Acupuncture improves immunity and fatigue after chemotherapy in breast cancer patients by inhibiting the Leptin/AMPK signaling pathway.

OBJECTIVE: Acupuncture has become a popular complementary treatment in oncology. This study is based on RNA-Seq transcriptome sequencing technology to investigate the molecular mechanisms underlying the effect of acupuncture-mediated regulation of the Leptin/AMPK signaling pathway on mitochondrial dysfunction-induced fatigue in breast cancer patients after chemotherapy. METHODS: Peripheral blood samples from 10 patients with post-operative chemotherapy for breast cancer were selected for transcriptome sequencing to screen the key molecular pathways involved in fatigue after chemotherapy in breast cancer patients. Besides, peripheral blood samples were collected from 138 post-operative chemotherapy patients with breast cancer to study the composite fatigue and quality of life scores. Flow cytometry was used to detect T lymphocyte subsets in peripheral blood-specific immune cells. In addition, a blood cell analyzer was used to measure peripheral blood leukocyte counts, and MSP-PCR was used to detect mitochondrial DNA mutations in peripheral blood leukocytes. RESULTS: Transcriptome bioinformatics analysis screened 147 up-regulated mRNAs and 160 down-regulated mRNAs. Leptin protein was confirmed as the key factor. Leptin was significantly higher in the peripheral blood of breast cancer patients who developed fatigue after chemotherapy. Acupuncture treatment effectively improved post-chemotherapy fatigue and immune status in breast cancer patients, suppressed the expression of Leptin/AMPK signaling pathway-related factor and leukocyte counts, and significantly reduced the rate of mitochondrial DNA mutations in peripheral blood leukocytes. CONCLUSION: The Leptin/AMPK signaling pathway may be the key molecular pathway affecting the occurrence of fatigue after chemotherapy in breast cancer patients. Leptin may improve post-chemotherapy fatigue in breast cancer patients by activating AMPK phosphorylation and alleviating mitochondrial functional impairment.

[Effects of Leptin and Leptin-associated Signaling Pathways on the Occurrence and Progression of Abdominal Aortic Aneurysms].

Abdominal aortic aneurysm(AAA) is a chronic dilated artery disease induced by atherosclerosis,infection,trauma and other related causes.The available studies about AAA mainly focus on the inflammatory response,senility,and microenvironmental changes,while the research on the metabolic changes such as glucose metabolism and lipid metabolism remains to be conducted.As a critical regulatory factor in endocrine,glucose,and lipid metabolisms,leptin is associated with a variety of signaling pathways such as adenosine monophosphate-activated protein kinase,Janus kinase/signal transducer and activator of transcription,and cytokine-cytokine receptor,as demonstrated by the KEGG pathway enrichment analysis.Moreover,these signaling pathways are generally involved in regulating the occurrence of AAA.In addition,leptin affects the occurrence of a variety of diseases such as obesity,diabetes,and hyperlipidemia,which contribute to the formation of AAA.Diabetes might be a protective factor for the formation of AAA,while the relationship of hyperlipidemia and obesity with the formation of AAA remains unclear.Therefore,leptin might play an essential role in the formation of AAA.Further studies about the effect of leptin on AAA may provide the potential research direction and facilitate the discovery of therapeutic targets.

Leptin Promotes Monosodium Urate Crystal-Induced Inflammation in Human and Murine Models of Gout.

Gouty arthritis is an inflammatory disease that is triggered by abnormal uric acid metabolism, which is usually attributed to obesity, a risk factor of hyperuricemia and gout attack. A high level of leptin in plasma is a marker of individuals with obesity. Population studies show that leptin promotes obesity-related arthritis, such as osteoarthritis, but it is unknown whether leptin contributes to gouty arthritis, another form of obesity-related arthritis. Our present study showed that the levels of leptin and leptin receptor in patients with active gouty arthritis were elevated. Leptin facilitates the stimulation of human synoviocytes, mouse peritoneal macrophages, and HL-60 cells induced by monosodium urate, leading to higher levels of acute gout-related proinflammatory factors. Leptin obviously exacerbates the inflammation of monosodium urate-induced acute gouty arthritis in wild-type mice, whereas that in leptin-deficient C57BL6/Job/ob mice is markedly alleviated. The proinflammatory effect of leptin in acute gouty arthritis is partly mediated by mTORC1 signaling pathway. Our study reveals that leptin may serve as a novel prevention and treatment target in acute gouty arthritis.

