by designer drugs (DREADDs) in DMH of DIO Leprb-Cre mice and measured breathing during sleep, the hypercapnic ventilatory response (HCVR), VCO2, and O2 consumption (VO2). Results Activation of LEPRb-positive DMH neurons increased inspiratory flow and minute ventilation during REM sleep, without affecting sleep architecture. The effect was pronounced during inspiratory flow limitation, suggeting that upper airway obstruction during REM sleep was relieved. Activation of these neurons increased the HCVR and this response was blunted by a serotonin receptor antagonist, methysergide. Activation of these neurons augmented VCO2, VO2, and VE/VCO2, suggesting that breathing was stimulated out of proportion to increases in metabolism. In vitro experiments revealed that LEPRb-positive DMH neurons project to 5-HT neurons in the dorsal raphe (DR) and that optogenetic stimulation of these neurons evoked excitatory postsynaptic currents in 5-HT neurons of the DR. Administration of retrograde Cre-dependent AAV harboring caspase to the DR in Leprb-Cre mice deleted LEPRb-positive DMH neurons and abolished respiratory and metabolic effects of chemogenetic stimulation. Apoptosis of LEPRb-positive DMH neurons projecting to the DR also prevented the increase in ventilation during REM sleep induced by intranasal leptin. Conclusion Leptin increases the HCVR, improves upper airway patency during sleep, and increases VCO2 acting on LEPRb-positive DMH neurons projecting to the DR. We conclude that LEPRb-positive DMH neurons projecting to the DR couple metabolism and breathing in obesity. Support (if any) NIH (R01 HL128970, R01 HL133100, and R01 HL138932), AHA (#915167).

Protective effect of Prolactin releasing peptide against 1,2-diacetylbenzene -induced neuroinflammation

Prolactin-releasing peptide (PrRP) has been investigated as a potential therapeutic for diabetes by the effect of food intake reduction, increasing leptin signaling, and insulin tolerance. Recent studies focused on its synaptogenesis and protective effects against neurodegeneration. Whereas 1,2-diacetylbenzene (DAB), a common metabolite of a neurotoxicant 1,2-diethyl benzene, causes memory impairment and neurotoxicity partly through the inflammatory process. Our present study assessed the effect of PrRP in microglia and its action in balancing the inflammation to protect against DAB. We observed that PrRP modulated NADPH oxidase - regulated NLRP3 inflammasome and PRL signaling pathways differently between physical and toxic conditions in microglia.

A comprehensive review on the research progress of PTP1B inhibitors as antidiabetics.

Diabetes mellitus (DM) is a serious global health concern affecting over 500 million people. To put it simply, it is one of the most dangerous metabolic illnesses. Insulin resistance is the root cause of 90% of all instances of diabetes, all of which are classified as Type 2 DM. Untreated, it poses a hazard to civilization since it can lead to terrifying consequences and even death. Oral hypoglycemic medicines presently available act in a variety of ways, targeting various organs and pathways. The use of protein tyrosine phosphatase 1B (PTP1B) inhibitors, on the contrary, is a novel and effective method of controlling type 2 diabetes. PTP1B is a negative insulin signaling pathway regulator; hence, inhibiting PTP1B increases insulin sensitivity, glucose absorption, and energy expenditure. PTP1B inhibitors also restore leptin signaling and are considered a potential obesity target. In this review, we have compiled a summary of the most recent advances in synthetic PTP1B inhibitors from 2015 to 2022 which have scope to be developed as clinical antidiabetic drugs.

Child and adolescent obesity

The prevalence of child and adolescent obesity has plateaued at high levels in most high-income countries and is increasing in many low-income and middle-income countries. Obesity arises when a mix of genetic and epigenetic factors, behavioural risk patterns and broader environmental and sociocultural influences affect the two body weight regulation systems: energy homeostasis, including leptin and gastrointestinal tract signals, operating predominantly at an unconscious level, and cognitive-emotional control that is regulated by higher brain centres, operating at a conscious level. Health-related quality of life is reduced in those with obesity. Comorbidities of obesity, including type 2 diabetes mellitus, fatty liver disease and depression, are more likely in adolescents and in those with severe obesity. Treatment incorporates a respectful, stigma-free and family-based approach involving multiple components, and addresses dietary, physical activity, sedentary and sleep behaviours. In adolescents in particular, adjunctive therapies can be valuable, such as more intensive dietary therapies, pharmacotherapy and bariatric surgery. Prevention of obesity requires a whole-system approach and joined-up policy initiatives across government departments. Development and implementation of interventions to prevent paediatric obesity in children should focus on interventions that are feasible, effective and likely to reduce gaps in health inequalities.

