Association of leptin receptor expression in placenta and peripheral blood mononuclear cell with maternal weight in birth outcomes.

INTRODUCTION: The pregnancy period represents the most intense period of growth and development. Pre-pregnancy weight influences weight gain during pregnancy. Leptin is a hormone mainly derived from white adipose tissue, during pregnancy leptin is also produced by the placenta. It has been suggested that the effects of placental leptin on the mother may contribute to endocrine-mediated alterations in energy balance; a dysregulation in leptin levels or its receptors may lead to poor birth outcomes. Therefore, the main goal of the present study was to analyze the differences in birth outcomes by maternal weight with the expression level of leptin receptor in maternal peripheral blood mononuclear cell (PBMC) and placental tissue. METHODS: Women with full-term gestation and its offspring were enrolled. Total RNA from maternal PBMC and placenta was obtained to perform the analysis of expression of the leptin receptor (LEPR) gene trough real-time PCR technique. Data were analyzed using one-way ANOVA or Mann-Whitney u test when applicable. Pearson correlation coefficient was used to determine the relationship between continuous variables (Stata v.13); p ≤ 0.05 was considered statistically significant. RESULTS: No statistically significant differences were found between LEPR expression level and the BMI studied groups in maternal PBMC and placental tissue. Interaction between gestational weight gain (GWG) and LEPR in maternal PBMC explain in a 32% the variability of the newborn weight. CONCLUSIONS: LEPR expression level in maternal PBMC correlates with newborn measurements independent from sex. GWG can affect fetal development by increasing fetal birth weight.

Increased leptin-b expression and metalloprotease expression contributed to the pyridoxine-associated toxicity in zebrafish larvae displaying seizure-like behavior.

Epilepsy is a common neurological disorder affecting people of all ages, races and ethnic backgrounds world-wide. Vitamin B6 supplementation has been widely used as an adjuvant for treating epilepsy. However, the adverse effects, including nausea and peripheral sensory neuropathy, caused by long-term and high-dose consumption of vitamin B6 have undermined the usefulness of vitamin B6 supplementation, justifying additional experimental scrutiny of vitamin B6-associated toxicity. In the current study, we found that the presence of pyridoxine, the inactive form of B6 vitamer included in most nutrient supplements, increased the mortality of the larvae displaying chemical-induced epilepsy. The expression of leptin-b, one zebrafish ortholog of human leptin, was significantly increased in the larvae displaying seizures. Increased leptin-b expression alleviated larval seizure-like behavior when exposed to epilepsy inducer, but also increased larval mortality in the presence of pyridoxine. Meanwhile, elevated adam17 and mmp13 mRNA level were found in the larvae simultaneously exposed to epilepsy-inducer and pyridoxine. Adding TNF-α inhibitor and mmp13 inhibitor effectively improved the survival of larvae injected with leptin-b mRNA and exposed to pyridoxine subsequently. We conclude that increased leptin-b and metalloprotease expression contributed, at least partly, to the pyridoxine-associated toxicity observed in larvae displaying seizures.

A Study on the Immunohistochemical Expressions of Leptin and Leptin Receptor in Clear Cell Renal Cell Carcinoma.

