Search

Others have shown that leptin and cholecystokinin (CCK) act synergistically to suppress food intake. Experiments described here tested whether leptin in the ventromedial hypothalamus (VMH) contributes to the synergy with peripheral CCK in male Sprague Dawley rats. A subthreshold injection of 50-ng leptin into the VMH 1 h before a peripheral injection of 1 µg/kg CCK did not change the response to CCK in rats offered chow or low-fat purified diet, but did exaggerate the reduction in intake of high-fat diet 30 min and 1 h after injection in rats that had been food deprived for 8 h. By contrast, deletion of leptin receptor-expressing cells in the VMH using leptin-conjugated saporin (Lep-Sap) abolished the response to peripheral CCK in chow-fed rats. Lateral ventricle injection of 2-µg leptin combined with peripheral CCK exaggerated the inhibition of chow intake for up to 6 h in control rats treated with Blank-saporin, but not in Lep-Sap rats. Blank-Saporin rats offered low- or high-fat purified diet also demonstrated a dose-response inhibition of intake that reached significance with 1 µg/kg of CCK for both diets. CCK did not inhibit intake of Lep-Sap rats in either low- or high-fat-fed rats. Thus, although basal activation of VMH leptin receptors makes a significant contribution to the synergy with CCK, increased leptin activity in the VMH does not exaggerate the response to CCK in intact rats offered low-fat diets, but does enhance the response in those offered high-fat diet. NEW & NOTEWORTHY Leptin is a feedback signal in the control of energy balance, whereas cholecystokinin (CCK) is a short-term satiety signal that inhibits meal size. The two hormones synergize to promote satiety. We tested whether leptin receptors in the ventromedial nucleus of the hypothalamus (VMH) contribute to the synergy. The results suggest that there is a requirement for a baseline level of activation of leptin receptors in the VMH in order for CCK to promote satiety.

Patients with bipolar disorder (BD) exhibit individual variability in the treatment outcome, and genetic background could contribute to BD itself and the treatment outcome. Leptin levels significantly change in BD patients treated with valproate (VPA), but whether LEPR polymorphisms are associated with treatment response is still unknown. This longitudinal study aimed to investigate the associations between LEPR polymorphisms and VPA treatment response in BD patients who were drug naïve at their first diagnosis of BD. The single-nucleotide polymorphisms (SNPs) of LEPR (rs1137101, rs1137100, rs8179183, and rs12145690) were assayed, and the LEPR polymorphism frequencies of alleles and genotypes were not significantly different between the controls ( n = 77) and BD patients ( n = 130). In addition, after the 12-week course of VPA treatment in BD patients, the LEPR polymorphisms showed significant effects on changes in disease severity. Moreover, considering the effect of the LEPR haplotype, the frequency of the CAGG haplotype in BD patients was higher than that in the controls (9.3 vs. 2.9%, p = 0.016), and the LEPR CAGG haplotype was associated with a better treatment response than the other haplotypes in BD patients receiving VPA treatment. Therefore, LEPR polymorphisms might serve as mediators involved in the therapeutic action of VPA treatment.

Retrotransposon is an important component of the mammalian genome. Previous studies have shown that the expression of protein-coding genes was affected by the insertion of retrotransposon into the proximal genes, and the phenotype variations would be related to the retrotransposon insertion polymorphisms (RIPs). In this study, leptin (LEP), leptin receptor (LEPR), and leptin receptor overlapping transcript (LEPROT), which play important roles in the regulation of fat synthesis and body weight, were screened to search for the RIPs and their effect on phenotype and gene expression, as well as to further study the function of the insertion. The results showed that three RIPs located in intron 1 of LEPROT and intron 2 and 21 of LEPR were identified, and they were all SINEA1, which was one type of retrotransposon. The SINE insertion at the LEPROT was the dominant allele in native pig breeds. The age of 100 kg body weight of SINE+/+ Large White individuals was significantly higher than those of SINE+/− and SINE−/− individuals (p < 0.05). The LEPROT gene expression in the liver and suet of 30-day-old SINE−/− Sujiang piglets were significantly higher than those of SINE+/+ and SINE+/− piglets (p < 0.01). The dual-luciferase reporter gene assay showed that SINE insertion in PK15 and 3T3-L1 cells significantly reduced the promoter activity of the LEPROT gene (p < 0.01). Therefore, SINE insertion can be a repressor to reduce the expression of LEPROT and could be a useful molecular marker for assisted selection of growth traits in pig breeding.

Leptin is required for fertility, including initiation of estrous cycles. It is therefore challenging to assess the role of leptin signaling during pregnancy. Although neuron-specific transgene approaches suggest that leptin signaling in the central nervous system is most important, experiments with pharmacologic inhibition of leptin in the uterus or global replacement of leptin during pregnancy suggest leptin signaling in the reproductive tract may be required. Here, conditional leptin receptor knockout (Lepr cKO) with a progesterone receptor-driven Cre recombinase was used to examine the importance of leptin signaling in pregnancy. Lepr cKO mice have almost no leptin receptor in uterus or cervix, and slightly reduced leptin receptor levels in corpus luteum. Estrous cycles and progesterone concentrations were not affected by Lepr cKO. Numbers of viable embryos did not differ between primiparous control and Lepr cKO dams on Days 6.5 and 17.5 of pregnancy, despite a slight reduction in the ratio of embryos to corpora lutea, showing that uterine leptin receptor signaling is not required for embryo implantation. Placentas of Lepr cKO dams had normal weight and structure. However, over four parities, Lepr cKO mice produced 22% fewer live pups than controls, and took more time from pairing to delivery by their fourth parity. Abnormal birth outcomes of either dystocia or dead pups occurred in 33% of Lepr cKO deliveries but zero control deliveries, and the average time to deliver each pup after crouching was significantly increased. Thus, leptin receptor signaling in the reproductive tract is required for normal labor and delivery., (Published by Oxford University Press on behalf of Society for the Study of Reproduction 2022.)

Leptin exerts its effects on energy balance by inhibiting food intake and increasing energy expenditure via leptin receptors in the hypothalamus. While LepR neurons in the arcuate nucleus of the hypothalamus, the primary target of leptin, have been extensively studied, LepR neurons in other hypothalamic nuclei remain understudied. LepR neurons in the lateral hypothalamus contribute to leptin's effects on food intake and reward, but due to the low abundance of this population it has been difficult to study their molecular profile and responses to energy deficit. We here explore the transcriptome of LepR neurons in the LH and their response to energy deficit. Male LepR-Cre mice were injected in the LH with an AAV carrying Cre-dependent L10:GFP. Few weeks later the hypothalami from fed and food-restricted (24-h) mice were dissected and the TRAP protocol was performed, for the isolation of translating mRNAs from LepR cells in the LH, followed by RNA sequencing. After mapping and normalization, differential expression analysis was performed with DESeq2. We confirm that the isolated mRNA is enriched in LepR transcripts and other known neuropeptide markers of LepR LH neurons, of which we investigate the localization patterns in the LH. We identified novel markers of LepR LH neurons with association to energy balance and metabolic disease, such as Acvr1c, Npy1r, Itgb1, and genes that are differentially regulated by food deprivation, such as Fam46a and Rrad. Our dataset provides a reliable and extensive resource of the molecular makeup of LH LepR neurons and their response to food deprivation., (© 2022. The Author(s).)

Dermal papilla (DP) cells regulate hair follicle epithelial cells and melanocytes by secreting functional factors, playing a key role in hair follicle morphogenesis and hair growth. DP cells can reconstitute new hair follicles and induce hair regeneration, providing a potential therapeutic strategy for treating hair loss. However, current methods for isolating DP cells are either inefficient (physical microdissection) or only applied to genetically labeled mice. We systematically screened for the surface proteins specifically expressed in skin DP using mRNA expression databases. We identified two antibodies against receptors LEPTIN Receptor (LEPR ) and Scavenger Receptor Class A Member 5 (SCARA5) which could specifically label and isolate DP cells by flow cytometry from mice back skin at the growth phase. The sorted LEPR + cells maintained the DP characteristics after culturing in vitro, expressing DP marker alkaline phosphatase and functional factors including RSPO1/2 and EDN3, the three major DP secretory factors that regulate hair follicle epithelial cells and melanocytes. Furthermore, the low-passage LEPR + DP cells could reconstitute hair follicles on nude mice using chamber graft assay when combined with epithelial stem cells. The method of isolating functional DP cells we established here lays a solid foundation for developing DP cell-based therapy., (© 2022 International Society for Advancement of Cytometry.)