The Causes and Potential Injurious Effects of Elevated Serum Leptin Levels in Chronic Kidney Disease Patients.

Leptin is an adipokine that regulates appetite and body mass and has many other pleiotropic functions, including regulating kidney function. Increased evidence shows that chronic kidney disease (CKD) is associated with hyperleptinemia, but the reasons for this phenomenon are not fully understood. In this review, we focused on potential causes of hyperleptinemia in patients with CKD and the effects of elevated serum leptin levels on patient kidney function and cardiovascular risk. The available data indicate that the increased concentration of leptin in the blood of CKD patients may result from both decreased leptin elimination from the circulation by the kidneys (due to renal dysfunction) and increased leptin production by the adipose tissue. The overproduction of leptin by the adipose tissue could result from: (a) hyperinsulinemia; (b) chronic inflammation; and (c) significant lipid disturbances in CKD patients. Elevated leptin in CKD patients may further deteriorate kidney function and lead to increased cardiovascular risk.

Reduced Endothelial Leptin Signaling Increases Vascular Adrenergic Reactivity in a Mouse Model of Congenital Generalized Lipodystrophy.

The adipokine leptin, which is best-known for its role in the control of metabolic function, is also a master regulator of cardiovascular function. While leptin has been approved for the treatment of metabolic disorders in patients with congenital generalized lipodystrophy (CGL), the effects of chronic leptin deficiency and the treatment on vascular contractility remain unknown. Herein, we investigated the effects of leptin deficiency and treatment (0.3 mg/day/7 days) on aortic contractility in male Berardinelli-Seip 2 gene deficient mice (gBscl2-/-, model of CGL) and their wild-type control (gBscl2+/+), as well as in mice with selective deficiency in endothelial leptin receptor (LepREC-/-). Lipodystrophy selectively increased vascular adrenergic contractility via NO-independent mechanisms and induced hypertrophic vascular remodeling. Leptin treatment and Nox1 inhibition blunted adrenergic hypercontractility in gBscl2-/- mice, however, leptin failed to rescue vascular media thickness. Selective deficiency in endothelial leptin receptor did not alter baseline adrenergic contractility but abolished leptin-mediated reduction in adrenergic contractility, supporting the contribution of endothelium-dependent mechanisms. These data reveal a new direct role for endothelial leptin receptors in the control of vascular contractility and homeostasis, and present leptin as a safe therapy for the treatment of vascular disease in CGL.

Leptin impairs the therapeutic effect of ionizing radiation in oral squamous cell carcinoma cells.

PURPOSE: Leptin, an important hormone controlling energy homeostasis, has been linked to the pathogenesis of oral squamous cell carcinoma (OSCC). Evidence indicates that head and neck cancer patients undergoing radiotherapy show decreased leptin levels after radiotherapy treatment. Thus, we investigated, through phenotypic and molecular analyses, whether leptin can compromise the therapeutic effect of ionizing radiation and neoplastic behavior of OSCC cells. METHODS: The human OSCC-derived cell lines SCC9 and SCC4 were treated with human recombinant leptin and exposed to 6 Gy of irradiation. We performed the in vitro assays of cell migration, death, proliferation, and colony-forming ability. The reactive oxygen species (ROS) levels and proteome analysis by mass spectrometry were also conducted. RESULTS: Leptin was able to increase cell proliferation, migration, and colony-forming ability, despite the suppressive effect induced by irradiation. Furthermore, the leptin promoted a significant reduction of ROS intracellular accumulation, and increased expression of the cancer-related proteins, as ACTC1, KRT6A, and EEF2 in irradiated OSCC cells. CONCLUSIONS: Our findings suggest that leptin impairs responsivity of OSCC cells to the ionizing radiation, reducing the suppressive effects of irradiation on the neoplastic phenotype, and increasing protein expression critical to carcinogenesis.

