Hypomethylated leptin receptor reduces cerebral ischaemia-reperfusion injury by activating the JAK2/STAT3 signalling pathway.

OBJECTIVE: To investigate the cerebroprotective effects of leptin in vitro and in vivo via the Janus kinase-2 (JAK2)/transcription factor signal transducer and activators of transcription-3 (STAT3) pathway and leptin receptors (LEPR). METHODS: The study used the cellular oxygen-glucose deprivation (OGD) model in PC12 cells and the middle cerebral artery occlusion (MCAO) rat model of cerebral ischaemia-reperfusion injury (CIRI) to assess changes in gene expression and protein levels following leptin pretreatment. The methylated DNA immunoprecipitation (MeDIP) assay measured DNA methylation levels. RESULTS: The optimal leptin concentration for exerting neuroprotective effects against ischaemia-reperfusion injury in PC12 cells was 200 ng/ml in vitro, but excessive leptin diminished this effect. Leptin pretreatment in the MCAO rat model demonstrated a similar effect to previously reported leptin administration post-CIRI. In addition to regulating the expression of inflammation-related cytokines, Western blot analysis showed that leptin pretreatment upregulated BCL-2 and downregulated caspase 3 levels. The MeDIP analysis demonstrated that DNA methylation regulated LEPR gene expression in the MCAO rat model when leptin pretreatment was used. CONCLUSION: Exogenous leptin might bind to extra-activated LEPR by reducing the methylation level of the LEPR gene promoter region, which leads to an increase in phosphorylated JAK2/STAT3 and apoptotic signalling pathways.

Clinical and molecular characterisation of children with monogenic obesity: a case series.

INTRODUCTION: To study the clinical profile and molecular diagnosis of children with severe early-onset non-syndromic monogenic obesity. METHODS: The clinical and molecular data (performed using whole exome sequencing) of 7 children with early-onset (< 5 years) non-syndromic monogenic obesity were extracted from the Obesity Clinic files and analysed retrospectively. RESULTS: The median (IQR) age at presentation was 18 (10.5-27) months. Of the 7 patients, 5 were boys, 3 had a history of parental consanguinity, and 4 had a family history of severe early-onset obesity. All patients exhibited hyperphagia and showed signs of insulin resistance. Dyslipidaemia and fatty liver were observed in 4. The variants identified in 6 patients included 2 in leptin receptor, and one each in melanocortin 4 receptor, pro-opiomelanocortin, leptin, and neurotrophic tyrosine kinase receptor type 2 genes. Notably, 4 of these variants were novel. CONCLUSIONS: This case series provides valuable insights into the spectrum of genetic mutations associated with non-syndromic monogenic obesity in North Indian children. The findings underscore the significance of next-generation sequencing in identifying the aetiology of severe early-onset obesity.

Increased Permeability of the Blood-Brain Barrier in a Diabetic Mouse Model (Leprdb/db Mice).

Type 2 Diabetes Mellitus (T2DM) is linked to multiple complications, including cognitive impairment, and the prevalence of memory-related neurodegenerative diseases is higher in T2DM patients. One possible theory is the alteration of the microvascular and macrovascular environment of the blood-brain barrier (BBB). In this study, we employed different approaches, including RT-PCR, functional pharmacokinetic studies using sodium fluorescein (NaFL), and confocal microscopy, to characterize the functional and molecular integrity of the BBB in a T2DM animal model, leptin receptor-deficient mutant mice (Leprdb/db mice). As a result, VCAM-1, ICAM-1, MMP-9, and S100b (BBB-related markers) dysregulation was observed in the Leprdb/db animal model compared to littermate wild-type mice. The brain concentration of sodium fluorescein (NaFL) increased significantly in Leprdb/db untreated mice compared to insulin-treated mice. Therefore, the permeability of NaFL was higher in Leprdb/db control mice than in all remaining groups. Identifying the factors that increase the BBB in Leprdb/db mice will provide a better understanding of the BBB microvasculature and present previously undescribed findings of T2DM-related brain illnesses, filling knowledge gaps in this emerging field of research.

LEP inhibits intramuscular adipogenesis through the AMPK signaling pathway in vitro.