Relative leptin resistance in childhood to absolute leptin resistance in maturity suggests sleep, eating behaviour, and the psychological state as probable causes. The current body of research provides inconclusive evidence linking G2548A and Q223R to obesity. Furthermore, we could find very little data that have observed the association between the environment and gene polymorphism, especially in the multiethnic population that exists in Malaysia. This study searched for a possible link between sleeping habits, eating behaviour, and stress indicators with plasma leptin and its genetic variation in young adult Malaysian healthcare students. The study involved 185 first- and second-year medical and dental students from a healthcare university. Polymerase Chain Reaction−Restriction Fragment Length Polymorphism(PCR-RFLP) determined the genotype, Enzyme Linked Immunoabsorbant Assay (ELISA) tested the serum leptin, and a self-administered questionnaire evaluated sleep, eating behaviour, and psychological condition. Gender and ethnicity are linked to fasting plasma leptin levels (p < 0.001). Plasma leptin also affects stress, anxiety, and sadness. Leptin (LEP) and Leptin Receptor (LEPR) polymorphisms were not associated with BMI, plasma leptin, sleep, eating behaviour, or psychological state. Young adult Malaysian Indians were obese and overweight, while Chinese were underweight. These findings imply overweight and obese participants were in stage I of leptin resistance and lifestyle change or leptin therapy could prevent them from becoming cripplingly obese as they age.

Alveolar macrophages (AMs) are critical mediators of pulmonary inflammation. Given the unique lung tissue environment, whether there exist AM-specific mechanisms that control inflammation is not known. Here, we found that among various tissue-resident macrophage populations, AMs specifically expressed Lepr , encoding receptor for a key metabolic hormone leptin. AM-intrinsic Lepr signaling attenuated pulmonary inflammation in vivo, manifested as subdued acute lung injury yet compromised host defense against Streptococcus pneumoniae infection. Lepr signaling protected AMs from necroptosis and thus constrained neutrophil recruitment and tissue damage secondary to release of proinflammatory cytokine interleukin-1α. Mechanistically, Lepr signaling sustained activation of adenosine monophosphate-activated protein kinase in a Ca 2+ influx-dependent manner and rewired cellular metabolism, thus preventing excessive lipid droplet formation and overloaded metabolic stress in a lipid-rich alveolar microenvironment. In conclusion, our results defined AM-expressed Lepr as a metabolic checkpoint of pulmonary inflammation and exemplified a macrophage tissue adaptation strategy for maintenance of immune homeostasis.

Objectives: Non-syndromic monogenic obesity is a rare cause of early-onset severe obesity in the childhood period. The aim of this study was to screen four obesity related genes ( LEP, LEPR, MC4R and POMC ) in children and adolescents who had severe, non-syndromic early onset obesity., Methods: Next-generation sequencing of all exons in LEP, LEPR, MC4R and POMC was performed in 154 children and adolescents with early onset severe obesity obesity., Results: Fifteen different variants in nineteen patients were identified with a variant detection rate of 12.3%. While six different heterozygous variants were observed in MC4R gene (10/154 patients; 6.5%), five different variants in POMC gene (four of them were heterozygous and one of them was homozygous) (6/154 patients; 3.9%) and four different homozygous variants in LEPR gene (3/154 patients; 1.9%) were described. However, no variants were detected in the LEP gene. The most common pathogenic variant was c.496G>A in MC4R gene, which was detected in four unrelated patients. Six novel variants (6/15 variants; 40%) were described in seven patients. Four of them including c.233C>A and c.752T>C in MC4R gene and c.761dup and c.1221dup in LEPR gene were evaluated as pathogenic or likely pathogenic., Conclusions: In conclusion, MC4R variants are the most common genetic cause of monogenic early-onset obesity, consistent with the literature. The c.496G>A variant in MC4R gene is highly prevalent in early-onset obese patients., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

The present study, in addition to molecular characterization of leptin (lepa) and its receptor (lepr) of spotted snakehead Channa punctata, is focussed on physicochemical, structural, evolutionary and selection pressure analyses which are poorly elucidated in teleosts in spite of that existence of these genes is well reported in several fish species. The putative full-length Lep and Lepr of C. punctata showed conserved structural and functional domains, especially the residues responsible for structural integrity and signal transduction. Conversely, residues predicted essential for Lep-Lepr interaction displayed divergence between teleosts and tetrapods. Impact of substitutions/deletions predicted using protein variation effect analyser tool highlighted species specificity in ligand-receptor interaction. Physicochemical properties of ligand and receptor predicted for the first time in vertebrates revealed high aliphatic and instability indices for both Lepa and Lepr, indicating thermostability of proteins but their instability under ex vivo conditions. Positive grand average of hydropathy score of Lepa suggests its hydrophobic nature conjecturing existence of leptin binding proteins in C. punctata. In addition to disulphide bonding, a novel posttranslational modification (S-126 phosphorylation) was predicted in Lepa of C. punctata. In Lepr, disulphide bond formation and N-linked glycosylation near WSXWS motif in ECD, and phosphorylation at tyrosine residues in ICD were predicted. Leptin and its receptor sequence of C. punctata cladded with its homolog from C. striata and C. argus of order Anabantiformes. Leptin system of Anabantiformes was phylogenetically closer to that of Pleuronectiformes, Scombriformes and Perciformes. Selection pressure analysis showed higher incidence of negative selection in teleostean leptin genes indicating limited adaptation in their structure and function. However, evidence of pervasive and episodic diversifying selection laid a foundation of co-evolution of Lepa and Lepr in teleosts., Competing Interests: The authors have declared that no competing interests exist.

The testis expresses peroxisome proliferator-activated receptor-γ (PPAR-γ), but its involvement in regulating diabetes-induced testicular dysfunction and DNA damage repair is not known. Pioglitazone-induced activation of PPAR-γ for 12 weeks in db/db obese diabetic mice increases bodyweights and reduces blood glucose levels, but PPAR-γ inhibition by 2-chloro-5-nitro-N-phenylbenzamide does not alter these parameters; instead, improves testis and epididymis weights and sperm count. Neither activation nor inhibition of PPAR-γ normalizes the diabetes-induced seminiferous epithelial degeneration. The PPAR-γ activation normalizes testicular lipid peroxidation, but its inhibition reduces lipid peroxidation and oxidative DNA damage (8-oxo-dG) in diabetic mice. As a response to diabetes-induced oxidative DNA damage, the base-excision repair (BER) mechanism proteins- 8-oxoguanine DNA glycosylases (OGG1/2) and X-ray repair cross-complementing protein-1 (XRCC1) increase, whereas the redox-factor-1 (REF1), DNA polymerase (pol) δ and poly (ADP-ribose) polymerase-1 (PARP1) show a tendency to increase suggesting an attempt to repair the oxidative DNA damage. The PPAR-γ stimulation inhibits OGG2, DNA pol δ, and XRCC1 in diabetic mice testes, but PPAR-γ inhibition reduces oxidative DNA damage and normalizes BER protein levels. In conclusion, type 2 diabetes negatively affects testicular structure and function and increases oxidative DNA damage and BER protein levels due to increased DNA damage. The PPAR-γ modulation does not significantly affect the structural changes in the testis. The PPAR-γ stimulation aggravates diabetes-induced effects on testis, including oxidative DNA damage and BER proteins, but PPAR-γ inhibition marginally recovers these diabetic effects indicating the involvement of the receptor in the reproductive effects of diabetes., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The mechanisms underlying the association of overall and central body fatness with poorer breast cancer outcomes remain unclear; altered gene and/or protein expression of the adipokines and their receptors in breast tumors might play a role., Methods: In a sample of Black and White women with primary invasive breast cancer, we investigated associations of body mass index (BMI), waist circumference, hip circumference, waist-to-hip ratio (WHR), fat mass index (FMI), and percent body fat with protein expression (log-transformed, n = 722) and gene expression (log2-transformed, n = 148) of leptin (LEP), leptin receptor (LEPR), adiponectin (ADIPOQ), and adiponectin receptors 1 and 2 (ADIPOR1, ADIPOR2). Multivariable linear models, adjusting for race, menopausal status, and estrogen receptor status, were used to assess these associations, with Bonferroni correction for multiple comparisons., Results: In multivariable models, we found that increasing BMI (β = 0.0529, 95% CI: 0.0151, 0.0906) and FMI (β = 0.0832, 95% CI: 0.0268, 0.1397) were associated with higher LEP gene expression, corresponding to 34.5% and 38.3% increases in LEP gene expression for a standard deviation (SD) increase in BMI and FMI, respectively. Increasing BMI (β = 0.0028, 95% CI: 0.0011, 0.0045), waist circumference (β = 0.0013, 95% CI: 0.0005, 0.0022), hip circumference (β = 0.0015, 95% CI: 0.0007, 0.0024), and FMI (β = 0.0041, 95% CI: 0.0015, 0.0067) were associated with higher LEPR protein expression. These associations equate to 16.8%, 17.6%, 17.7%, 17.2% increases in LEPR protein expression for a 1-SD increase in BMI, waist circumference, hip circumference, and FMI, respectively. Further, these associations were stronger among White and postmenopausal women and ER+ cases; formal tests of interaction yielded evidence of effect modification by race. No associations of body fatness with LEP protein expression, LEPR gene expression, or protein or gene expression of ADIPOQ, ADIPOR1, and ADIPOR2 were found., Conclusions: These findings support an association of increased body fatness - beyond overall body size measured using BMI - with higher LEP gene expression and higher LEPR protein expression in breast tumor tissues. Clarifying the impact of adiposity-related adipokine and adipokine receptor expression in breast tumors on long-term breast cancer outcomes is a critical next step., Competing Interests: Author EC is employed by the company Kaiser Permanente Northern California. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Llanos, Aremu, Cheng, Chen, Chekmareva, Cespedes Feliciano, Qin, Lin, Omene, Khoury, Hong, Yao, Ambrosone, Bandera and Demissie.)