BACKGROUND: The mechanisms that link obesity and cancer development are not well-defined. Investigation of leptin and leptin receptor expressions may help define some of the mechanisms. These proteins are known for associating with the immune response, angiogenesis and, signalling pathways such as JAK2/STAT3, PI3K, and AKT pathways. Tissue proteins can be easily detected with immunohistochemistry (IHC), a technique widely used both in diagnostic and research laboratories. The identification of altered levels of leptin and leptin receptor proteins in tumour tissues may lead to targeted treatment for cancer. OBJECTIVE: The objective of this study was to use IHC to compare leptin and leptin receptor expressions in clear cell renal cell carcinomas (ccRCC) in non-obese and obese patients to determine the association between these proteins with the clinicopathological features and prognosis of ccRCC. Patients and Methods. The study involved 60 patients who underwent nephrectomy of which 34 were obese, as assessed using body mass index (BMI). Nephrectomy samples provided tissues of ccRCC and adjacent non-cancerous kidney. The intensity and localization of leptin and leptin receptor protein expressions were evaluated using IHC and correlated with clinicopathological features and clinical outcomes. Aperio ImageScope morphometry and digital pathology were applied to assess the IHC results. The chi-square test was used to determine if there was any significant association between the proteins and the clinicopathological features. The Kaplan-Meier test was used to determine the overall survival, disease-free survival, and recurrence-free survival. A value of p < 0.05 was considered significant. RESULTS: There was neither significant difference in the overall cellular and nuclear expressions of leptin and leptin receptor between non-cancerous kidney and ccRCC tissues nor in non-obese and obese individuals with ccRCC. CONCLUSION: In this present study, it was revealed that leptin and leptin receptor were not associated with tumour characteristics and progression of ccRCC patients. Interestingly, nuclear expression of leptin was significantly associated with overall survival. However, the significance of these proteins as biomarkers in other RCC histotypes is still unclear.

The energy budget and fat accumulation in striped hamsters (Cricetulus barabensis) during post-lactation.

Adaptive adjustments of energy intake and body fat play an important role in allowing animals' to meet the energy demands of thermoregulation during cold conditions and reproduction. Body fat is usually metabolized during lactation, which is one of the most energetically demanding activities of female mammals, however the effect of this on the energy budget and body fat regulation after lactation remains unclear. We compared the energy intake and body fat of female striped hamsters (Cricetulus barabensis) fed either a high-fat or low-fat diet for 21 days after the end of lactation (post-lactation, PL) to those of virgin controls. Serum leptin levels and the expression of hypothalamic orexigenic and anorexigenic neuropeptide genes were also measured and compared. Although lactating females consumed significantly more food, they had significantly lower body fat than virgin controls. The energy intake and body fat levels of the PL females were, however, significantly higher than those of virgin females. This was particularly true for the PL females that were fed high-fat diet. These females had significantly higher serum leptin concentrations, but lower hypothalamic leptin receptor gene expression, than virgin females. Neither orexigenic nor anorexigenic neuropeptide levels in the hypothalamus differed significantly between the PL and virgin females. This suggests that a negative energy balance during lactation drives fat accumulation after lactation. Furthermore, leptin resistance may occur after the end of lactation, causing females to consume more food, and accumulate more fat, than virgin females.

Leptin receptor-expressing nucleus tractus solitarius neurons suppress food intake independently of GLP1 in mice.

Leptin receptor-expressing (LepRb-expressing) neurons of the nucleus tractus solitarius (NTS; LepRbNTS neurons) receive gut signals that synergize with leptin action to suppress food intake. NTS neurons that express preproglucagon (Ppg) (and that produce the food intake-suppressing PPG cleavage product glucagon-like peptide-1 [GLP1]) represent a subpopulation of mouse LepRbNTS cells. Using Leprcre, Ppgcre, and Ppgfl mouse lines, along with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), we examined roles for Ppg in GLP1NTS and LepRbNTS cells for the control of food intake and energy balance. We found that the cre-dependent ablation of NTS Ppgfl early in development or in adult mice failed to alter energy balance, suggesting the importance of pathways independent of NTS GLP1 for the long-term control of food intake. Consistently, while activating GLP1NTS cells decreased food intake, LepRbNTS cells elicited larger and more durable effects. Furthermore, while the ablation of NTS Ppgfl blunted the ability of GLP1NTS neurons to suppress food intake during activation, it did not impact the suppression of food intake by LepRbNTS cells. While Ppg/GLP1-mediated neurotransmission plays a central role in the modest appetite-suppressing effects of GLP1NTS cells, additional pathways engaged by LepRbNTS cells dominate for the suppression of food intake.

Hydrogen Sulfide Inhibits Formaldehyde-Induced Senescence in HT-22 Cells via Upregulation of Leptin Signaling.