Association between genetic polymorphisms of leptin receptor and preeclampsia in Chinese women

Objective Leptin signaling plays an important role in regulating metabolism and reproduction. In the present study, we investigated the relationship between polymorphisms of leptin receptor (LEPR) gene A223G and A668G and preeclampsia (PE) and evaluated influences of genotypes on clinical, metabolic, and oxidative stress indices in Chinese women. Methods This is a case-control study including 322 patients with PE and 1295 healthy pregnant women. The two polymorphisms were genotyped by polymerase chain reaction-restriction fragments length polymorphism method. Clinical and biochemical parameters were analyzed. Results The frequencies of the AA + AG genotypes (28.6% vs. 36.1%) and A allele (14.9% vs. 19.8%) of LEPR A223G polymorphism, and those of the AA + AG genotypes (17.7% vs. 24.6%) and A allele (9.0% vs. 12.9%) of LEPR A668G polymorphism were significantly lower in the PE group than those in the control group. The 223A and 668A alleles were protective factors against PE in the regression model, which included age and delivery body mass index as covariates (OR = 0.684, 95% CI: 0.506–0.926, p = .014; OR = 0.650, 95% CI: 0.456–0.927, p = .017, respectively). When the 668GG/223GG combined genotype served as the reference category, the 668A/223A combined allele had further enhanced the protective effect on PE (OR = 0.558, 95% CI: 0.374–0.833, p = .004). Patients possessing the LEPR 223A allele had higher total antioxidant capacity and lower oxidative stress index (p < .05), while those with the LEPR 668A allele had higher high-density lipoprotein cholesterol levels (p = .045) compared with those carrying the corresponding GG genotype. Conclusions The 223A and 668A alleles of LEPR polymorphisms are genetic protective factors for PE in Chinese women. The two alleles may exert a beneficial effect on oxidative stress and lipid metabolism in patients.

Effects of Leptin and Body Weight on Inflammation and Knee Osteoarthritis Phenotypes in Female Rats.

Leptin is a proinflammatory adipokine that contributes to obesity-associated osteoarthritis (OA), especially in women. However, the extent to which leptin causes knee OA separate from the effect of increased body weight is not clear. We hypothesized that leptin is necessary to induce knee OA in obese female rats but not sufficient to induce knee OA in lean rats lacking systemic metabolic inflammation. The effect of obesity without leptin signaling was modeled by comparing female lean Zucker rats to pair fed obese Zucker rats, which possess mutant fa alleles of the leptin receptor gene. The effect of leptin without obesity was modeled in female F344BN F1 hybrid rats by systemically administering recombinant rat leptin versus saline for 23 weeks via osmotic pumps. Primary OA outcomes included cartilage histopathology and subchondral bone micro-computed tomography. Secondary outcomes included targeted cartilage proteomics, serum inflammation, and synovial fluid inflammation following an acute intra-articular challenge with interleukin-1β (IL-1β). Compared to lean Zucker rats, obese Zucker rats developed more severe tibial osteophytes and focal cartilage lesions in the medial tibial plateau, with modest changes in proximal tibial epiphysis trabecular bone structure. In contrast, exogenous leptin treatment, which increased plasma leptin sixfold without altering body weight, caused mild generalized cartilage fibrillation and reduced Safranin O staining compared to vehicle-treated animals. Leptin also significantly increased subchondral and trabecular bone volume and bone mineral density in the proximal tibia. Cartilage metabolic and antioxidant enzyme protein levels were substantially elevated with leptin deficiency and minimally suppressed with leptin treatment. In contrast, leptin treatment induced greater changes in systemic and local inflammatory mediators compared to leptin receptor deficiency, including reduced serum IL-6 and increased synovial fluid IL-1β. In conclusion, rat models that separately elevate leptin or body weight develop distinct OA-associated phenotypes, revealing how obesity increases OA pathology through both leptin-dependent and independent pathways. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Leptin signaling in the dorsomedial hypothalamus couples metabolism and breathing in obesity