Introduction: Leptin is an adipokine hormone that regulates insulin sensitivity and lipid profile, which may contribute to complications like gestational diabetes.The goal of the study was to examine if there was a link between the leptin (LEP)/leptin receptor (LEPR) gene polymorphism and insulin resistance in pregnant women, and to determine the extent to which the leptin gene polymorphism could cause insulin resistance.. Methods: 208 pregnant women participated in this cross-sectional study of which 74 were insulin resistant cases and 134 were insulin sensitive controls. The study was carried out from December 2018 to December 2020 at a charitable hospital in Mangalore, Karnataka, India. Genotyping of leptin and its receptor gene were carried out using the Polymerase Chain Reaction- Restriction fragment Length Polymorphism (PCR-RFLP) method. Serum levels of leptin, insulin, and C peptide were assayed using Enzyme Linked Immuno Sorbent Assay (ELISA) and lipid profile by automated chemistry analyzer. Statistical analysis was carried out using SPSS 23. Results: Insignificant association was observed between leptin receptor gene polymorphisms and insulin resistance, and leptin gene and insulin resistant women. There was no significant difference in the serum leptin levels among the cases and control (61.62±29.23 and 59.88±22.25). However, fasting blood sugar, insulin, C peptide, Triglycerides (TG), and very low-density Lipoprotein (VLDL) levels were significantly higher in cases as compared to controls (p=0.0068, p<0.0001, p<0.0001 and 0.01 respectively). Homeostatic Model Assessment for Insulin Resistance (HOMA IR) was greater in subjects with homozygous dominant, 'GG' of LEPR (p=0.0409) and hyperinsulinemia (p=0.023) as compared to other genotypes. However, hyperglycaemia was observed in subjects with homozygous dominant, 'AA' of leptin gene (p=0.0173). Conclusion: No significant association was found between leptin and leptin receptor gene polymorphisms with insulin resistance in pregnancy. However, genotyping of these genes may be useful in predicting insulin resistance and gestational diabetes in pregnancy., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Adiga U et al.)

Type 2 diabetes is the most prevalent endocrine disease in the world, and recently the gut microbiota have become a potential target for its management. Recent studies have illustrated that this disease may predispose individuals to certain microbiome compositions, and treatments like metformin have been shown to change gut microbiota and their associated metabolic pathways. However, given the limitations and side effects associated with pharmaceuticals currently being used for therapy of diabetes, there is a significant need for alternative treatments. In this study, we investigated the effects of a root extract from Rhodiola rosea in a Leptin receptor knockout (db/db) mouse model of type 2 diabetes. Our previous work showed that Rhodiola rosea had anti-inflammatory and gut microbiome-modulating properties, while extending lifespan in several animal models. In this study, treatment with Rhodiola rosea improved fasting blood glucose levels, altered the response to exogenous insulin, and decreased circulating lipopolysaccharide and hepatic C-reactive protein transcript levels. We hypothesize that these changes may in part reflect the modulation of the microbiota, resulting in improved gut barrier integrity and decreasing the translocation of inflammatory biomolecules into the bloodstream. These findings indicate that Rhodiola rosea is an attractive candidate for further research in the management of type 2 diabetes., (© 2022. The Author(s).)

Introduction: Leptin, along with its receptor, are linked with mechanisms affecting a diverse array of pregnancy-specific pathologies that include gestational diabetes and intrauterine growth restriction. The goal of the study was to examine if there was a link between the leptin (LEP)/leptin receptor (LEPR) gene polymorphism and insulin resistance in pregnant women, and to determine the extent to which the leptin gene polymorphism could cause insulin resistance.. Methods: 208 pregnant women participated in this cross-sectional study of which 74 were insulin resistant cases and 134 were insulin sensitive controls. The study was carried out from December 2018 to December 2020 at a charitable hospital in Mangalore, Karnataka, India. Genotyping of leptin and its receptor gene were carried out using the Polymerase Chain Reaction- Restriction fragment Length Polymorphism (PCR-RFLP) method. Serum levels of leptin, insulin, and C peptide were assayed using Enzyme Linked Immuno Sorbent Assay (ELISA). Statistical analysis was carried out using SPSS 23. Results: Insignificant association was observed between leptin receptor gene polymorphisms and insulin resistance, and leptin gene and insulin resistant women. There was no significant difference in the serum leptin levels among the cases and control (61.62±29.23 and 59.88±22.25). However, fasting blood sugar, insulin, C peptide, Triglycerides (TG), and very low-density Lipoprotein (VLDL) levels were significantly higher in cases as compared to controls (p=0.0068, p<0.0001, p<0.0001 and 0.01 respectively). Homeostatic Model Assessment for Insulin Resistance (HOMA IR) was greater in subjects with homozygous dominant, 'GG' of LEPR (p=0.0409) and hyperinsulinemia (p=0.023) as compared to other genotypes. However, hyperglycaemia was observed in subjects with homozygous dominant, 'AA' of leptin gene (p=0.0173). Conclusion: No significant association was found between leptin and leptin receptor gene polymorphisms with insulin resistance in pregnancy. However, genotyping of these genes may be useful in predicting insulin resistance and gestational diabetes in pregnancy., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Adiga U et al.)

Leptin resistance is a hallmark of obesity. Treatments aiming to improve leptin sensitivity are considered a promising therapeutical approach against obesity. However, leptin receptor (LepR) signaling also modulates several neurovegetative aspects, such as the cardiovascular system and hepatic gluconeogenesis. Thus, we investigated the long-term consequences of increased leptin sensitivity, considering the potential beneficial and deleterious effects. To generate a mouse model with increased leptin sensitivity, the suppressor of cytokine signaling 3 (SOCS3) was ablated in LepR-expressing cells (LepR ∆SOCS3 mice). LepR ∆SOCS3 mice displayed reduced food intake, body adiposity and weight gain, as well as improved glucose tolerance and insulin sensitivity, and were protected against aging-induced leptin resistance. Surprisingly, a very high mortality rate was observed in aging LepR ∆SOCS3 mice. LepR ∆SOCS3 mice showed cardiomyocyte hypertrophy, increased myocardial fibrosis and reduced cardiovascular capacity. LepR ∆SOCS3 mice exhibited impaired post-ischemic cardiac functional recovery and middle-aged LepR ∆SOCS3 mice showed substantial arhythmic events during the post-ischemic reperfusion period. Finally, LepR ∆SOCS3 mice exhibited fasting-induced hypoglycemia and impaired counterregulatory response to glucopenia associated with reduced gluconeogenesis. In conclusion, although increased sensitivity to leptin improved the energy and glucose homeostasis of aging LepR ∆SOCS3 mice, major autonomic/neurovegetative dysfunctions compromised the health and longevity of these animals. Consequently, these potentially negative aspects need to be considered in the therapies that increase leptin sensitivity chronically.

Introduction: Body fat distribution is known to contribute to a variety of pathologies. Research Questions: We aimed to assess whether this distribution is associated with clinical outcomes in renal transplant recipients (RTR) and to examine its relationship with leptin and adiponectin gene variants and plasma concentrations. Design: Bioelectrical impedance analyses were performed in 236 RTR. Leptin/adiponectin levels were measured by immunoassay and relevant polymorphisms in the leptin receptor (LEPR) and adiponectin (ADIPOQ) genes were identified. Associations were assessed by logistic regression modeling. Results: The waist-to-height ratio (WHr) displayed a significant association with delayed graft function, acute rejection and post-transplant diabetes mellitus, with OR values of 2.04 (1.02-4.08) p = 0.045; 3.08 (1.22-7.79) p = 0.017 and 2.79 (1.16-6.74) p = 0.022, respectively. Waist circumference was linked to delayed graft function [OR = 1.03 (1.01-1.05), p = 0.025] and AR [OR = 1.041 (1.01-1.07), p = 0.009]. Leptin levels were significantly higher in patients who experienced rejection [19.91 ± 23.72 versus 11.22 ± 16.42 ng/ml; OR = 1.021 (1.01-1.04), p = 0.017]. The ADIPOQ rs1501299TT genotype showed a significant association with higher WHr (0.63 ± 0.11 vs 0.59 ± 0.87 for GG/GT genotypes; p = 0.015) and WC values (102.3 ± 14.12 vs 96.38 ± 14.65 for GG/GT genotypes; p = 0.021). Conclusion: WC, and especially WHr, are associated with adverse outcomes in renal transplantation and are affected by variability in the ADIPOQ gene.