It has been previously demonstrated that hydrogen sulfide (H2S) prevents formaldehyde (FA)-induced neurotoxicity. However, the exact mechanisms underlying this protection remain to be fully elucidated. Neuronal senescence is involved in FA-induced neurotoxicity. Leptin signaling has anti-aging function. The present work was to investigate the protection of H2S against FA-induced neuronal senescence and the mediatory role of leptin signaling. FA-exposed HT-22 cells were used as the vitro model of FA-induced neuronal senescence. The senescence-associated ß-galactosidase (SA-ß-Gal) positive cell was detected by ß-galactosidase staining. The expressions of P16INK4a, P21CIP1, leptin, and lepRb (leptin receptor) were measured by western blot. The proliferation, viability, and apoptosis of cells were evaluated by Trypan blue exclusion assay, Cell Counting Kit-8 (CCK-8) assay, and Flow cytometry analysis, respectively. We found that H2S suppressed FA-induced senescence, as evidenced by the decrease in SA-ß-Gal positive cells, the downregulations of P16INK4a and P21CIP1, as well as decrease in cell growth arrest, in HT-22 cells. Also, H2S upregulated the expressions of leptin and lepRb in FA-exposed HT-22 cells. Furthermore, leptin tA (a specific inhibitor of the leptin) abolished the protective effects of H2S on FA-induced senescence and neurotoxicity (as evidenced by the increase in cell viability and the decrease in cell apoptosis) in HT-22 cells. These results indicated that H2S prevents FA-induced neuronal senescence via upregulation of leptin signaling. Our findings offer a novel insight into the mechanisms underlying the protection of H2S against FA-induced neurotoxicity. FA upregulates the expressions of P16INK4a and P21CIP1 via inhibiting leptin signaling, which in turn induces senescence in HT-22 cells; H2S downregulates the expressions of P16INK4a and P21CIP1 via reversing FA-downregulated leptin signaling, which in turn prevents FA-induced senescence in HT-22 cells.

The Effect of the Leptin and Leptin Receptor Expression on the Efficacy of Neoadjuvant Chemotherapy in Breast Cancer.

BACKGROUND The purpose of the present study was to evaluate the effect of leptin and leptin receptor (LEPR) expression on the efficacy of neoadjuvant chemotherapy in breast cancer. MATERIAL AND METHODS There were 325 breast cancer patients with complete data enrolled in this study. Patients were categorized into 3 groups: pathological complete response group, non-pathological complete response group, and progressive disease group. Immunohistochemistry was performed to determine leptin and its receptor LEPR expression levels that were compared among the 3 groups. RESULTS Compared with the non-pathological complete response group, patients in the pathological complete response group had increased leptin and LEPR expression, although the difference was not statistically significant (P=0.194, P=0.110). In addition, the expression of leptin and LEPR in the pathological complete response group was also higher than that in the progressive disease group, and the difference of LEPR expression was statistically significant (P=0.008) while the leptin expression was not (P=0.065). There were more HER2+ breast cancer patients in the pathological complete response group categorized into strong positive, and positive expression of leptin and LEPR compared with the progressive disease group (P<0.05). There were significant differences of leptin and LEPR expression among breast cancer patients under different molecular subtypes HER2+, HR+, and triple negative, in which the triple negative patients had the highest expression of leptin and LEPR. In addition, patients in the progressive disease group had high and low expression of leptin and LEPR: 13.25% versus 11.32% and 13.1% versus 10.42% respectively. CONCLUSIONS Overexpression of leptin and LEPR improved the therapeutic efficacy of neoadjuvant chemotherapy for patients with breast cancer, especially for those with HER2+ subtype. Overexpression of leptin and LEPR was distinct among the different molecular subtypes of breast cancer, suggesting a certain predictive value for breast cancer prognosis.

Hepatic leptin receptor expression can partially compensate for IL-6Rα deficiency in DEN-induced hepatocellular carcinoma.