Leptin can indirectly regulate fatty-acid metabolism and synthesis in muscle in vivo and directly in incubated muscle ex vivo. In addition, non-synonymous mutations in the bovine leptin gene (LEP) are associated with carcass intramuscular fat (IMF) content. However, the effects of LEP on lipid synthesis of adipocytes have not been clearly studied at the cellular level. Therefore, this study focused on bovine primary intramuscular preadipocytes to investigate the effects of LEP on the proliferation and differentiation of intramuscular preadipocytes, as well as its regulatory mechanism in lipid synthesis. The results showed that both the LEP and leptin receptor gene (LEPR) were highly expressed in IMF tissues, and their mRNA expression levels were positively correlated at different developmental stages of intramuscular preadipocytes. The overexpression of LEP inhibited the proliferation and differentiation of intramuscular preadipocytes, while interference with LEP had the opposite effect. Additionally, LEP significantly promoted the phosphorylation level of AMPKα by promoting the protein expression of CAMKK2. Meanwhile, rescue experiments showed that the increasing effect of AMPK inhibitors on the number of intramuscular preadipocytes was significantly weakened by the overexpression of LEP. Furthermore, the overexpression of LEP could weaken the promoting effect of AMPK inhibitor on triglyceride content and droplet accumulation, and prevent the upregulation of adipogenic protein expression (SREBF1, FABP4, FASN, and ACCα) caused by AMPK inhibitor. Taken together, LEP acted on the AMPK signaling pathway by regulating the protein expression of CAMKK2, thereby downregulating the expression of proliferation-related and adipogenic-related genes and proteins, ultimately reducing intramuscular adipogenesis.

Glutamate neurotransmission from leptin receptor cells is required for typical puberty and reproductive function in female mice.

The hypothalamic ventral premammillary nucleus (PMv) is a glutamatergic nucleus essential for the metabolic control of reproduction. However, conditional deletion of leptin receptor long form (LepRb) in vesicular glutamate transporter 2 (Vglut2) expressing neurons results in virtually no reproductive deficits. In this study, we determined the role of glutamatergic neurotransmission from leptin responsive PMv neurons on puberty and fertility. We first assessed if stimulation of PMv neurons induces luteinizing hormone (LH) release in fed adult females. We used the stimulatory form of designer receptor exclusively activated by designer drugs (DREADDs) in LeprCre (LepRb-Cre) mice. We collected blood sequentially before and for 1 hr after intravenous clozapine-N-oxide injection. LH level increased in animals correctly targeted to the PMv, and LH level was correlated to the number of Fos immunoreactive neurons in the PMv. Next, females with deletion of Slc17a6 (Vglut2) in LepRb neurons (LeprΔVGlut2) showed delayed age of puberty, disrupted estrous cycles, increased gonadotropin-releasing hormone (GnRH) concentration in the axon terminals, and disrupted LH secretion, suggesting impaired GnRH release. To assess if glutamate is required for PMv actions in pubertal development, we generated a Cre-induced reexpression of endogenous LepRb (LeprloxTB) with concomitant deletion of Slc17a6 (Vglut2flox) mice. Rescue of Lepr and deletion of Slc17a6 in the PMv was obtained by stereotaxic injection of an adeno-associated virus vector expressing Cre recombinase. Control LeprloxTB mice with PMv LepRb rescue showed vaginal opening, follicle maturation, and became pregnant, while LeprloxTB;Vglut2flox mice showed no pubertal development. Our results indicate that glutamatergic neurotransmission from leptin sensitive neurons regulates the reproductive axis, and that leptin action on pubertal development via PMv neurons requires Vglut2.

The Expression of Genes Related to Reverse Cholesterol Transport and Leptin Receptor Pathways in Peripheral Blood Mononuclear Cells Are Decreased in Morbid Obesity and Related to Liver Function.

Obesity is frequently accompanied by non-alcoholic fatty liver disease (NAFLD). These two diseases are associated with altered lipid metabolism, in which reverse cholesterol transport (LXRα/ABCA1/ABCG1) and leptin response (leptin receptor (Ob-Rb)/Sam68) are involved. The two pathways were evaluated in peripheral blood mononuclear cells (PBMCs) from 86 patients with morbid obesity (MO) before and six months after Roux-en-Y gastric bypass (RYGB) and 38 non-obese subjects. In the LXRα pathway, LXRα, ABCA1, and ABCG1 mRNA expressions were decreased in MO compared to non-obese subjects (p < 0.001, respectively). Ob-Rb was decreased (p < 0.001), whereas Sam68 was increased (p < 0.001) in MO. RYGB did not change mRNA gene expressions. In the MO group, the LXRα pathway (LXRα/ABCA1/ABCG1) negatively correlated with obesity-related variables (weight, body mass index, and hip), inflammation (C-reactive protein), and liver function (alanine-aminotransferase, alkaline phosphatase, and fatty liver index), and positively with serum albumin. In the Ob-R pathway, Ob-Rb and Sam68 negatively correlated with alanine-aminotransferase and positively with albumin. The alteration of LXRα and Ob-R pathways may play an important role in NAFLD development in MO. It is possible that MO patients may require more than 6 months following RYBGB to normalize gene expression related to reverse cholesterol transport or leptin responsiveness.