Factors associated with high milk production levels have been linked to alterations in the endometrial epidermal growth factor (EGF) profile, a cause of reduced fertility in dairy cows. Therefore, we examined the leptin system that connects nutritional status and reproduction in dairy cattle related to reduced fertility in repeat breeder cows. Plasma leptin concentrations were measured in 18 heifers, 20 high-yielding control cows, and 26 repeat breeder cows, showing an altered EGF profile. Then, all repeat breeder cows were infused with seminal plasma (SP) into the vagina at the next estrus to normalize the EGF profile, while heifers and control cows were infused with vehicle alone. All animals were examined for EGF profiles. Eighteen repeat breeder cows, nine heifers, and nine control cows were also determined for leptin receptor (Ob-R) expression levels in the estrous cycle before and after the infusion. SP normalized the EGF profile in 53.8% of the repeat breeder cows. Leptin concentrations were similar in all groups, regardless of the treatment results for the EGF profile. In contrast, Ob-R levels in repeat breeder and control cows were similar and higher than those in heifers before SP treatment. Ob-R in repeat breeders showing a normal EGF profile after treatment decreased to an intermediate level between heifers and control cows and may provide a clue to take measures against repeat breeding in dairy cows.

Appetite regulation has been recognized as a promising target for the prevention of obesity, which has become a worldwide health issue. Polymorphisms in the genes of hormones or receptors including Leu72Met for ghrelin and Gln223Arg for the leptin receptor could play a role in dietary intake, hunger, and satiety process. The aim of this study was to analyze subjective appetite assessments, dietary intake, and appetite hormones in relationship to these polymorphisms. Subjects ( n = 132) with normal BMIs were enrolled. Dietary intake was analyzed with 3-day diet records. Subjective appetite was measured by visual analogue scales. Biochemical parameters were measured after 12 h of fasting and 120' following ingestion of a test meal. Ghrelin and leptin levels were measured by ELISA assay (enzyme-linked immunosorbent assay) and insulin by chemiluminescence assay. The polymorphisms were determined by allelic discrimination using TaqMan ® probes. Fasting ghrelin levels differed significantly between men and women. The consumption of fruit and bread/starch with added sugar servings, as indicated by dietary records, and measured ghrelin levels were higher in carriers of Leu72Met/Met72Met compared to Leu72Leu carriers; total sugar intake was higher in Gln223Gln carriers than in Gln223Arg/Arg223Arg carriers. In conclusion, the Leu72Met and Gln223Arg polymorphism in ghrelin and LEPR may contribute to differential responses to a standardized meal as evidenced by higher postprandial levels of ghrelin and may also contribute to a higher dietary sugar intake.

Leptin is a peptide hormone secreted from the adipose tissues and its signaling plays a central role in metabolic regulation of growth, especially on fat mass. In addition, leptin is also involved in regulating reproduction in mammals. In teleosts, there are two leptin ligands (lepa and lepb) and one cognate leptin receptor (lepr); however, their functions are still elusive. In this study, we created null-function mutants for lepa, lepb and lepr in zebrafish using CRISPR/Cas9 method and analyzed their phenotypes with emphasis on puberty onset, one major function widely reported for leptin in mammals. We demonstrated that the loss of leptin ligands or their receptor resulted in no obesity from prepubertal stage to adulthood. We then focused on leptin involvement in controlling puberty onset. We first confirmed the somatic threshold for puberty onset in females and proposed a criterion and somatic threshold for male puberty onset. We examined gonadal development and sex maturation in different genotypic combinations including single mutants (lepa-/-, lepb-/- and lepr-/-), double mutants (lepa-/-;lepb-/-) and triple mutants (lepa-/-;lepb-/-;lepr-/-). Our results showed that once the fish reached the thresholds, the siblings of all genotypes displayed comparable gonadal development in both sexes without obvious signs of changed puberty onset. In conclusion, this comprehensive genetic study on the lep-lepr system demonstrated that in contrast to its counterpart in mammals, leptin system plays little role in controlling growth and reproduction especially puberty onset in zebrafish., (© The Author(s) 2022. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Obesity is a complex multifactorial abnormality that has a well-confirmed genetic basis. However, the problem still lies in identifying the polymorphisms linked to body mass and composition. Therefore, this study aimed to analyze associations between FTO (rs9939609), FABP2 (rs1799883), and LEP (rs2167270), LEPR (rs1137101), and MC4R (rs17782313) polymorphisms and obesity-related parameters. Unrelated Caucasian males (n = 165) were recruited. All participants had similar physical activity levels. The participants were divided into two groups depending on their body mass index (BMI) and fat mass index (FMI). All samples were genotyped using real-time polymerase chain reaction (real-time PCR). When tested individually, only one statistically significant result was found. The FTO A/T polymorphism was significantly associated with FMI (p = 0.01). The chance of having increased FMI was >2-fold higher for the FTO A allele carriers (p < 0.01). Gene−gene interaction analyses showed the additional influence of all investigated genes on BMI and FMI. In summary, it was demonstrated that harboring the FTO A allele might be a risk factor for elevated fat mass. Additionally, this study confirmed that all five polymorphisms are involved in the development of common obesity in the studied population and the genetic risk of obesity is linked to the accumulation of numerous variants.

Leptin is a small peptide mainly secreted by adipocyte, which acts on the central nervous system of the hypothalamus to regulate the body's energy balance by inhibiting food intake, it also can directly act on specific cells through leptin receptors (for example, ObRa, which exists in the blood-brain barrier or kidneys), thereby affect cell metabolism. Excessive deposition of extracellular matrix (ECM) causes damage to normal tissues or destruction of organ structure, which will eventually lead to tissue or organ fibrosis. The sustainable development of fibrosis can lead to structural damage and functional decline of organs, and even exhaustion, which seriously threatens human health and life. In recent years, studies have found that leptin directly alleviates the fibrosis process of various tissues and organs in mammals. Therefore, we speculate that leptin may become a significant treatment for fibrosis of various tissues and organs in the future. So, the main purpose of this review is to explore the specific mechanism of leptin in the process of fibrosis in multiple tissues and organs, and to provide a theoretical basis for the treatment of various tissues and organs fibrosis and related diseases caused by it, which is of great significance in the future., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Monogenic obesity is a severe, genetically determined disorder that affects up to 1/1000 newborns. Recent reports on potential new therapeutics and innovative clinical approaches have highlighted the need for early identification of individuals with rare genetic variants that can alter the functioning of the leptin-melanocortin signalling pathway, in order to speed up clinical intervention and reduce the risk of chronic complications. Therefore, next-generation DNA sequencing of central genes in the leptin-melanocortin pathway was performed in 1508 children and adolescents with and without obesity, aged 2-19 years. The recruited cohort comprised approximately 5% of the national paediatric population with obesity. The model-estimated effect size of rare variants in the leptin-melanocortin signalling pathway on longitudinal weight gain between carriers and non-carriers was derived. In total, 21 (1.4%) participants had known disease-causing heterozygous variants (DCVs) in the genes under investigation, and 62 (4.1%) participants were carriers of rare variants of unknown clinical significance (VUS). The estimated frequency of potential genetic variants associated with obesity (including rare VUS) ranged between 1/150 (VUS and DCV) and 1/850 (DCV) and differed significantly between participants with and without obesity. On average, the variants identified would result in approximately 7.6 kg (7.0-12.9 kg at the 95th percentile of body weight) (girls) and 8.4 kg (8.2-14.4 kg) (boys) of additional weight gain in carriers at age 18 years compared with subjects without obesity. In conclusion, children with a genetic predisposition to obesity can be promptly identified and may account for more than 6% of obesity cases. Early identification of genetic variants in the LEPR , PCSK1 , POMC , MC3R and MC4R genes could reduce the societal burden and improve the clinical management of early severe childhood obesity and its implementation should be further investigated., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Šket, Kotnik, Bizjan, Kocen, Mlinarič, Tesovnik, Debeljak, Battelino and Kovač.)