OBJECTIVE: The current obesity pandemic represents a major health burden, given that it predisposes to the development of numerous obesity-associated disorders. The obesity-derived adipokines not only impair systemic insulin action but also increase the incidence of hepatocellular carcinoma (HCC), a highly prevalent cancer with poor prognosis. Thus, worldwide incidences of HCC are expected to further increase, and defining the molecular as well as cellular mechanisms will allow for establishing new potential treatment options. The adipose tissue of obese individuals increases circulating leptin and interleukin-6 (IL-6) levels, which both share similar signaling capacities such as Signal Transducer and Activator of Transcription 3 (STAT3) and Phosphoinositide 3-kinase (PI3K)/Akt activation. While mouse models with deficient IL-6 signaling show an ameliorated but not absent Diethylnitrosamine (DEN)-induced HCC development, the morbid obesity in mice with mutant leptin signaling complicates the dissection of hepatic leptin receptor (LEPR) and IL-6 signaling in HCC development. Here we have investigated the function of compensating hepatic LEPR expression in HCC development of IL-6Rα-deficient mice. METHODS: We generated and characterized a mouse model of hepatic LEPR deficiency that was intercrossed with IL-6Rα-deficient mice. Cohorts of single and double knockout mice were subjected to the DEN-HCC model to ascertain liver cancer development and characterize metabolic alterations. RESULTS: We demonstrate that both high-fat diet (HFD)-induced obesity and IL-6Rα deficiency induce hepatic Lepr expression. Consistently, double knockout mice show a further reduction in tumor burden in DEN-induced HCC when compared to control and single LepRL-KO/IL-6Rα knock out mice, whereas metabolism remained largely unaltered between the genotypes. CONCLUSIONS: Our findings reveal a compensatory role for hepatic LEPR in HCC development of IL-6Rα-deficient mice and suggest hepatocyte-specific leptin signaling as promoter of HCC under obese conditions.

Evidence for leptin receptor immunoreactivity in the gastrointestinal tract and gastric leptin regulation in the rainbow trout (Oncorhynchus mykiss).

In this study, evidence for leptin receptor (LR) and gastric leptin immunoreactivity along the digestive tract of the rainbow trout (Oncorhynchus mykiss), is reported. Besides this, the regulation of gastric leptin and its transcript by fatty acids was analyzed in vitro. LR was detected mainly in the cells of the stomach gastric glands and in the brush border of the epithelium of the anterior, middle and distal intestine. In the stomach LR was co-distributed with leptin. The regulation of gastric leptin and its transcript by fatty acids was analyzed by in vitro incubations. Rabbit polyclonal antibodies anti rainbow trout leptin were developed and employed to detect leptin concentration in the stomach and in the incubation medium. Stomach slices were incubated with butyric (4:0), oleic (18:1n-9), α-linolenic (18:3n-3) and arachidonic fatty acids (20:4n-6). All fatty acids caused an increase in the protein in both the stomach and culture medium, while leptin transcript was not modified. Overall, the results confirm the gastric leptin release upon nutritional modulation.

Chronic Intake of Commercial Sweeteners Induces Changes in Feeding Behavior and Signaling Pathways Related to the Control of Appetite in BALB/c Mice.

Nonnutritive sweetener use is a common practice worldwide. Although considered safe for human consumption, accumulating evidence suggests these compounds may affect metabolic homeostasis; however, there is no consensus on the role of frequent sweetener intake in appetite and weight loss. We sought to determine whether frequent intake of commercial sweeteners induces changes in the JAK2/STAT3 signaling pathway in the brain of mice, as it is involved in the regulation of appetite and body composition. We supplemented adult BALB/c mice with sucrose, steviol glycosides (SG), or sucralose, daily, for 6 weeks. After supplementation, we evaluated body composition and expression of total and phosphorylated JAK2, STAT3, and Akt, as well as SOCS3 and ObRb, in brain tissue. Our results show that frequent intake of commercial SG decreases energy intake, adiposity, and weight gain in male animals, while increasing the expression of pJAK2 and pSTAT3 in the brain, whereas sucralose increases weight gain and pJAK2 expression in females. Our results suggest that chronic intake of commercial sweeteners elicits changes in signaling pathways that have been related to the control of appetite and energy balance in vivo, which may have relevant consequences for the nutritional state and long term health of the organism.

The Leptin, Dopamine and Serotonin Receptors in Hypothalamic POMC-Neurons of Normal and Obese Rodents.