Update on Therapeutic Options in Lipodystrophy.

PURPOSE OF REVIEW: The purpose of this review is to summarize the therapeutic approach for lipodystrophy syndromes with conventional treatment options and metreleptin therapy in detail and to point out the current investigational treatments in development. RECENT FINDINGS: The observation of leptin deficiency in patients with lipodystrophy and the potential of leptin replacement to rescue metabolic abnormalities in animal models of lipodystrophy were followed by the first clinical study of leptin therapy in patients with severe lipodystrophy. This and several other long-term studies demonstrated important benefits of recombinant human leptin (metreleptin) to treat metabolic abnormalities of lipodystrophy. These studies ultimately led to the recent FDA approval of metreleptin for the treatment of generalized lipodystrophy and EMA approval for both generalized and partial lipodystrophy. Additional research efforts in progress focus on novel treatment options, predominantly for patients with partial lipodystrophy. Current treatment of generalized lipodystrophy includes metreleptin replacement as an adjunct to diet and standard treatment approach for metabolic consequences of lipodystrophy. Beyond metreleptin, a number of different compounds and treatment modalities are being studied for the treatment of partial lipodystrophy.

Leptin alone and in combination with interleukin-1-beta induced cartilage degradation potentially inhibited by EPA and DHA.

Osteoarthritis (OA) is the most common form of arthritis. Obesity has been believed to be an important risk factor for OA development and the progression of not only load-bearing joints, but low-load-bearing joints as well. Increased leptin has been the focus of a link between obesity and OA. In this study, the effects of pathological (100ng/ml) or supra-pathological (10µg/ml) concentrations of leptin alone or in combination with IL1ß on cartilage metabolisms were studied in porcine cartilage explant. The involved mechanisms were examined in human articular chondrocytes (HACs). Moreover, the protective effect of omega-3 polyunsaturated acids, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA) was also investigated. Leptin (10µg/ml) alone or in combination with IL1ß could induce cartilage destruction, although lower concentrations had no effect. Leptin activated NFκB, ERK, JNK and p38 in HACs, which led to the induction of MMP3, MMP13 and ADAMTS4 secretions. The combined effect could further induce those enzymes through the additive effect on activation of NFκB and JNK. Interestingly, both EPA and DHA could inhibit cartilage damage induced by leptin plus IL1ß by reducing the activation of NFκB and JNK, which led to the decrease of ADAMTS4 secretion. Altogether, only a supra-pathological concentration of leptin alone or in combination with IL1ß could induce cartilage destruction, whereas a pathological one could not. This effect could be inhibited by EPA and DHA. To gain greater understanding of the link between leptin and OA, the effect of different levels of leptin on several states of OA cartilage requires further investigation.

Insights into the Mechanisms That May Clarify Obesity as a Risk Factor for Multiple Sclerosis.

PURPOSE OF REVIEW: The proportion to which genetic and environmental factors contribute to the etiology of multiple sclerosis (MS) is still incompletely understood. An interesting association between MS etiology and obesity has recently been shown although the mechanisms underlying this association are still unknown. We propose deregulated gut microbiota and increased leptin levels as possible mechanisms underlying MS etiology in obese individuals. RECENT FINDINGS: Alterations in the human gut microbiota and leptin levels have recently been established as immune modulators in both MS patients and obese individuals. A resemblance between pro-inflammatory bacterial profiles in MS and obese individuals was observed. Furthermore, elevated leptin levels push the immune system towards a more pro-inflammatory state and inhibit the regulatory immune response. Deregulated gut microbiota and elevated leptin levels may explain the increased risk of developing MS in obese individuals. Further research to confirm causality is warranted.