Objectives: Leptin resistance is one of the important causes of obesity in children. Besides known causes of leptin resistance like mutations in leptin and leptin receptor genes, overexpression of SOCS3 in arcuate nucleus is a potential cause of leptin resistance. We aimed to determine the effects of circulating miRNAs on leptin resistance in obese children by targeting SOCS3 pathway., Methods: miRNAs potentially targeting SOCS3 were determined by using online target prediction databases. Polymorphisms in miRNA target sequences were determined by using online genome browsers. miRNA expression levels of obese (n=35) and non-obese (n=30) children were determined by qPCR method, genotyping were performed by real-time PCR method and serum leptin, leptin receptor and SOCS3 levels were measured by ELISA method., Results: miRNA profiling have shown that serum miR-218-5p levels are significantly (p<0.05) increased in accordance with serum leptin levels in obese children., Conclusions: In this study we used target prediction methods for evaluating potential miRNAs which may involve in development of leptin resistance. We have shown that miR-218-5p might be taking part in leptin resistance in obese children., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Reproduction is an energetically costly event across vertebrates and tightly linked to nutritional status and energy reserves. In mammals, the hormone leptin is considered as a link between energy homeostasis and reproduction. However, its role in fish reproduction is still unclear. In this study, we investigated the possible role of leptin in the regulation of reproduction in zebrafish, using a loss of function leptin receptor (lepr) strain. Impaired leptin signaling resulted in severe reproductive deficiencies in female zebrafish. lepr mutant females laid significantly fewer eggs, with low fertilization rates compared to wild-type females. Folliculogenesis was not affected, but oocyte maturation and ovulation were disrupted in lepr mutants. Interestingly, the expression of luteinizing hormone beta (lhb) in the pituitary was significantly lower in mutant females. Analysis of candidate genes in the ovaries and isolated fully grown follicles revealed differential expression of genes involved in steroidogenesis, oocyte maturation and ovulation in the mutants, which are known to be regulated by LH signaling. Moreover, subfertility in lepr mutants could be partially restored by administration of human chorionic gonadotropin. In conclusion, our results show that leptin deficiency does not affect early stages of follicular development, but leptin might be essential in later steps, such as in oocyte maturation and ovulation. To our knowledge, this is the first time that leptin is associated to reproductive deficiencies in zebrafish., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Recent advances in genetic analysis have significantly helped in progressively attenuating the heritability gap of obesity and have brought into focus monogenic variants that disrupt the melanocortin signaling. In a previous study, next-generation sequencing revealed a monogenic etiology in ∼50% of the children with severe obesity from a consanguineous population in Pakistan. Here we assess rare variants in obesity-causing genes in young adults with severe obesity from the same region. Genomic DNA from 126 randomly selected young adult obese subjects (BMI 37.2 ± 0.3 kg/m2; age 18.4 ± 0.3 years) was screened by conventional or augmented whole-exome analysis for point mutations and copy number variants (CNVs). Leptin, insulin, and cortisol levels were measured by ELISA. We identified 13 subjects carrying 13 different pathogenic or likely pathogenic variants in LEPR, PCSK1, MC4R, NTRK2, POMC, SH2B1, and SIM1. We also identified for the first time in the human, two homozygous stop-gain mutations in ASNSD1 and IFI16 genes. Inactivation of these genes in mouse models has been shown to result in obesity. Additionally, we describe nine homozygous mutations (seven missense, one stop-gain, and one stop-loss) and four copy-loss CNVs in genes or genomic regions previously linked to obesity-associated traits by genome-wide association studies. Unexpectedly, in contrast to obese children, pathogenic mutations in LEP and LEPR were either absent or rare in this cohort of young adults. High morbidity and mortality risks and social disadvantage of children with LEP or LEPR deficiency may in part explain this difference between the two cohorts., (© 2022 by the American Diabetes Association.)

Background: The aim of our study was to investigate the association of leptin (LEP) gene (rs11761556, rs12706832, rs2167270), leptin receptor (LEPR) gene (rs1137100, rs1137101, rs1805096) variants and pulmonary tuberculosis (PTB) susceptibility, as well as their several clinical manifestations, in a Chinese population., Methods: This study included a cohort of 489 PTB patients and 489 healthy controls, and six SNPs were genotyped by improved multiple ligase detection reaction (iMLDR)., Results: We found that there were no significant differences regarding the allele and genotype frequencies of LEP rs11761556, rs12706832, rs2167270, LEPR rs1137100, rs1137101, rs1805096 between PTB patients and healthy controls (all P > 0.05), as well as the results of the dominant model and recessive model (all P > 0.05). In the LEP gene, the rs11761556 AA genotype frequency was significantly associated with the development of fever and pulmonary infection in PTB patients (P = 0.035, P = 0.049). In addition, the relation between main haplotypes and PTB patients was also analyzed, but only haplotype CAG in LEP was significantly associated with PTB susceptibility (P = 0.012)., Conclusions: LEP and LEPR heritable variation were not contribute to the pathogenesis of PTB in Chinese. While rs11761556 variant might associate with several clinical features of PTB., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Leptin is a pleiotropic hormone known for regulating appetite and metabolism. To characterize the role of leptin signaling in rainbow trout, we used CRISPR/Cas9 genome editing to disrupt the leptin receptor (LepR) genes, lepra1 and lepra2 . We compared wildtype (WT) and mutant fish that were either fed to satiation or feed deprived for six weeks. The LepR mutants exhibited a hyperphagic phenotype, which led to heavier body weight, faster specific growth rate, increased viscero- and hepatosomatic indices, and greater condition factor. Muscle glycogen, plasma leptin, and leptin transcripts ( lepa1 ) were also elevated in fed LepR mutant fish. Expression levels of several hypothalamic genes involved in feed regulation were analyzed ( agrp , npy , orexin , cart-1 , cart-2 , pomc-a1 , pomc-b ). No differences were detected between fed WT and mutants except for pomc-b (proopiomelanocortin-b), where levels were 7.5-fold higher in LepR fed mutants, suggesting that pomc-b expression is regulated by leptin signaling. Fatty acid (FA) content did not statistically differ in muscle of fed mutant fish compared to WT. However, fasted mutants exhibited significantly lower muscle FA concentrations, suggesting that LepR mutants exhibit increased FA mobilization during fasting. These data demonstrate a key role for leptin signaling in lipid and energy mobilization in a teleost fish.

Leptin is best known for its role in adipostasis, but it also regulates blood glucose levels. The molecular mechanism by which leptin controls glucose homeostasis remains largely unknown. Here, we use a zebrafish model to show that Wnt signaling mediates the glucoregulatory effects of leptin. Under normal feeding conditions, leptin regulates glucose homeostasis but not adipostasis in zebrafish. In times of nutrient excess, however, we found that leptin also regulates body weight and size. Using a Wnt signaling reporter fish, we show that leptin activates the canonical Wnt pathway in vivo. Utilizing two paradigms for hyperglycemia, it is revealed that leptin regulates glucose homeostasis via the Wnt pathway, as pharmacological inhibition of this pathway impairs the glucoregulatory actions of leptin. Our results may shed new light on the evolution of the physiological function of leptin., (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Background & Aims: Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis., Methods: To elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate-mapping mouse lines with 5-bromodeoxyuridine dosing. RNA sequencing of fluorescence-activated cell sorting-purified CRC CAFs was performed to identify a potential therapeutic target in CAFs. To examine the prognostic significance of the stromal target, CRC patient RNA sequencing data and tissue microarray were used. CRC organoids were injected into the colons of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis., Results: Our lineage-tracing studies revealed that in CRC, many ACTA2 + CAFs emerge through proliferation from intestinal pericryptal leptin receptor (Lepr) + cells. These Lepr-lineage CAFs, in turn, express melanoma cell adhesion molecule (MCAM), a CRC stroma-specific marker that we identified with the use of RNA sequencing. High MCAM expression induced by transforming growth factor β was inversely associated with patient survival in human CRC. In mice, stromal Mcam knockout attenuated orthotopically injected colorectal tumoroid growth and improved survival through decreased tumor-associated macrophage recruitment. Mechanistically, fibroblast MCAM interacted with interleukin-1 receptor 1 to augment nuclear factor κB-IL34/CCL8 signaling that promotes macrophage chemotaxis., Conclusions: In colorectal carcinogenesis, pericryptal Lepr-lineage cells proliferate to generate MCAM + CAFs that shape the tumor-promoting immune microenvironment. Preventing the expansion/differentiation of Lepr-lineage CAFs or inhibiting MCAM activity could be effective therapeutic approaches for CRC., (Copyright © 2022 AGA Institute. All rights reserved.)