Bioactive Peptides from Meretrix lusoria Enzymatic Hydrolysate as a Potential Treatment for Obesity in db/db Mice.

Obesity is acknowledged as a significant risk factor for cardiovascular disease, often accompanied by increased inflammation and diabetes. Bioactive peptides derived from marine animal proteins show promise as safe and effective anti-obesity agents by regulating adipocyte differentiation through the AMPK signaling pathway. Therefore, this study aims to investigate the anti-obesity and anti-diabetic effects of bioactive compounds derived from a Meretrix lusoria Protamex enzymatic hydrolysate (MLP) fraction (≤1 kDa) through a 6-week treatment (150 mg/kg or 300 mg/kg, administered once daily) in leptin receptor-deficient db/db mice. The MLP treatment significantly decreased the body weight, serum total cholesterol, triglycerides, and LDL-cholesterol levels while also exhibiting a beneficial effect on hepatic and serum marker parameters in db/db mice. A histological analysis revealed a reduction in hepatic steatosis and epididymal fat following MLP treatment. Furthermore, poor glucose tolerance was improved, and hepatic antioxidant enzyme activities were elevated in MLP-treated mice compared to db/db control mice. Western blot analysis showed an increased expression of the AMPK protein after MLP treatment. In addition, the expression of lipogenic genes decreased in db/db mice. These findings indicate that bioactive peptides, which are known to regulate blood glucose levels, lipid metabolism, and adipogenesis, could be beneficial functional food additives and pharmaceuticals.

The effects of leptin on human cytotrophoblast invasion are gestational age and dose-dependent.

Introduction: Leptin and its receptors are expressed by the human placenta throughout gestation, yet the role of leptin in early human placental development is not well characterized. Leptin is overexpressed in the placentas from preeclamptic (PE) pregnancies. PE can result from the impaired invasion of fetal placental cells, cytotrophoblasts (CTBs), into the maternal decidua. We hypothesized that elevated leptin levels would impair human CTB invasion. Methods: The effects of leptin on the invasion of human CTBs were evaluated in three cell models, HTR-8/SVneo cells, primary CTBs, and placental villous explants using invasion assays. Further, leptin receptor expression was characterized in all three cell models using RT-PCR. Further phosphokinase assays were performed in HTR-8/SVneo cells to determine signaling pathways involved in CTB invasion in response to differential leptin doses. Results: We found that, prior to 8 weeks gestation, leptin promoted CTB invasion in the explant model. After 11 weeks gestation in explants, primary CTBs and in HTR-8/SVneo cells, leptin promoted invasion at moderate but not at high concentrations. Further, leptin receptor characterization revealed that leptin receptor expression did not vary over gestation, however, STAT, PI3K and MAPK pathways showed different signaling in response to varied leptin doses. Discussion: These data suggest that the excess placental leptin observed in PE may cause impaired CTB invasion as a second-trimester defect. Leptin's differential effect on trophoblast invasion may explain the role of hyperleptinemia in preeclampsia pathogenesis.

A Comprehensive Study of the Association between LEPR Gene rs1137101 Variant and Risk of Digestive System Cancers.

Objective: The leptin receptor, encoded by the LEPR gene, is involved in tumorigenesis. A potential functional variant of LEPR, rs1137101 (Gln223Arg), has been extensively investigated for its contribution to the risk of digestive system (DS) cancers, but results remain conflicting rather than conclusive. Here, we performed a case-control study and subsequent meta-analysis to examine the association between rs1137101 and DS cancer risk. Methods: A total of 1,727 patients with cancer (gastric/liver/colorectal: 460/480/787) and 800 healthy controls were recruited. Genotyping of rs1137101 was conducted using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay and confirmed using Sanger sequencing. Twenty-four eligible studies were included in the meta-analysis. Results: After Bonferroni correction, the case-control study revealed that rs1137101 was significantly associated with the risk of liver cancer in the Hubei Chinese population. The meta-analysis suggested that rs1137101 is significantly associated with the risk of overall DS, gastric, and liver cancer in the Chinese population. Conclusion: The LEPR rs1137101 variant may be a genetic biomarker for susceptibility to DS cancers (especially liver and gastric cancer) in the Chinese population.