Postoperative Adverse Cardiovascular Events Associated with Leptin and Adverse Age After Elective Major Non-Cardiac Surgery: An Asian Single-Center Study.

BACKGROUND The postoperative adverse cardiovascular events (PACE) after surgery can result in prolonged length of stay and poorer prognosis. The purpose of this Asian single-center study was to investigate the potential predicative role of leptin for PACE in elderly patients undergoing major non-cardiac surgery. MATERIAL AND METHODS The patients in the study were prospectively recruited from a series of elderly patients (≥60 years) undergoing elective major non-cardiac surgery (≥2 hours) in our hospital from June 2013 to June, 2016. The demographic and clinical data and the preoperative serum biomarkers of each participant were recorded in details. Suspected PACE were assessed by the same experienced expert based on clinical, blood, and other accessory tests. The univariate and multiple logistic regression analyses were plotted to evaluate the potential independent predictive factors for PACE. RESULTS A total of 270 elderly patients (145 males and 125 females), undergoing major elective non-cardiac surgery, were finally enrolled in this study. Older age, higher revised cardiac risk index score, higher levels of systolic blood pressure, B-type natriuretic peptide and leptin, the preoperative medication of beta blocker and lipid-lowering agents were positive predictors of PACE by univariate analyses (p<0.05). Our results indicated that preoperative leptin level (OR 1.84, 95% CI 1.08-3.42; p=0.015) and advanced age (OR 0.24, 95% CI 0.09-0.94; p=0.041) were significantly associated with the occurrence of PACE by multiple logistic regression analyses. CONCLUSIONS Preoperative serum leptin level and advanced age were two independent risk factors for PACE among elderly patients undergoing elective major non-cardiac surgery.

Leptin Aggravates Reflux Esophagitis by Increasing Tissue Levels of Macrophage Migration Inhibitory Factor in Rats.

Leptin, produced primarily by the adipose tissue, acts as a pro-inflammatory modulator, thereby contributing to the development of obesity-related disease. Although high levels of leptin in the obese are closely related to gastroesophageal reflux disease, the mechanism by which leptin influences esophageal inflammation remains unknown. Macrophage migration inhibitory factor (MIF) is produced by immune cells, such as T lymphocytes and macrophages, and MIF is known to induce the production of tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß) and interleukin 6 (IL-6). We therefore investigated the mechanism whereby leptin aggravates reflux esophagitis, by focusing on esophageal tissue levels of MIF and CD3+ T lymphocytes, both of which are crucial for the reflux-induced epithelial damage. Esophageal inflammation was surgically induced in male Wistar rats by ligating the forestomach and narrowing the duodenum to facilitate gastroesophageal reflux, followed by administration of leptin or vehicle with an osmotic pump system for 1 week. We demonstrated that the administration of leptin exacerbated the reflux esophagitis with the apparent infiltration of CD3+ T lymphocytes and caused the significant increase in the esophageal tissue levels of MIF. Moreover, the leptin caused increases in the esophageal tissue levels of TNF-α, IL-1ß and IL-6, downstream targets of MIF. Importantly, the increases in these pro-inflammatory cytokines were accompanied by increased protein levels of phospho-STAT3 and phospho-AKT, pivotal molecules of leptin signaling pathways. In conclusion, through enhancing the MIF-induced inflammatory signaling, leptin could contribute to the development of gastroesophageal reflux disease.

Intramuscular injection of exogenous leptin induces adiposity, glucose intolerance and fatty liver by repressing the JAK2-STAT3/PI3K pathway in a rat model.