Leptin receptor-positive skeletal progenitors constitute an essential cell population in the bone, yet their heterogeneity remains incompletely understood. In this issue, Mo et al (2021) report a single-cell RNA sequencing resource that deconvolutes the pool of LEPR + skeletal cells under homeostatic and various pathologic conditions, uncovering context-dependent contributions to diverse cell types and functions., (© 2022 The Authors.)

Proinflammatory cytokines play a causal role in the development of hyperinsulinemia and T2MD. FOXO1, a transcription factor which is known to enhance proinflammation, was recently shown to be involved in obesity-induced β cell dysfunction. However, molecular mechanisms for the association remained elusive. In this study, we first found that both leptin (10 nM) and TNF- α (20 ng/ml) significantly inhibited glucose-stimulated insulin secretion (GSIS) of INS-1E cells. When in combination, the GSIS function of INS-1E cells was significantly increased compared with that of the leptin alone treatment, indicating that TNF- α attenuated the inhibiting effect of leptin on GSIS of INS-1E cells. Similarly, we found that TNF- α has the same inhibitory effect on leptin in regulating insulin synthesis and secretion, and the survival and apoptosis of insulin cells. Further studies showed that TNF- α blocks leptin pathway by reducing the expression of leptin receptor (LepRb, also called OBRb) and inhibiting the activation of STAT3, a key molecule involved in the leptin signaling pathway in INS-1E cells. Besides, the downregulated expression of phosphorylated FOXO1 was found to be involved in the possible mechanism of TNF- α . Overexpression of constitutively active FOXO1 markedly aggravated the LepRb reduction by TNF- α treatment of INS-1E cells, and the endogenous FOXO1 knockdown abolished the effect of TNF- α on INS-1E cells. Furthermore, we have proved that FOXO1 could directly bind to the promoter of LepRb as a negative transcription regulator. Taken together, the results of this study reveal that TNF- α -induced LepRb downregulated in pancreatic β cells and demonstrate that transcriptional reduction of FOXO1 might be the primary mechanism underlying TNF- α promoting INS-1E leptin resistance and β cell dysfunction. Conclusions . Our current studies based on INS-1E cells in vitro indicate that the inflammatory factor TNF- α plays an important role in the development of INS-1E leptin resistance and glucose metabolism disorders, probably through FOXO1-induced transcription reduction of LepRb promoter in pancreatic β cells, and FOXO1 may be a novel target for treating β cell dysfunction in obesity-induced hyperinsulinemia and T2DM., Competing Interests: The authors declare no competing interests., (Copyright © 2022 Yang Zhang et al.)

Due to the self-renewal characteristics and tumorigenic abilities of cancer stem cells (CSCs), CSCs have been demonstrated to play vital roles in carcinogenesis and antitumor therapy. Our previous report found that Krüppel-like family members (KLFs) and zinc finger protein 32 (ZNF32) play oncogenic roles in carcinogenesis. However, the roles and mechanism of ZNF32 in CSCs are still unknown. Our study demonstrated that ZNF32 was highly expressed in colorectal CSCs, which promoted their self-renewal capacity and tumorigenicity. Overexpression of ZNF32 in colorectal cancer (CRC) cells increased their self-renewal capacity. Furthermore, we identified the leptin receptor (LEPR) as the downstream target gene of ZNF32 and verified that the ZNF32-mediated regulation of CRC self-renewal is achieved via the LEPR- signal transducer and activator of transcription 3 (STAT3) pathway. Moreover, ZNF32 regulated the expression of SOX2, a core transcription factor in stem cells. Finally, we demonstrated that ZNF32 and LEPR were positively correlated in CRC tissues. ZNF32 expression was negatively correlated with the prognosis of CRC patients. Therefore, therapeutically targeting the ZNF32-LEPR-STAT3 pathway in the clinic is tempting., (© 2022. The Author(s).)

The aim of this cross-sectional observational study is to determine the contribution of polymorphisms of energy metabolism genes into metabolic disorders in Russian and Buryat adolescents with overweight and obesity. The study included 354 Russian and Buryat adolescents aged 13-18 years. Body mass index and serum levels of glucose, insulin, and leptin were measured and insulin resistance index HOMA-IR was calculated. Molecular genetic analysis for the presence of 9 loci of energy metabolism genes LEP, LEPR, POMC, FTO, and MC4R were analyzed. It was found that the risk of metabolic disorders is associated with the presence of polymorphic loci of leptin receptor gene LEPR and melanocortin receptor gene MC4R (LEPR rs1137100+LEPR rs1137101 and LEPR rs1137100+MC4R rs17782313) in Russian adolescents with overweight and obesity and polymorphisms of the gene FTO (FTO rs9939609+rs8050136) associated with fat mass and obesity in Buryat adolescents., (© 2022. Springer Science+Business Media, LLC, part of Springer Nature.)

The leptin receptor (LepR) acts as a signaling nexus for the regulation of glucose uptake and obesity, among other metabolic responses. The functional role of LepR under leptin-deficient conditions remains unclear. This study reports that epiregulin (EREG) governed glucose uptake in vitro and in vivo in Lep ob mice by activating LepR under leptin-deficient conditions. Single and long-term treatment with EREG effectively rescued glucose intolerance in comparative insulin and EREG tolerance tests in Lep ob mice. The immunoprecipitation study revealed binding between EREG and LepR in adipose tissue of Lep ob mice. EREG/LepR regulated glucose uptake without changes in obesity in Lep ob mice via mechanisms, including ERK activation and translocation of GLUT4 to the cell surface. EREG-dependent glucose uptake was abolished in Lepr db mice which supports a key role of LepR in this process. In contrast, inhibition of the canonical epidermal growth factor receptor (EGFR) pathway implicated in other EREG responses, increased glucose uptake. Our data provide a basis for understanding glycemic responses of EREG that are dependent on LepR unlike functions mediated by EGFR, including leptin secretion, thermogenesis, pain, growth, and other responses. The computational analysis identified a conserved amino acid sequence, supporting an evolutionary role of EREG as an alternative LepR ligand.

Adiponectin and insulin resistance creates a vicious cycle that exacerbates type 2 diabetes. Earlier, we observed that female leptin receptor-deficient BLKS mice (BKS-db/db) were more sensitive to an adiponectin mimetic GTDF than males, which led us to explore if E2 plays a crucial role in modulation of adiponectin-sensitivity. Male but not female BKS-db/db mice were resistant to metabolic effects of globular adiponectin treatment. Male BKS-db/db displayed reduced skeletal muscle AdipoR1 protein expression, which was consequent to elevated polypyrimidine tract binding protein 1 (PTB) and miR-221. E2 treatment in male BKS-db/db, and ovariectomized BALB/c mice rescued AdipoR1 protein expression via downregulation of PTB and miR-221, and also directly increased AdipoR1 mRNA by its classical nuclear receptors. Estrogen receptor regulation via dietary or pharmacological interventions may improve adiponectin resistance and consequently ameliorate insulin resistance in type 2 diabetes., (Copyright © 2021. Published by Elsevier B.V.)