Evidence That Peripheral Leptin Resistance in Omental Adipose Tissue and Liver Correlates with MASLD in Humans.

Leptin regulates lipid metabolism, maximizing insulin sensitivity; however, peripheral leptin resistance is not fully understood, and its contribution to metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. This study evaluated the contribution of the leptin axis to MASLD in humans. Forty-three participants, mostly female (86.04%), who underwent cholecystectomy were biopsied. Of the participants, 24 were healthy controls, 8 had MASLD, and 11 had metabolic dysfunction-associated steatohepatitis (MASH). Clinical and biochemical data and the gene expression of leptin, leptin receptor (LEPR), suppressor of cytokine signaling 3 (SOCS3), sterol regulatory element-binding transcription factor 1 (SREBF1), stearoyl-CoA desaturase-1 (SCD1), and patatin-like phospholipase domain-containing protein 2 (PNPLA2), were determined from liver and adipose tissue. Higher serum leptin and LEPR levels in the omental adipose tissue (OAT) and liver with MASH were found. In the liver, LEPR was positively correlated with leptin expression in adipose tissue, and SOCS3 was correlated with SREBF1-SCD1. In OAT, SOCS3 was correlated with insulin resistance and transaminase enzymes (p < 0.05 for all. In conclusion, we evidenced the correlation between the peripheral leptin resistance axis in OAT-liver crosstalk and the complications of MASLD in humans.

Involvement of ObRb receptor, nitric oxide, and BKCa channel signaling pathways in leptin-induced relaxation of pregnant mouse uterus.

The purpose of this study was to determine the receptor subtype and the underlying mechanisms involved in the relaxant effect to leptin in mid- and late-pregnant mouse uterus. We determined the relative mRNA expression of receptor subtypes, eNOS, and BKCa channel by quantitative PCR and also the overall receptor expression by immunohistochemistry. Isometric tension studies were conducted to evaluate the effects of leptin and to delineate its mechanisms. A selective siRNA for the ObRb receptor was used to determine the participation of the receptor subtype in biochemical and molecular effects of leptin. The relaxant response to leptin was greater in mid-pregnancy compared to late pregnancy and was mediated by the activation of BKCa channels by eNOS-derived nitric oxide in an ObRb receptor-dependent manner. In comparison to mid-pregnancy, expression of short forms (mainly ObRa receptor) of the receptor was significantly increased in late pregnancy, whereas ObRb receptor expression was similar in both phases. The results of the study suggest that ObRb receptor mediates leptin-induced increase in eNOS expression and NO synthesis. Leptin-induced eNOS expression and activation cause cGMP-independent stimulation of BKCa channels causing uterine relaxation. Increased short forms of the receptors and reduced BKCa channels exert a negative effect on uterine relaxation in late pregnancy. Leptin may have a physiological role in maintaining uterine quiescence in mid-pregnancy and its reduced relaxant response in late gestation may facilitate labor. Further, ObRb receptor agonists may be useful in the management of preterm labor.

Multiple genetic polymorphisms are associated with the risk of metabolic syndrome, fatty liver, and airflow limitation: A Taiwan Biobank study.