The pro-opiomelanocortin (POMC)-expressing neurons of the hypothalamic arcuate nucleus (ARC) are involved in the control of food intake and metabolic processes. It is assumed that, in addition to leptin, the activity of these neurons is regulated by serotonin and dopamine, but only subtype 2C serotonin receptors (5-HT2CR) was identified earlier on the POMC-neurons. The aim of this work was a comparative study of the localization and number of leptin receptors (LepR), types 1 and 2 dopamine receptors (D1R, D2R), 5-HT1BR and 5-HT2CR on the POMC-neurons and the expression of the genes encoding them in the ARC of the normal and diet-induced obese (DIO) rodents and the agouti mice (A y /a) with the melanocortin obesity. As shown by immunohistochemistry (IHC), all the studied receptors were located on the POMC-immunopositive neurons, and their IHC-content was in agreement with the expression of their genes. In DIO rats the number of D1R and D2R in the POMC-neurons and their expression in the ARC were reduced. In DIO mice the number of D1R and D2R did not change, while the number of LepR and 5-HT2CR was increased, although to a small extent. In the POMC-neurons of agouti mice the number of LepR, D2R, 5-HT1BR and 5-HT2CR was increased, and the D1R number was reduced. Thus, our data demonstrates for the first time the localization of different types of the serotonin and dopamine receptors on the POMC-neurons and a specific pattern of the changes of their number and expression in the DIO and melanocortin obesity.

Severe energy deficit upregulates leptin receptors, leptin signaling, and PTP1B in human skeletal muscle.

In obesity, leptin receptors (OBR) and leptin signaling in skeletal muscle are downregulated. To determine whether OBR and leptin signaling are upregulated with a severe energy deficit, 15 overweight men were assessed before the intervention (PRE), after 4 days of caloric restriction (3.2 kcal·kg body wt-1·day-1) in combination with prolonged exercise (CRE; 8 h walking + 45 min single-arm cranking/day) to induce an energy deficit of ~5,500 kcal/day, and following 3 days of control diet (isoenergetic) and reduced exercise (CD). During CRE, the diet consisted solely of whey protein (n = 8) or sucrose (n = 7; 0.8 g·kg body wt-1·day-1). Muscle biopsies were obtained from the exercised and the nonexercised deltoid muscles and from the vastus lateralis. From PRE to CRE, serum glucose, insulin, and leptin were reduced. OBR expression was augmented in all examined muscles associated with increased maximal fat oxidation. Compared with PRE, after CD, phospho-Tyr1141OBR, phospho-Tyr985OBR, JAK2, and phospho-Tyr1007/1008JAK2 protein expression were increased in all muscles, whereas STAT3 and phospho-Tyr705STAT3 were increased only in the arms. The expression of protein tyrosine phosphatase 1B (PTP1B) in skeletal muscle was increased by 18 and 45% after CRE and CD, respectively (P < 0.05). Suppressor of cytokine signaling 3 (SOCS3) tended to increase in the legs and decrease in the arm muscles (ANOVA interaction: P < 0.05). Myosin heavy chain I isoform was associated with OBR protein expression (r = -0.75), phospho-Tyr985OBR (r = 0.88), and phospho-Tyr705STAT3/STAT3 (r = 0.74). In summary, despite increased PTP1B expression, skeletal muscle OBR and signaling are upregulated by a severe energy deficit with greater response in the arm than in the legs likely due to SOCS3 upregulation in the leg muscles.NEW & NOTEWORTHY This study shows that the skeletal muscle leptin receptors and their corresponding signaling cascade are upregulated in response to a severe energy deficit, contributing to increase maximal fat oxidation. The responses are more prominent in the arm muscles than in the legs but partly blunted by whey protein ingestion and high volume of exercise. This occurs despite an increase of protein tyrosine phosphatase 1B protein expression, a known inhibitor of insulin and leptin signaling.

Leptin acts on neoplastic behavior and expression levels of genes related to hypoxia, angiogenesis, and invasiveness in oral squamous cell carcinoma.