Individuals with obesity hypoventilation syndrome (OHS) are unable to increase ventilation to match increased CO 2 production (VCO 2 ). Obstructive sleep apnea (OSA), defined by the closure of the upper airway during sleep, is present in 90% of OHS patients. Leptin, an adipocyte-produced hormone, acts in leptin receptor (LEPR b ) positive neurons and was implicated in the pathophysiology of OSA and OHS. Diet-induced obese (DIO) C57BL/6J mice shows features of OHS and OSA. Leptin-mediated neural pathways may link metabolism and breathing in obesity. We hypothesized that LEPR b -positive neurons in the dorsomedial hypothalamus (DMH) are necessary and sufficient to match control of breathing to VCO 2 and that the stimulation of these neurons relieves OHS in DIO mice. We examined our hypothesis using in vivo and in vitro studies. We expressed designer receptors exclusively activated by designer drugs (DREADDs) in DMH of DIO Lepr b -Cre mice and measured breathing during sleep, the hypercapnic ventilatory response (HCVR), VCO 2 , and O 2 consumption (VO 2 ). Activation of LEPR b -positive DMH neurons increased inspiratory flow and minute ventilation during REM sleep, without affecting sleep architecture. The effect was pronounced during inspiratory flow limitation, suggesting that upper airway obstruction during REM sleep was relieved. Activation of these neurons increased the HCVR and this response was blunted by a serotonin receptor antagonist, methysergide. Activation of these neurons augmented VCO 2 , VO 2 , and VE/VCO 2 , suggesting that breathing was stimulated out of proportion to increases in metabolism. In vitro experiments revealed that LEPR b -positive DMH neurons project to 5-HT neurons in the dorsal raphe (DR) and that optogenetic stimulation of these neurons evoked excitatory postsynaptic currents in 5-HT neurons of the DR. Administration of retrograde Cre-dependent AAV harboring caspase to the DR in Lepr b -Cre mice deleted LEPR b -positive DMH neurons and abolished respiratory and metabolic effects of chemogenetic stimulation. Apoptosis of LEPR b -positive DMH neurons projecting to the DR also prevented the increase in ventilation during REM sleep induced by intranasal leptin. Leptin increases the HCVR, improves upper airway patency during sleep, and increases VCO 2 acting on LEPR b -positive DMH neurons projecting to the DR. We conclude that LEPR b -positive DMH neurons projecting to the DR couple metabolism and breathing in obesity. NIH (R01 HL128970, R01 HL133100, and R01 HL138932), AHA (#915167). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Leptin is a key regulator of glucose homeostasis in obesity

Approximately 9 out of 10 people with type-2 diabetes are overweight. Leptin is a hormone secreted from white fat cells that exerts control over both food intake and energy expenditure. We described the central mechanisms underlying the hypertensive effects of hyperleptinemia in obesity. Work presented here used continuous radiotelemetric glucose monitoring in mice in combination with multiple gold standard techniques in order to determine the effects of dorsomedial hypothalamic (DMH) leptin signalling on peripheral glucose control. A leptin receptor (LepR) antagonist administered directly into the brain impaired DIO mouse glucose tolerance demonstrating that leptin retains the ability to regulate blood glucose concentration in obesity. Knockdown of DMH LepR function using short hairpin adeno-associated virus (AAV) RNA significantly reduced brown adipose tissue (BAT) thermogenesis by -0.8 ± 0.1°C and increased basal blood glucose (14.3 ± 0.6mmol/l to 9.4 ± 0.5mmol/l) and impaired glucose tolerance. Conversely, chemogenic activation of LepR-expressing DMH neurons significantly elevated BAT thermogenesis (1.5 ± 0.2 °C increase). This increased BAT temperature was immediately followed by a decrease in plasma blood glucose concentration (7.6 ± 0.5 mmol/l to 5.8 ± 0.5 mmol/l). Work presented here demonstrates that increasing the activity of LepR expressing neurons in the DMH can improve glucose tolerance in obesity though an elevation of BAT metabolic activity. This work was supported by the National Heart Foundation of Australia (SES), The National Health and Medical Research Council of Australia (SES and MAC). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Tgr5-/- mice are protected from ethanol-induced metabolic alterations through enhanced leptin and Fgf21 signaling.