BACKGROUND: Links have been reported between the airflow limitation and both metabolic syndrome (MetS) and fatty liver (FL). Additionally, associations between genetic factors and risks of MetS, FL, and airflow limitation have been identified separately in different studies. Our study aims to simultaneously explore the association between specific single nucleotide polymorphisms (SNPs) of certain genes and the risk of the three associated diseases. METHODS: In this retrospective cross-sectional nationwide study, 150,709 participants from the Taiwan Biobank (TWB) were enrolled. We conducted a genotype-phenotype association analysis of nine SNPs on seven genes (ApoE-rs429358, MBOAT7-rs641738, LEPR-rs1805096, APOC3-rs2854116, APOC3-rs2854117, PPP1R3B-rs4240624, PPP1R3B-rs4841132, TM6SF2-rs58542926, and IFNL4-rs368234815) using data from the TWB1.0 and TWB2.0 genotype dataset. Participants underwent a series of assessments including questionnaires, blood examinations, abdominal ultrasounds, and spirometry examinations. RESULTS: MetS was associated with FL and airflow limitation. ApoE-rs429358, LEPR-rs1805096, APOC3-rs2854116, APOC3-rs2854117, PPP1R3B-rs4240624, PPP1R3B-rs4841132, and TM6SF2-rs58542926 were significantly associated with the risk of MetS. The cumulative impact of T alleles of ApoE-rs429358 and TM6SF2-rs58542926 on the risk of FL was observed (p-value for trend < 0.001). Individuals without MetS and airflow limitation carrying LEPR-rs1805096 G_G genotype exhibited a reduction in the forced expiratory volume in 1 s percentage prediction (Coefficient -35, 95 % confidence interval (CI) -69.7- -0.4), low forced vital capacity percentage prediction (Coefficient -41.6, 95 % CI -82.6- -0.6), and low vital capacity percentage prediction (Coefficient -42.2, 95 % CI -84.2- -0.1). CONCLUSIONS: MetS significantly correlated with FL and airflow limitation. Multiple SNPs were notably associated with MetS. Specifically, T alleles of ApoE-rs429358 and TM6SF2-rs58542926 cumulatively increased the risk of FL. LEPR-rs1805096 shows a trend-wise association with pulmonary function, which is significant in patients without MetS or airflow limitation.

Prime editing-mediated correction of the leptin receptor in muscle cells of db/db mice.

Genetic diseases can be caused by monogenic diseases, which result from a single gene mutation in the DNA sequence. Many innovative approaches have been developed to cure monogenic genetic diseases, namely by genome editing. A specific type of genomic editing, prime editing, has the potential advantage to edit the human genome without requiring double-strand breaks or donor DNA templates for editing. Additionally, prime editing does not require a precisely positioned protospacer adjacent motif (PAM) sequence, which offers flexible target and more precise genomic editing. Here we detail a novel construction of a prime editing extended guide RNA (pegRNA) to target mutated leptin receptors in B6.BKS(D)-Leprdb/J mice (db/db mice). The pegRNA was then injected into the flexor digitorum brevis (FDB) muscle of db/db mice to demonstrate in vivo efficacy, which resulted in pegRNA mediated base transversion at endogenous base transversion. Genomic DNA sequencing confirmed that prime editing could correct the mutation of leptin receptor gene in db/db mice. Furthermore, prime editing treated skeletal muscle exhibited enhanced leptin receptor signals. Thus, the current study showed in vivo efficacy of prime editing to correct mutant protein and rescue the physiology associated with functional protein.

Impact of the leptin receptor gene on pig performance and quality traits.

The recessive T allele of the missense polymorphism rs709596309 C > T of the leptin receptor gene is associated with intramuscular fat. However, its overall impact on pork production is still partial. In this work, we investigated the all-round effects of the TT genotype on lean growth efficiency and carcass, meat and fat quality using data from an experiment that compared the performance of 48 TT and 48 C- (24 CT and 24 CC) Duroc barrows. The TT pigs were less efficient for lean growth than the C- pigs. Although heavier, their carcasses had less lean content, were shorter and had lighter loins. Apart from increasing marbling and saturated fatty acid content, changes caused by the TT genotype in meat and fat quality are likely not enough to be perceived by consumers. The effect on visual marbling score exceeded that on intramuscular fat content, which suggests a direct influence of the T allele on the pattern of fat distribution in muscle. With current low-protein diets, the T allele is expected to be cost-effective only in niche markets where a very high level of marbling is critical.

GRP94 is an IGF-1R chaperone and regulates beta cell death in diabetes.

High workload-induced cellular stress can cause pancreatic islet ß cell death and dysfunction, or ß cell failure, a hallmark of type 2 diabetes mellitus. Thus, activation of molecular chaperones and other stress-response genes prevents ß cell failure. To this end, we have shown that deletion of the glucose-regulated protein 94 (GRP94) in Pdx1+ pancreatic progenitor cells led to pancreas hypoplasia and reduced ß cell mass during pancreas development in mice. Here, we show that GRP94 was involved in ß cell adaption and compensation (or failure) in islets from leptin receptor-deficient (db/db) mice in an age-dependent manner. GRP94-deficient cells were more susceptible to cell death induced by various diabetogenic stress conditions. We also identified a new client of GRP94, insulin-like growth factor-1 receptor (IGF-1R), a critical factor for ß cell survival and function that may mediate the effect of GRP94 in the pathogenesis of diabetes. This study has identified essential functions of GRP94 in ß cell failure related to diabetes.