Leptin, one of the main hormones controlling energy homeostasis, has been associated with different cancer types. In oral cancer, its effect is not well understood. We investigated, through in vitro and in vivo assays, whether leptin can affect the neoplastic behavior of oral squamous cell carcinoma. Expression of genes possibly linked to the leptin pathway was assessed in leptin-treated oral squamous cell carcinoma cells and also in tissue samples of oral squamous cell carcinoma and oral mucosa, including leptin, leptin receptor, hypoxia-inducible factor 1-alpha, E-cadherin, matrix metalloproteinase-2, matrix metalloproteinase-9, Col1A1, Ki67, and mir-210. Leptin treatment favored higher rates of cell proliferation and migration, and reduced apoptosis. Accordingly, leptin-treated oral squamous cell carcinoma cells show decreased messenger RNA caspase-3 expression, and increased levels of E-cadherin, Col1A1, matrix metalloproteinase-2, matrix metalloproteinase-9, and mir-210. In tissue samples, hypoxia-inducible factor 1-alpha messenger RNA and protein expression of leptin and leptin receptor were high in oral squamous cell carcinoma cases. Serum leptin levels were increased in first clinical stages of the disease. In animal model, oral squamous cell carcinoma-induced mice show higher leptin receptor expression, and serum leptin level was increased in dysplasia group. Our findings suggest that leptin seems to exert an effect on oral squamous cell carcinoma cells behavior and also on molecular markers related to cell proliferation, migration, and tumor angiogenesis.

A dangerous liaison: Leptin and sPLA2-IIA join forces to induce proliferation and migration of astrocytoma cells.

Glioblastoma, the most aggressive type of primary brain tumour, shows worse prognosis linked to diabetes or obesity persistence. These pathologies are chronic inflammatory conditions characterized by altered profiles of inflammatory mediators, including leptin and secreted phospholipase A2-IIA (sPLA2-IIA). Both proteins, in turn, display diverse pro-cancer properties in different cell types, including astrocytes. Herein, to understand the underlying relationship between obesity and brain tumors, we investigated the effect of leptin, alone or in combination with sPLA2-IIA on astrocytoma cell functions. sPLA2-IIA induced up-regulation of leptin receptors in 1321N1 human astrocytoma cells. Leptin, as well as sPLA2-IIA, increased growth and migration in these cells, through activation/phosphorylation of key proteins of survival cascades. Leptin, at concentrations with minimal or no activating effects on astrocytoma cells, enhanced growth and migration promoted by low doses of sPLA2-IIA. sPLA2-IIA alone induced a transient phosphorylation pattern in the Src/ERK/Akt/mTOR/p70S6K/rS6 pathway through EGFR transactivation, and co-addition of leptin resulted in a sustained phosphorylation of these signaling regulators. Mechanistically, EGFR transactivation and tyrosine- and serine/threonine-protein phosphatases revealed a key role in this leptin-sPLA2-IIA cross-talk. This cooperative partnership between both proteins was also found in primary astrocytes. These findings thus indicate that the adipokine leptin, by increasing the susceptibility of cells to inflammatory mediators, could contribute to worsen the prognosis of tumoral and neurodegenerative processes, being a potential mediator of some obesity-related medical complications.

Leptin Function and Regulation.

We summarize the biological impact of leptin signaling as well as the molecular and cellular characteristics of leptin action. Our focus is principally in the central nervous system and we describe the properties of the neuronal networks that are mediators of leptin's effects on ingestive behavior, energy balance, and the reproductive system. The molecular targets of leptin's effects are also responsible for the attenuation and termination of the intracellular signal transduction pathway for leptin, providing a clear understanding of the mechanisms leading to leptin resistance or insensitivity. Using the tools of comparative biology, we explore the potential functions of leptin in fish and birds. Based on the highly variable expression of leptin in multiple tissues, a clear lack of expression of leptin in adipocytes in numerous species of fish and birds and an absence of changes of leptin concentrations in blood that are correlated with changes in nutritional status, it is clear that leptin is unlikely to function as a signal for triglyceride stores in nonmammalian species. This comparative survey serves to highlight the unique function of leptin in mammalian biology as a modulator of energy balance, sexual development, and fertility. © 2018 American Physiological Society. Compr Physiol 8:351-369, 2018.