Background: Obesity and type 2 diabetes are two interrelated metabolic disorders characterized by insulin resistance and a mild chronic inflammatory state. We previously observed that leptin (ob/ob) and leptin receptor (db/db) knockout mice display a distinct inflammatory tone in the liver and adipose tissue. The present study aimed at investigating whether alterations in these tissues of the molecules belonging to the endocannabinoidome (eCBome), an extension of the endocannabinoid (eCB) signaling system, whose functions are important in the context of metabolic disorders and inflammation, could reflect their different inflammatory phenotypes., Results: The basal eCBome lipid and gene expression profiles, measured by targeted lipidomics and qPCR transcriptomics, respectively, in the liver and subcutaneous or visceral adipose tissues, highlighted a differentially altered eCBome tone, which may explain the impaired hepatic function and more pronounced liver inflammation remarked in the ob/ob mice, as well as the more pronounced inflammatory state observed in the subcutaneous adipose tissue of db/db mice. In particular, the levels of linoleic acid-derived endocannabinoid-like molecules, of one of their 12-lipoxygenase metabolites and of Trpv2 expression, were always altered in tissues exhibiting the highest inflammation. Correlation studies suggested the possible interactions with some gut microbiota bacterial taxa, whose respective absolute abundances were significantly different between ob/ob and the db/db mice., Conclusions: The present findings emphasize the possibility that bioactive lipids and the respective receptors and enzymes belonging to the eCBome may sustain the tissue-dependent inflammatory state that characterizes obesity and diabetes, possibly in relation with gut microbiome alterations., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Leptin signaling in placentas of obese women may influence fetal growth and may be dependent on fetal sex. The aim of this study was to investigate placental gene expression of leptin, its receptor and inflammatory cytokines in obese mothers in relation to offspring birth weight and sex., Methods: In total, 109 placental tissue samples from severely obese women (body mass index in first trimester ≥35 kg/m 2 ) giving birth vaginally at term to a healthy child were included. Quantitative real-time PCR was used for the analysis of leptin (LEP), its receptor LEPR with two splice variants, interleukin (IL)1B, chemokine (C-X-C motif) ligand 8 (CXCL8), tumour necrosis factor (TNF), IL6, IL10, hypoxia-inducible factor 1-alpha (HIF1A) and insulin receptor (INSR). The subjects were divided into three groups based on LEP expression percentiles (<25th percentile; 25-75th percentile and >75th percentile)., Results: A reverse U-shaped association between LEP expression and birth weight z-scores was found (R 2  = 0.075, p = 0.005). Placental LEPRb expression was downregulated (p = 0.034) in those with highest LEP expression. Female infants had higher birth weight z-scores than males (0.58 (-1.49-2.88) vs 0.21 (-1.50-2.93), p = 0.020) and their placental LEPRb expression was upregulated (p = 0.047). The associations between expression of different genes differed by sex., Discussion: A reverse U-shaped relationship between placental LEP expression and offspring birth weight z-scores was found together with sexual dimorphism in LEPRb expression indicating a complex regulation of fetal growth by placental leptin signaling in maternal obesity., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Leptin is a hormone secreted from adipocytes that regulates metabolism and energy homeostasis through the leptin receptor (LEPR). The aim of this study was to investigate the association of leptin receptor gene Q223R gene polymorphism, and plasma leptin level among obese breast cancer females., Materials and Methods: The study enrolled 160 breast cancer patients and 160 healthy control females. LEPR Q223R polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum leptin was determined using enzyme-linked immunosorbent assay human leptin kit.  Immunohistochemical tests from paraffin blocks were carried out for estrogen and progesterone staging using the precise antibodies., Results: An association was found between LEPR gene Q223R gene polymorphism among obese breast cancer females. Statistical difference was found between GG (60.6%) Arg/Arg genotype (OR=2.986; 95%CI=1.540 to 5.789; p= 0.001) compared to AA (33.1%) Gln/Gln genotype. GG Q223R LEPR polymorphism showed statistically significant difference among obese breast cancer patients (BMI more than 25) compared to control (P < 0.0001). GG genotype of Q223R LEPR polymorphism showed statistically significant increased leptin level (p-value =0.0001) among obese patients (mean± SD; 23.39±4.32) compared to control (17.83±5.67)., Conclusions: Q223R LEPR polymorphism GG genotype was associated with increased leptin profile among obese breast cancer females.

The present review provides a comparative insight into structure, function and control of leptin system in fishes, herptiles, birds and mammals. In general, leptin acts as an anorexigenic hormone since its administration results in decrease of food intake in vertebrates. Nonetheless, functional paradox arises in fishes from contradictory observations on level of leptin during fasting and re-feeding. In addition, leptin is shown to modulate metabolic functions in fishes, reptiles, birds and mammals. Leptin also regulates reproductive and immune functions though more studies are warranted in non-mammalian vertebrates. The expression of leptin and its receptor is influenced by numerous factors including sex steroids, stress and stress-induced catecholamines and glucocorticoids though their effect in non-mammalian vertebrates is hard to be generalized due to limited studies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Leptin, an anorectic hormone, regulates food intake, energy expenditure and body weight. We assessed the implication of tongue leptin in the modulation of oro-sensory detection of dietary fatty acids in mice. The RT-PCR analysis showed that mRNA encoding leptin and leptin receptor (Ob-Rb) was expressed in mice taste bud cells (TBC). Confocal microscopic studies showed that the lipid sensor CD36 was co-expressed with leptin in mice TBC. Silencing of leptin or Ob-Rb mRNA in tongue papillae upregulated preference for a long-chain fatty acid (LCFA), i.e., linoleic acid (LA), in a two-bottle paradigm in mice. Furthermore, tongue leptin application decreased the preference for the LCFA. These results suggest that tongue leptin exerts an inhibitory action on fatty acid preference. In isolated mice TBC, leptin decreased LCFA-induced increases in free intracellular calcium concentrations, [Ca 2+ ]i. Leptin and LCFA induced the phosphorylation of ERK1/2 and STAT-3 and there were no additive or opposite effects of the two agents on the degree of phosphorylation. However, leptin, but not the LCFA, induced phosphoinositide-3-kinase (PI-3-K)-dependent Akt phosphorylation in TBC. Furthermore, leptin induced hyperpolarization, whereas LCFA induced depolarization in TBC. Our study demonstrates that tongue leptin exerts an inhibitory action on oro-sensory detection of a dietary fatty acid by interfering with Ca 2+ signaling and membrane potential in mice TBC.

The objective of the present study was to identify the association of the TNF -α- 308G/A and leptin receptor ( LEPR ) Gln223Arg polymorphisms with the risk of development of type 2 diabetes mellitus (T2DM)., Methods: A total of 160 volunteers were studied: 108 with T2DM and 52 participants as control, who served as the control group. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) for the genomic region of TNF -α- 308G/A and LEPR Gln223Arg were carried out., Results: The frequency of LEPR Gln223Arg genotypes in T2DM and control groups showed significant differences in the distribution of genotypes ( p < 0.05). The frequency also of TNF-α- 308G/A genotypes in T2DM and control subjects showed significant differences in the distribution of genotypes ( p < 0.05)., Conclusion: Our results indicate that there are significant differences in the distribution of genotypes and alleles between the individuals with T2DM and control subjects ( p < 0.05).

Background: The incidence of diabetes and diabetic peripheral neuropathy continues to rise, and studies have shown that macrophages play an important role in their pathogenesis. To date, macrophage tracking has largely been achieved using genetically-encoded fluorescent proteins. Here we present a novel two-color fluorescently labeled perfluorocarbon nanoemulsion (PFC-NE) designed to monitor phagocytic macrophages in diabetic neuropathy in vitro and in vivo using non-invasive near-infrared fluorescent (NIRF) imaging and fluorescence microscopy., Methods: Presented PFC-NEs were formulated with perfluorocarbon oil surrounded by hydrocarbon shell carrying two fluorescent dyes and stabilized with non-ionic surfactants. In vitro assessment of nanoemulsions was performed by measuring fluorescent signal stability, colloidal stability, and macrophage uptake and subsequent viability. The two-color PFC-NE was administered to Lepr db/db and wild-type mice by tail vein injection, and in vivo tracking of the nanoemulsion was performed using both NIRF imaging and confocal microscopy to assess its biodistribution within phagocytic macrophages along the peripheral sensory apparatus of the hindlimb., Results: In vitro experiments show two-color PFC-NE demonstrated high fluorescent and colloidal stability, and that it was readily incorporated into RAW 264.7 macrophages. In vivo tracking revealed distribution of the two-color nanoemulsion to macrophages within most tissues of Lepr db/db and wild-type mice which persisted for several weeks, however it did not cross the blood brain barrier. Reduced fluorescence was seen in sciatic nerves of both Lepr db/db and wild-type mice, implying that the nanoemulsion may also have difficulty crossing an intact blood nerve barrier. Additionally, distribution of the nanoemulsion in Lepr db/db mice was reduced in several tissues as compared to wild-type mice. This reduction in biodistribution appears to be caused by the increased number of adipose tissue macrophages in Lepr db/db mice., Conclusions: The nanoemulsion in this study has the ability to identify phagocytic macrophages in the Lepr db/db model using both NIRF imaging and fluorescence microscopy. Presented nanoemulsions have the potential for carrying lipophilic drugs and/or fluorescent dyes, and target inflammatory macrophages in diabetes. Therefore, we foresee these agents becoming a useful tool in both imaging inflammation and providing potential treatment in diabetic peripheral neuropathy., (© 2021. The Author(s).)