Characterization of adaptive expression regulation of yellowtail kingfish (Seriola lalandi) leptin, receptor, and receptor overlapping transcript genes in response to fasting and re-feeding strategies.

Leptins and other related genes have been proven to play vital roles in food intake, weight control, and other life activities. While the function of leptins in yellowtail kingfish (Seriola lalandi) has not yet been explored, in the present study, we investigated the structure and preliminary function of four leptin-related genes in S. lalandi. In detail, the sequence of two leptin genes (lepa and lepb), one leptin receptor gene (lepr), and one leptin receptor overlapping transcript (leprot) gene were obtained by homology cloning and RACE methods, in which lepa and lepb have similar structure. Moreover, homologous sequence alignment and evolutionary analysis of all four genes were clustered with Seriola dumerili. The tissue distribution of these four genes in thirteen tissues of yellowtail kingfish was detected by RT-qPCR. Both lepa and leprot were highly expressed in the brain and ovary, while lepb was highly expressed in the pituitary, gill, muscle, and ovary; lepr was highly expressed in the gill, kidney, and ovary. Additionally, these four genes also played roles in embryo development and early growth and development of larvae and juveniles of yellowtail kingfish. Finally, the function of leptin and leptin-related genes was investigated during fasting and re-feeding adaption of yellowtail kingfish. The results showed that these four genes have different regulation functions in five tissues; for example, the mRNA levels of lepa, lepr, and leprot in the brain decreased during fasting and immediately increased after re-feeding, while the mRNA level of lepb did not show significant fluctuation during starvation but significantly lowered after re-feeding. However, lepa and lepb mRNA levels were significantly elevated during fasting and returned to control levels after re-feeding, and there were no significant changes in the expression of lepr and leprot in the liver during fasting and after re-feeding. Moreover, the body mass of fish in the experimental group was measured, and compensatory growth was found after the resumption of feeding. These results suggested that leptin and receptor genes play different functions in different tissues to regulate the physiological state of fish in food deficiency and gain processes.

LEPR/FOS/JUNB signaling pathway contributes to chronic restraint stress-induced tumor proliferation.

BACKGROUND & AIMS: Psychosocial stress has become an unavoidable part of life, which was reported to promote tumor development. Chronic stress significantly promotes the norepinephrine (NE) secretion and the expression of leptin receptor (LEPR), leading to tumor invasion, metastasis, and proliferation. However, the mechanism of chronic stress-induced tumor proliferation remains unclear. METHODS: To reveal the effect of chronic stress on tumor proliferation, subcutaneous tumor models combined with chronic restraint stress (CRS) were established. Combined with the transcript omics database of liver cancer patients, the target pathways were screened and further verified by in vitro experiments. RESULTS: The results showed that the CRS with subcutaneous tumor transplantation (CRS + tumor) group exhibited significantly larger tumor sizes than the subcutaneous tumor transplantation (tumor) group. Compared with the tumor group, CRS obviously increased the mRNA levels of LEPR, FOS, and JUNB of tumor tissues in the CRS + tumor group. Furthermore, the treatment with norepinephrine (NE) significantly elevated the survival rate of H22 cells and enhanced the expression of LEPR, FOS, and JUNB in vitro. Silencing LEPR significantly reduced the expression of FOS and JUNB, accompanied by a decrease in H22 cell viability. CONCLUSIONS: Our study demonstrated that CRS activates the LEPR-FOS-JUNB signaling pathway by NE, aggravating tumor development. These findings might provide a scientific foundation for investigating the underlying pathological mechanisms of tumors in response to chronic stress.

Maternal high fat diet programs spatial learning and central leptin signaling in mouse offspring in a sex-specific manner.