Alcohol-associated liver disease (ALD) is caused by chronic use of alcohol and ranges from hepatic steatosis to fibrosis and cirrhosis. Bile acids are physiological detergents that also regulate hepatic glucose and lipid homeostasis by binding to several receptors. One such receptor, Takeda G protein-coupled receptor 5 (TGR5), may represent a therapeutic target for ALD. Here, we used a chronic 10-day + binge ethanol-feeding model in mice to study the role of TGR5 in alcohol-induced liver injury. Female C57BL/6J wild-type mice and Tgr5-/- mice were pair-fed Lieber-DeCarli liquid diet with ethanol (5% v/v) or isocaloric control diet for 10 days followed by a gavage of 5% ethanol or isocaloric maltose control, respectively, to represent a binge-drinking episode. Tissues were harvested 9 hours following the binge, and metabolic phenotypes were characterized through examination of liver, adipose, and brain mechanistic pathways. Tgr5-/- mice were protected from alcohol-induced accumulation of hepatic triglycerides. Interestingly, liver and serum levels of Fgf21 were significantly increased during ethanol feeding in Tgr5-/- mice, as was phosphorylation of Stat3. Parallel to Fgf21 levels, increased leptin gene expression in white adipose tissue and increased leptin receptor in liver were detected in Tgr5-/- mice fed ethanol diet. Adipocyte lipase gene expression was significantly increased in Tgr5-/- mice regardless of diet, whereas adipose browning markers were also increased in ethanol-fed Tgr5-/- mice, indicating potential for enhanced white adipose metabolism. Lastly, hypothalamic mRNA targets of leptin, involved in the regulation of food intake, were significantly increased in Tgr5-/- mice fed ethanol diet. Tgr5-/- mice are protected from ethanol-induced liver damage and lipid accumulation. Alterations in lipid uptake and Fgf21 signaling, and enhanced metabolic activity of white adipose tissue, may mediate these effects.

Treatment with bergamot (Citrus bergamia) leaves extract attenuates leptin resistance in obese rats.

Low-grade chronic inflammation in obesity is associated with leptin resistance. In order to alleviate this pathological condition, bioactive compounds capable of attenuating oxidative stress and inflammation have been researched, and bergamot (Citrus bergamia) presents these properties. The aim was to evaluate the effect of bergamot leaves extract on leptin resistance in obese rats. Animals were divided into 2 groups: control diet (C, n=10) and high sugar-fat diet (HSF, n=20) for 20 weeks. After detecting hyperleptinemia, animals were divided to begin the treatment with bergamot leaves extract (BLE) for 10 weeks: C+placebo (n=7), HSF+placebo (n=7), and HSF+BLE (n=7) by gavage (50mg/kg). Evaluations included nutritional, hormonal and metabolic parameters; adipose tissue dysfunction; inflammatory, oxidative markers and hypothalamic leptin pathway. HSF group presented obesity, metabolic syndrome, adipose tissue dysfunction, hyperleptinemia and leptin resistance compared to control group. However, the treated group showed a decrease in caloric consumption and attenuation of insulin resistance. Moreover, dyslipidemia, adipose tissue function, and leptin levels showed an improvement. At the level of the hypothalamus, the treated group showed a reduction of oxidative stress, inflammation and modulation of leptin signaling. In conclusion, BLE properties were able to improve leptin resistance through recovery of the hypothalamic pathway.

Association between Stearoyl CoA Desaturase (SCD) Gene Polymorphisms and Milk Production in Holstein Cattle Breed

The SCD gene is a significant component of the leptin signaling pathway. The SCD gene has also been suggested as a candidate essential gene that can change the ratio of saturated to unsaturated fatty acids in milk and increase the amount of conjugated linoleic fatty acid, which is thought to have anti-cancer properties. The current research was carried out on Holstein cows to determine the association between SCD (Stearoyl-Coenzyme A Desaturase) gene polymorphism and total milk yield at 305 days (TMY305) and daily milk yield (DMY). The polymorphism in the SCD gene was identified using the PCR-RFLP technique and the SatI restriction enzyme for genotyping at SNP c.878T&gt;C in the exon 5. The TT, TC, and CC genotype frequencies were 0.21, 0.50, and 0.29 respectively. While the allele frequencies of T and C were 0.46 and 0.54, respectively. According to the Chi-square test results, the SCD/c.878T&gt;C distribution was in Hardy-Weinberg disequilibrium (P&lt;0.05). Statistical analysis indicated a significant association between the SCD gene polymorphism and TMY305 (P&lt;0.05). The TC genotypes showed a higher mean TMY305 compared to the TT and CC genotypes.