In early stage of diabetes, insulin secretion from pancreatic β-cells is increased to deal with the elevated blood glucose. Previous studies have reported that islet-produced carbon monoxide (CO) is associated with increased glucose-stimulated insulin secretion from β-cells. However, this compensatory mechanism by which CO may act to enhance β-cell function remain unclear. In this study, we revealed that CO promoted intracellular calcium ([Ca 2+ ] i ) elevation and glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells in leptin receptor deficient db/db mice but not in C57 mice. The stimulatory effects of CO on β-cell function in db/db mice was blocked by inhibition of Phospholipase C (PLC) signaling pathway. We further demonstrated that CO triggered [Ca 2+ ] i transients and enhanced GSIS in C57 islets when β-cells overexpressed with PLCγ1 and PLCδ1, but not PLCβ1. On the other hand, reducing PLCγ1 and PLCδ1 expressions in db/db islets dramatically attenuated the stimulatory effects of CO on β-cell function, whereas interfering PLCβ1 expression had no effects on CO-induced β-cell function enhancement. Our findings showing that CO elevated [Ca 2+ ] i and enhanced GSIS by activating PLC signaling through PLCγ1 and PLCδ1 isoforms in db/db pancreatic β-cells may suggest an important mechanism by which CO promotes β-cell function to prevent hyperglycemia. Our study may also provide new insights into the therapy for type II diabetes and offer a potential target for therapeutic applications of CO., Competing Interests: Declaration of competing interest No potential conflict of interests was declared by the authors., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: Diabetic cardiomyopathy (DCM) is a serious complication of diabetes, but its pathogenesis is still unclear. This study investigated the mechanism of long noncoding RNA (lncRNA) NORAD in DCM., Methods: Male leptin receptor-deficient (db/db) mice and leptin control mice (db/ +) were procured. DCM model was established by subcutaneous injection of angiotensin II (ATII) in db/db mice. NORAD lentivirus shRNA or Adv-miR-125a-3p was administered to analyze cardiac function, fibrosis, serum biochemical indexes, inflammation and fibrosis. Primary cardiomyocytes were extracted and transfected with miR-125a-3p mimic. The competing endogenous RNA (ceRNA) network of NORAD/miR-125a-3p/Fyn was verified. The levels of fibrosis- and inflammation-related factors were measured., Results: In db/db mice treated with ATII, the body weight and serum biochemical indexes were increased, while the cardiac function was decreased, and inflammatory cell infiltration and fibrosis were induced. NORAD was upregulated in diabetic and DCM mice. The 4-week intravenous injection of NORAD lentivirus shRNA reduced body weight and serum biochemical indexes, improved cardiac function, and attenuated inflammation and fibrosis in DCM mice. NORAD acted as a sponge to adsorb miR-125a-3p, and miR-125a-3p targeted Fyn. Intravenous injection of miR-125a-3p adenovirus improved cardiac function and fibrosis and reduced inflammatory responses in DCM mice. Co-overexpression of miR-125-3p and Fyn partly reversed the improving effect of miR-125-3p overexpression on cardiac fibrosis in DCM mice., Conclusion: NORAD lentivirus shRNA improved cardiac function and fibrosis and reduced inflammatory responses in DCM mice via the ceRNA network of NORAD/miR-125a-3p/Fyn. These findings provide a valuable and promising therapeutic target for the treatment of DCM., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The pathogenesis of diabetic nephropathy (DN) is related to macrophage (Mφ) recruitment to the kidneys, tumor necrosis factor-α (TNF-α) production, and oxidative stress. Toll-like receptor 9 (TLR9) activation is reportedly involved in systemic inflammation, and it exacerbates this condition in metabolic syndrome. Therefore, we hypothesized that TLR9 plays a role in the pathogenesis of DN. Two subsets of kidney Mφs in DN model ( db/db ) mice were analyzed using flow cytometry to evaluate their distribution and TLR9 expression and function. Mice were administered the CCR2 antagonist INCB3344 for 8 wk; changes in Mφ distribution and function and its therapeutic effects on DN pathology were examined. Bone marrow-derived CD11b high (BM-Mφ) and tissue-resident CD11b low Mφs (Res-Mφ) were identified in the mouse kidneys. As DN progressed, the BM-Mφ number, TLR9 expression, and TNF-α production increased significantly. In Res-Mφs, reactive oxygen species (ROS) production and phagocytic activity were enhanced. INCB3344 decreased albuminuria, serum creatinine level, BM-Mφ abundance, TLR9 expression, and TNF-α production by BM-Mφs and ROS production by Res-Mφs. Both increased activation of BM-Mφ via TLR9 and TNF-α production and increased ROS production by Res-Mφs were involved in DN progression. Thus, inactivating Mφs and their TLR9 expression by INCB3344 is a potential therapeutic strategy for DN. NEW & NOTEWORTHY We classified kidney macrophages (Mφs) into bone marrow-derived Mφs (BM-Mφs) expressing high CD11b and tissue-specific resident Mφ (Res-Mφs) expressing low CD11b. In diabetic nephropathy (DN) model mice, Toll-like receptor 9 (TLR9) expression and TNF-α production via TLR9 activation in BM-Mφs and ROS production in Res-Mφs were enhanced. Furthermore, CCR2 antagonist suppressed the kidney infiltration of BM-Mφs and their function and the ROS production by Res-Mφs, with concomitant TLR9 suppression. Our study presents a new therapeutic strategy for DN.

Adipose tissue secretes various peptides, including leptin. This hormone acts through the leptin receptor (Ob-R), which is expressed ubiquitously on the surface of various cells, including breast cancer cells and immune cells. Increasing evidence points to an interaction between the tumor microenvironment, tumor cells, and the immune system. Leptin plays an important role in breast cancer tumorigenesis and may be implicated in activation of the immune system. While breast cancer cannot be considered an immunogenic cancer, the triple-negative subtype is an exception. Specific immune cells - tumor infiltrating lymphocytes - are involved in the immune response and act as predictive and prognostic factors in certain breast cancer subtypes. The aim of this article is to review the interaction between adipose tissue, through the expression of leptin and its receptor, and the adaptive immune system in breast cancer., Competing Interests: LG-E reports personal fees from Roche, Eisai, Daiichi Sankyo, and Palex. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 García-Estevez, González-Martínez and Moreno-Bueno.)

This study determined if a perturbation in in utero adipogenesis leading to later life adipose tissue (AT) dysfunction underlies programming of cardiometabolic risk in offspring born to dams with metabolic dysfunction. Female mice heterozygous for the leptin receptor deficiency (Het db ) had 2.4-fold higher prepregnancy fat mass and in late gestation had higher plasma insulin and triglycerides compared with wild-type (Wt) females ( P < 0.05). To isolate the role of the intrauterine milieu, wild-type (Wt) offspring from each pregnancy were studied. Differentiation potential in isolated progenitors and cell size distribution analysis revealed accelerated adipogenesis in Wt pups born to Het db dams, accompanied by a higher accumulation of neonatal fat mass. In adulthood, whole body fat mass by NMR was higher in male (69%) and female (20%) Wt offspring born to Het db versus Wt pregnancies, along with adipocyte hypertrophy and hyperlipidemia (all P < 0.05). Lipidomic analyses by gas chromatography revealed an increased lipogenic index (16:0/18:2n6) after high-fat/fructose diet (HFFD). Postprandial insulin, ADIPO-IR, and ex vivo AT lipolytic responses to isoproterenol were all higher in Wt offspring born to Het db dams ( P < 0.05). Intrauterine metabolic stimuli may direct a greater proportion of progenitors toward terminal differentiation, thereby predisposing to hypertrophy-induced adipocyte dysfunction. NEW & NOTEWORTHY This study reveals that accelerated adipogenesis during the perinatal window of adipose tissue development predisposes to later life hypertrophic adipocyte dysfunction, thereby compromising the buffering function of the subcutaneous depot.

Previous studies indicate that leptin receptor (LepR) expression in GABAergic neurons is necessary for the biological effects of leptin. However, it is not clear whether LepR expression only in GABAergic neurons is sufficient to prevent the metabolic and neuroendocrine imbalances caused by LepR deficiency. In the present study, we produced mice that express the LepR exclusively in GABAergic cells (LepRVGAT mice) and compared them with wild-type (LepR+/+) and LepR-deficient (LepRNull/Null) mice. Although LepRVGAT mice showed a pronounced reduction in body weight and fat mass, as compared with LepRNull/Null mice, male and female LepRVGAT mice exhibited an obese phenotype relative to LepR+/+ mice. Food intake was normalized in LepRVGAT mice; however, LepRVGAT mice still exhibited lower energy expenditure in both sexes and reduced ambulatory activity in the females, compared with LepR+/+ mice. The acute anorexigenic effect of leptin and hedonic feeding were normalized in LepRVGAT mice despite the hyperleptinemia they present. Although LepRVGAT mice showed improved glucose homeostasis compared with LepRNull/Null mice, both male and female LepRVGAT mice exhibited insulin resistance. In contrast, LepR expression only in GABAergic cells was sufficient to normalize the density of agouti-related peptide (AgRP) and α-MSH immunoreactive fibers in the paraventricular nucleus of the hypothalamus. However, LepRVGAT mice exhibited reproductive dysfunctions, including subfertility in males and alterations in the estrous cycle of females. Taken together, our findings indicate that LepR expression in GABAergic cells, although critical to the physiology of leptin, is insufficient to normalize several metabolic aspects and the reproductive function in mice., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)