Environmental factors in early life have been demonstrated to increase the risk of neurodevelopmental disorders in offspring, especially the deficiency of the cognitive ability. Leptin has emerged as a key hormone that conveys information on energy stores, but there is growing appreciation that leptin signaling may also play an important role in neurodevelopment. The present study aimed to investigate whether maternal HFD exposure impairs the offspring learning and memory through the programming of central leptin system. We observed that hippocampus-dependent learning and memory were impaired in male but not female offspring from HFD-fed maternal ancestors (C57BL/6 mice), as assessed by novel object recognition and Morris water maze tests. Moreover, the chromatin immunoprecipitation results revealed the maternal HFD consumption led to the increasement in the binding of the histone marker H3K9me3 in male offspring, which mediates gene silencing in the leptin receptor promoter region. Furthermore, there was an increase in the expression of the histone methylase SUV39H1 in male but not female offspring, which regulates H3K9me3. Additionally, it has been observed that IL-6 and IL-1 also could lead to similar alternations when acting on cultured hippocampal neurons in vitro. Taken together, our data suggest that maternal HFD consumption influences male offspring hippocampal cognitive performance in a sex-specific manner, and central leptin signaling may serve as the cross-talk between maternal diet and cognitive impairment in offspring.

Central inhibition of HDAC6 re-sensitizes leptin signaling during obesity to induce profound weight loss.

Leptin resistance during excess weight gain significantly contributes to the recidivism of obesity to leptin-based pharmacological therapies. The mechanisms underlying the inhibition of leptin receptor (LepR) signaling during obesity are still elusive. Here, we report that histone deacetylase 6 (HDAC6) interacts with LepR, reducing the latter's activity, and that pharmacological inhibition of HDAC6 activity disrupts this interaction and augments leptin signaling. Treatment of diet-induced obese mice with blood-brain barrier (BBB)-permeable HDAC6 inhibitors profoundly reduces food intake and leads to potent weight loss without affecting the muscle mass. Genetic depletion of Hdac6 in Agouti-related protein (AgRP)-expressing neurons or administration with BBB-impermeable HDAC6 inhibitors results in a lack of such anti-obesity effect. Together, these findings represent the first report describing a mechanistically validated and pharmaceutically tractable therapeutic approach to directly increase LepR activity as well as identifying centrally but not peripherally acting HDAC6 inhibitors as potent leptin sensitizers and anti-obesity agents.

Leptin signalling regulates transcriptional differences in granulosa cells from genetically obese mice but not the activation of NLRP3 inflammasome.

Obesity is associated with increased ovarian inflammation and the establishment of leptin resistance. We presently investigated the role of impaired leptin signalling on transcriptional regulation in granulosa cells (GCs) collected from genetically obese mice. Furthermore, we characterised the association between ovarian leptin signalling, the activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and macrophage infiltration in obese mice. After phenotype characterisation, ovaries were collected from distinct group of animals for protein and mRNA expression analysis: (i) mice subjected to a diet-induced obesity (DIO) protocol, where one group was fed a high-fat diet (HFD) and another a standard chow diet (CD) for durations of 4 or 16 weeks; (ii) mice genetically deficient in the long isoform of the leptin receptor (ObRb; db/db); (iii) mice genetically deficient in leptin (ob/ob); and (iv) mice rendered pharmacologically hyperleptinemic (LEPT). Next, GCs from antral follicles isolated from db/db and ob/ob mice were subjected to transcriptome analysis. Transcriptional analysis revealed opposing profiles in genes associated with steroidogenesis and prostaglandin action between the genetic models, despite the similarities in body weight. Furthermore, we observed no changes in the mRNA and protein levels of NLRP3 inflammasome components in the ovaries of db/db mice or in markers of M1 and M2 macrophage infiltration. This contrasted with the downregulation of NLRP3 inflammasome components and M1 markers in ob/ob and 16-wk HFD-fed mice. We concluded that leptin signalling regulates NLRP3 inflammasome activation and the expression of M1 markers in the ovaries of obese mice in an ObRb-dependent and ObRb-independent manner. Furthermore, we found no changes in the expression of leptin signalling and NLRP3 inflammasome genes in GCs from db/db and ob/ob mice, which was associated with no effects on macrophage infiltration genes, despite the dysregulation of genes associated with steroidogenesis in homozygous obese db/db. Our results suggest that: (i) the crosstalk between leptin signalling, NLRP3 inflammasome and macrophage infiltration takes place in ovarian components other than the GC compartment; and (ii) transcriptional changes in GCs from homozygous obese ob/ob mice suggest structural rearrangement and organisation, whereas in db/db mice the impairment in steroidogenesis and secretory activity.