Small Molecule Degraders of Protein Tyrosine Phosphatase 1B and T-Cell Protein Tyrosine Phosphatase for Cancer Immunotherapy.

Protein tyrosine phosphatase 1B (PTP1B) and T-cell protein tyrosine phosphatase (TC-PTP) play non-redundant negative regulatory roles in T-cell activation, tumor antigen presentation, insulin and leptin signaling, and are potential targets for several therapeutic applications. Here, we report the development of a highly potent and selective small molecule degrader DU-14 for both PTP1B and TC-PTP. DU-14 mediated PTP1B and TC-PTP degradation requires both target protein(s) and VHL E3 ligase engagement and is also ubiquitination- and proteasome-dependent. DU-14 enhances IFN-γ induced JAK1/2-STAT1 pathway activation and promotes MHC-I expression in tumor cells. DU-14 also activates CD8+ T-cells and augments STAT1 and STAT5 phosphorylation. Importantly, DU-14 induces PTP1B and TC-PTP degradation in vivo and suppresses MC38 syngeneic tumor growth. The results indicate that DU-14, as the first PTP1B and TC-PTP dual degrader, merits further development for treating cancer and other indications.

Small Molecule Degraders of Protein Tyrosine Phosphatase 1B and T‐Cell Protein Tyrosine Phosphatase for Cancer Immunotherapy

AbstractProtein tyrosine phosphatase 1B (PTP1B) and T‐cell protein tyrosine phosphatase (TC‐PTP) play non‐redundant negative regulatory roles in T‐cell activation, tumor antigen presentation, insulin and leptin signaling, and are potential targets for several therapeutic applications. Here, we report the development of a highly potent and selective small molecule degrader DU‐14 for both PTP1B and TC‐PTP. DU‐14 mediated PTP1B and TC‐PTP degradation requires both target protein(s) and VHL E3 ligase engagement and is also ubiquitination‐ and proteasome‐dependent. DU‐14 enhances IFN‐γ induced JAK1/2‐STAT1 pathway activation and promotes MHC‐I expression in tumor cells. DU‐14 also activates CD8+ T‐cells and augments STAT1 and STAT5 phosphorylation. Importantly, DU‐14 induces PTP1B and TC‐PTP degradation in vivo and suppresses MC38 syngeneic tumor growth. The results indicate that DU‐14, as the first PTP1B and TC‐PTP dual degrader, merits further development for treating cancer and other indications.

Prenatal benzene exposure in mice alters offspring hypothalamic development predisposing to metabolic disease in later life

Maternal exposure to environmental contaminants during pregnancy poses a significant threat to a developing fetus, as these substances can easily cross the placenta and disrupt the neurodevelopment of offspring. Specifically, the hypothalamus is essential in the regulation of metabolism, notably during critical windows of development. An abnormal hormonal and inflammatory milieu during development can trigger persistent changes in the function of hypothalamic circuits, leading to long-lasting effects on the body's energy homeostasis and metabolism. We recently demonstrated that gestational exposure to clinically relevant levels of benzene induces severe metabolic dysregulation in the offspring. Given the central role of the hypothalamus in metabolic control, we hypothesized that prenatal exposure to benzene impacts hypothalamic development, contributing to the adverse metabolic effects in the offspring. C57BL/6JB dams were exposed to benzene at 50 ppm in the inhalation chambers exclusively during pregnancy (from E0.5 to E19). Transcriptomic analysis of the exposed offspring at postnatal day 21 (P21) revealed hypothalamic changes in genes related to metabolic regulation, inflammation, and neurodevelopment exclusively in males. Moreover, the hypothalamus of prenatally benzene-exposed male offspring displayed alterations in orexigenic and anorexigenic projections, impairments in leptin signaling, and increased microgliosis. Additional exposure to benzene during lactation did not promote further microgliosis or astrogliosis in the offspring, while the high-fat diet (HFD) challenge in adulthood exacerbated glucose metabolism and hypothalamic inflammation in benzene-exposed offspring of both sexes. These findings reveal the persistent adverse effects of prenatal benzene exposure on hypothalamic circuits and neuroinflammation, predisposing the offspring to long-lasting metabolic health conditions.