Glutamatergic Preoptic Area Neurons That Express Leptin Receptors Drive Temperature-Dependent Body Weight Homeostasis.

UNLABELLED: The preoptic area (POA) regulates body temperature, but is not considered a site for body weight control. A subpopulation of POA neurons express leptin receptors (LepRb(POA) neurons) and modulate reproductive function. However, LepRb(POA) neurons project to sympathetic premotor neurons that control brown adipose tissue (BAT) thermogenesis, suggesting an additional role in energy homeostasis and body weight regulation. We determined the role of LepRb(POA) neurons in energy homeostasis using cre-dependent viral vectors to selectively activate these neurons and analyzed functional outcomes in mice. We show that LepRb(POA) neurons mediate homeostatic adaptations to ambient temperature changes, and their pharmacogenetic activation drives robust suppression of energy expenditure and food intake, which lowers body temperature and body weight. Surprisingly, our data show that hypothermia-inducing LepRb(POA) neurons are glutamatergic, while GABAergic POA neurons, originally thought to mediate warm-induced inhibition of sympathetic premotor neurons, have no effect on energy expenditure. Our data suggest a new view into the neurochemical and functional properties of BAT-related POA circuits and highlight their additional role in modulating food intake and body weight. SIGNIFICANCE STATEMENT: Brown adipose tissue (BAT)-induced thermogenesis is a promising therapeutic target to treat obesity and metabolic diseases. The preoptic area (POA) controls body temperature by modulating BAT activity, but its role in body weight homeostasis has not been addressed. LepRb(POA) neurons are BAT-related neurons and we show that they are sufficient to inhibit energy expenditure. We further show that LepRb(POA) neurons modulate food intake and body weight, which is mediated by temperature-dependent homeostatic responses. We further found that LepRb(POA) neurons are stimulatory glutamatergic neurons, contrary to prevalent models, providing a new view on thermoregulatory neural circuits. In summary, our study significantly expands our current understanding of central circuits and mechanisms that modulate energy homeostasis.

Leptin promotes proliferation and metastasis of human gallbladder cancer through OB-Rb leptin receptor.

Emerging evidence has shown that leptin, an adipocyte-derived cytokine that is closely associated with obesity, play a significant role in carcinogenesis and tumorigenesis. However, its impact on gallbladder cancer (GBC) remains unclear. In this study, we firstly found that leptin and its functional receptor OB-Rb were significantly co-expressed in human GBC tissues and cell lines, the content of which were higher than those in normal human gallbladder tissues. Treatment with leptin promoted the proliferation, migration and invasion of GBC cells, which were attenuated by OB-Rb shRNA. Blocking in the G2/M period of cell cycle, increasing of MMP3 and MMP9, increasing of VEGF-C/D, activation of SOCS3/JAK2/p-STAT3 pathway was demonstrated after treatment with leptin. All of these positive responses were attenuated by OB-Rb receptor shRNA. Taken together, our findings suggest that leptin promoted the proliferation, migration and invasion of GBC cells by increasing OB-Rb expression through the SOCS3/JAK2/p-STAT3 signal pathway. Targeting the leptin/OB-Rb axis could be an attractive therapeutic strategy for treatment of GBC.

Combined parental obesity augments single-parent obesity effects on hypothalamus inflammation, leptin signaling (JAK/STAT), hyperphagia, and obesity in the adult mice offspring.

We aimed to evaluate the effects of maternal and/or paternal obesity on offspring body mass, leptin signaling, appetite-regulating neurotransmitters and local inflammatory markers. C57BL/6 mice received standard chow (SC, lean groups) or high-fat diet (HF, obese groups) starting from one month of age. At three months, HF mice became obese relative to SC mice. They were then mated as follows: lean mother and lean father, lean mother and obese father, obese mother and lean father, and obese mother and obese father. The offspring received the SC diet from weaning until three months of age, when they were sacrificed. In the offspring, paternal obesity did not lead to changes in the Janus kinase (JAK)/signal transducer and activation of the transcription (STAT) pathway or feeding behavior but did induce hypothalamic inflammation. On the other hand, maternal obesity resulted in increased weight gain, hyperleptinemia, decreased leptin OBRb receptor expression, JAK/STAT pathway impairment, and increased SOCS3 signaling in the offspring. In addition, maternal obesity elevated inflammatory markers and altered NPY and POMC expression in the hypothalamus. Interestingly, combined parental obesity exacerbated the deleterious outcomes compared to single-parent obesity. In conclusion, while maternal obesity is known to program metabolic changes and obesity in offspring, the current study demonstrated that obese fathers induce hypothalamus inflammation in offspring, which may contribute to the development of metabolic syndromes in adulthood.

Benefits of biphasic calcium phosphate hybrid scaffold-driven osteogenic differentiation of mesenchymal stem cells through upregulated leptin receptor expression.

BACKGROUND: The use of mesenchymal stem cells (MSCs) and coralline hydroxyapatite (HA) or biphasic calcium phosphate (BCP) as a bone substitute for posterolateral spinal fusion has been reported. However, the genes and molecular signals by which MSCs interact with their surrounding environment require further elucidation. METHODS: MSCs were harvested from bone grafting patients and identified by flow cytometry. A composite scaffold was developed using poly(lactide-co-glycolide) (PLGA) copolymer, coralline HA, BCP, and collagen as a carrier matrix for MSCs. The gene expression profiles of MSCs cultured in the scaffolds were measured by microarrays. The alkaline phosphatase (ALP) activity of the MSCs was assessed, and the expression of osteogenic genes and proteins was determined by quantitative polymerase chain reaction (Q-PCR) and Western blotting. Furthermore, we cultured rabbit MSCs in BCP or coralline HA hybrid scaffolds and transplanted these mixtures into rabbits for spinal fusion. We investigated the differences between BCP and coralline HA hybrid scaffolds by dual-energy X-ray absorptiometry (DEXA) and computed tomography (CT). RESULTS: Tested in vitro, the cells were negative for hematopoietic cell markers and positive for MSC markers. There was higher expression of 80 genes and lower of 101 genes of MSCs cultured in BCP hybrid scaffolds. Some of these genes have been shown to play a role in osteogenesis of MSCs. In addition, MSCs cultured in BCP hybrid scaffolds produced more messenger RNA (mRNA) for osteopontin, osteocalcin, Runx2, and leptin receptor (leptin-R) than those cultured in coralline HA hybrid scaffolds. Western blotting showed more Runx2 and leptin-R protein expression in BCP hybrid scaffolds. For in vivo results, 3D reconstructed CT images showed continuous bone bridges and fusion mass incorporated with the transverse processes. Bone mineral content (BMC) values were higher in the BCP hybrid scaffold group than in the coralline HA hybrid scaffold group. CONCLUSIONS: The BCP hybrid scaffold for osteogenesis of MSCs is better than the coralline HA hybrid scaffold by upregulating expression of leptin-R. This was consistent with in vivo data, which indicated that BCP hybrid scaffolds induced more bone formation in a spinal fusion model.

The thymoprotective function of leptin is indirectly mediated via suppression of obesity.

Leptin is an adipokine that regulates metabolism and plays an important role as a neuroendocrine hormone. Leptin mediates these functions via the leptin receptor, and deficiency in either leptin or its receptor leads to obesity in humans and mice. Leptin has far reaching effects on the immune system, as observed in obese mice, which display decreased thymic function and increased inflammatory responses. With expression of the leptin receptor on T cells and supporting thymic epithelium, aberrant signalling through the leptin receptor has been thought to be the direct cause of thymic involution in obese mice. Here, we demonstrate that the absence of leptin receptor on either thymic epithelial cells or T cells does not lead to the loss of thymic function, demonstrating that the thymoprotective effect of leptin is mediated by obesity suppression rather than direct signalling to the cellular components of the thymus.