You are What You Drink? How Associations Between Profiles of Beverage Consumption and Type 2 Diabetes Risk are Mediated by Biomarker Networks

BackgroundMultiple studies have independently investigated the associations of the consumption of individual beverage types and specific plasma biomarkers with the risk of type 2 diabetes (T2D). However, as individuals do not consume single beverage types exclusively and plasma biomarkers do not act in isolation, it remains unclear how patterns of beverage consumption and plasma biomarker networks associate both with each other and T2D risk. ObjectivesWe aimed to elucidate potential dietary determinants of T2D risk by defining a model that describes habitual beverage consumption profiles in relation to identified networks of circulating plasma biomarkers. MethodsThis study included 1,461 case and 1,568 control participants from case-control studies of T2D nested within the Nurses’ Health Study. Participants completed validated semiquantitative food frequency questionnaires that assessed habitual beverage consumption, and they provided blood samples from which 27 plasma biomarkers of cardiometabolic risk were identified. Common exploratory factor analysis (EFA) identified factors that separately described beverage consumption profiles and biomarker networks. Multivariable-adjusted regression elucidated the relationships between beverage and biomarker factors and T2D risk. ResultsEFA revealed five factors describing unique beverage consumption profiles and seven factors describing biomarker networks. The factor describing alcoholic beverage consumption was associated with a reduced risk of T2D (odds ratio [OR]: 0.50 [0.40, 0.64], P<0.001) mediated, in part, by the factor describing increased concentrations of adiponectin biomarkers (19.9% [12.0, 31.1] P = 0.004). The factor describing low-calorie sweetened beverage (LCSBs) consumption was associated with an increased risk of T2D (OR: 1.33 [1.03, 1.72], P = 0.021), and the factor describing lower concentrations of insulin-like growth factor binding proteins 1 and 2, and soluble leptin receptor, and increased leptin concentrations (P = 0.005). ConclusionsModerate alcohol consumption was associated with reduced T2D risk, mediated in part by increased circulating adiponectin. LCSB consumption was associated with both increased T2D risk and perturbed insulin-like growth factor and leptin signaling.

Identification of a GABAergic neural circuit governing leptin signaling deficiency-induced obesity.

The hormone leptin is known to robustly suppress food intake by acting upon the leptin receptor (LepR) signaling system residing within the agouti-related protein (AgRP) neurons of the hypothalamus. However, clinical studies indicate that leptin is undesirable as a therapeutic regiment for obesity, which is at least partly attributed to the poorly understood complex secondary structure and key signaling mechanism of the leptin-responsive neural circuit. Here, we show that the LepR-expressing portal neurons send GABAergic projections to a cohort of α3-GABAA receptor expressing neurons within the dorsomedial hypothalamic nucleus (DMH) for the control of leptin-mediated obesity phenotype. We identified the DMH as a key brain region that contributes to the regulation of leptin-mediated feeding. Acute activation of the GABAergic AgRP-DMH circuit promoted food intake and glucose intolerance, while activation of post-synaptic MC4R neurons in the DMH elicited exactly opposite phenotypes. Rapid deletion of LepR from AgRP neurons caused an obesity phenotype which can be rescued by blockage of GABAA receptor in the DMH. Consistent with behavioral results, these DMH neurons displayed suppressed neural activities in response to hunger or hyperglycemia. Furthermore, we identified that α3-GABAA receptor signaling within the DMH exerts potent bi-directional regulation of the central effects of leptin on feeding and body weight. Together, our results demonstrate a novel GABAergic neural circuit governing leptin-mediated feeding and energy balance via a unique α3-GABAA signaling within the secondary leptin-responsive neural circuit, constituting a new avenue for therapeutic interventions in the treatment of obesity and associated comorbidities.

Leptin regulates thymic plasmacytoid dendritic cell ability to influence the thymocyte distribution in vitro.

Leptin, the adipocyte-derived hormone, involved in regulating food intake and body weight, plays an important role in immunity and reproduction. Leptin signals via the specific membrane receptors expressed in most types of immune cells including dendritic cells (DCs) and thymocytes. Leptin enhances thymopoiesis and modulates T-cell-mediated immunity. Thymic plasmacytoid DCs (pDCs) are predominated in the thymus. They play an important role in thymocyte differentiation. We have analyzed whether leptin mediates its effects on human thymocytes by influencing on pDCs. We used leptin at concentration corresponding to its level during II-III trimesters of physiological pregnancy. We cultivated leptin-primed pDCs with autologous thymocytes and estimated the main thymocyte subsets expressing αβ chains of the T-cell receptor (αβTCR), natural regulatory T-cells (tTreg), natural T-helpers producing interleukin-17 (nTh17) and invariant natural killer T-cells (iNKT) in vitro. We have shown that leptin augmented CD86, CD276 expressions and depressed IL-10 productions by pDCs. Leptin-primed pDCs decreased the percentage of CD4+CD8+αβTCR+ thymocytes, increased CD4hiCD8-/loαβTCR+ cells. pDCs cultivated with leptin decreased the number of iNKT precursors, and did not change the number of tTreg and nTh17 precursors. Thus, leptin's important role in regulation of thymic pDC abilities to influence on the thymocyte distribution was indicated in vitro.

SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression

Adipose tissue modulates energy homeostasis by secreting leptin, but little is known about the factors governing leptin production. We show that succinate, long perceived as a mediator of immune response and lipolysis, controls leptin expression via its receptor SUCNR1. Adipocyte-specific deletion of Sucnr1 influences metabolic health according to nutritional status. Adipocyte Sucnr1 deficiency impairs leptin response to feeding, whereas oral succinate mimics nutrient-related leptin dynamics via SUCNR1. SUCNR1 activation controls leptin expression via the circadian clock in an AMPK/JNK-C/EBPα-dependent manner. Although the anti-lipolytic role of SUCNR1 prevails in obesity, its function as a regulator of leptin signaling contributes to the metabolically favorable phenotype in adipocyte-specific Sucnr1 knockout mice under standard dietary conditions. Obesity-associated hyperleptinemia in humans is linked to SUCNR1 overexpression in adipocytes, which emerges as the major predictor of adipose tissue leptin expression. Our study establishes the succinate/SUCNR1 axis as a metabolite-sensing pathway mediating nutrient-related leptin dynamics to control whole-body homeostasis.

Structural insights into the mechanism of leptin receptor activation

Leptin is an adipocyte-derived protein hormone that promotes satiety and energy homeostasis by activating the leptin receptor (LepR)–STAT3 signaling axis in a subset of hypothalamic neurons. Leptin signaling is dysregulated in obesity, however, where appetite remains elevated despite high levels of circulating leptin. To gain insight into the mechanism of leptin receptor activation, here we determine the structure of a stabilized leptin-bound LepR signaling complex using single particle cryo-EM. The structure reveals an asymmetric architecture in which a single leptin induces LepR dimerization via two distinct receptor-binding sites. Analysis of the leptin–LepR binding interfaces reveals the molecular basis for human obesity-associated mutations. Structure-based design of leptin variants that destabilize the asymmetric LepR dimer yield both partial and biased agonists that partially suppress STAT3 activation in the presence of wild-type leptin and decouple activation of STAT3 from LepR negative regulators. Together, these results reveal the structural basis for LepR activation and provide insights into the differential plasticity of signaling pathways downstream of LepR.

Ameliorative effects of zinc supplementation on cognitive function and hippocampal leptin signaling pathway in obese male and female rats

Obesity has been associated with cognitive impairments, increasing the probability of developing dementia. Recently, zinc (Zn) supplementation has attracted an increasing attention as a therapeutic agent for cognitive disorders. Here, we investigated the potential effects of low and high doses of Zn supplementation on cognitive biomarkers and leptin signaling pathway in the hippocampus of high fat diet (HFD)-fed rats. We also explored the impact of sex difference on the response to treatment. Our results revealed a significant increase in body weight, glucose, triglycerides (TG), total cholesterol (TC), total lipids and leptin levels in obese rats as compared to controls. HFD feeding also reduced brain-derived neurotrophic factor (BDNF) levels and increased acetylcholinesterase (AChE) activity in the hippocampus of both sexes. The low and high doses of Zn supplementation improved glucose, TG, leptin, BDNF levels and AChE activity in both male and female obese rats compared to untreated ones. Additionally, downregulated expression of leptin receptor (LepR) gene and increased levels of activated signal transducer and activator of transcription 3 (p-STAT3) that observed in hippocampal tissues of obese rats were successfully normalized by both doses of Zn. In this study, the male rats were more vulnerable to HFD-induced weight gain, most of the metabolic alterations and cognition deficits than females, whereas the female obese rats were more responsive to Zn treatment. In conclusion, we suggest that Zn treatment may be effective in ameliorating obesity-related metabolic dysfunction, central leptin resistance and cognitive deficits. In addition, our findings provide evidence that males and females might differ in their response to Zn treatment.