Obesity, diabetes and fatty liver disease are extremely common in leptin-resistant patients. Dysfunction of leptin or its receptor is associated with obesity. The present study aimed to assess the effects of intramuscular injection of exogenous leptin or its receptor on fat deposition and leptin-insulin feedback regulation. Forty-five 40-day old female Sprague Dawley (SD) rats were injected thrice with leptin or its receptor intramuscularly. Adiposity and fat deposition were assessed by assessing the Lee's index, body weight, food intake, and total cholesterol, high density lipoprotein, low density lipoprotein, and triglyceride levels, as well as histological properties (liver and adipose tissue). Serum glucose, leptin, and insulin amounts were evaluated, and glucose tolerance assessed to monitor glucose metabolism in SD rats; pancreas specimens were analyzed immunohistochemically. Hypothalamic phosphorylated Janus kinase 2 (p-JAK2), phosphorylated signal transducer and activator of transcription 3 (p-STAT3), and phosphatidylinositol-3-kinase (PI3K) signaling, and hepatic sterol regulatory element binding protein-1 (SREBP-1) were qualified by Western blotting. Leptin receptor immunogen reduced fat deposition, increased appetite, and lowered serum leptin levels, enhancing STAT3 signaling in hypothalamus and down-regulating hepatic SREBP-1. In contrast, SD rats administered leptin immunogen displayed significantly increased body weight and fat deposition, with up-regulated SREBP-1, indicating adiposity occurrence. SD rats administered leptin immunogen also showed glucose intolerance, ß- cell reduction in the pancreas, and deregulation of JAK2-STAT3/PI3K signaling, indicating that Lep rats were at risk of diabetes. In conclusion, intramuscular injection of exogenous leptin or its receptor, a novel rat model approach, can be used in obesity pathogenesis and therapeutic studies.

Immunogenicity associated with metreleptin treatment in patients with obesity or lipodystrophy.

OBJECTIVE: Recombinant human leptin (metreleptin) improves glycaemia and hypertriglyceridaemia in patients with generalized lipodystrophy; antibody development with in vitro neutralizing activity has been reported. We aimed to characterize antimetreleptin antibody development, including in vitro neutralizing activity. DESIGN: Two randomized controlled studies in patients with obesity (twice-daily metreleptin ± pramlintide for 20-52 weeks; 2006-2009); two long-term, open-label studies in patients with lipodystrophy (once-daily or twice-daily metreleptin for 2 months to 12·3 years; 2000-2014). PATIENTS: A total of 579 metreleptin-treated patients with obesity and 134 metreleptin-treated patients with lipodystrophy (antibody/neutralizing activity data: n = 105). MEASUREMENTS: Antimetreleptin antibodies, in vitro neutralizing activity. RESULTS: Antimetreleptin antibodies developed in most patients (obese: 96-100%; lipodystrophy: 86-92%). Peak antibody titers (approximately 1:125 to 1:3125) generally occurred within 4-6 months and decreased with continued therapy (lipodystrophy). Antibody development did not adversely impact efficacy or safety (patients with obesity), except for inflammatory injection site reactions, but was associated with elevated leptin concentrations. Three patients with obesity developed in vitro neutralizing activity coincident with weight gain. Weight later returned to baseline in one patient despite persistent neutralizing activity. Four patients with generalized lipodystrophy developed in vitro neutralizing activity concurrent with worsened metabolic control; two with confounding comorbidities had sepsis. One patient with lipodystrophy had resolution of neutralizing activity on metreleptin. CONCLUSIONS: Development of in vitro neutralizing activity could be associated with loss of efficacy but has not been consistently associated with adverse clinical consequences. Whether neutralization of endogenous leptin with clinical consequences occurs remains unclear.

Leptin plays a role in the multiplication of and inflammation in ovarian granulosa cells in polycystic ovary syndrome through the JAK1/STAT3 pathway.

OBJECTIVES: The authors determined the level of Expression of Leptin (LEP) in Polycystic Ovary Syndrome (PCOS) patients with or without obesity and in GCs treated with insulin. METHODS: LEP expression was first assessed in ovary cortex specimens collected from women with PCOS with or without obesity as well as from healthy controls. Ovarian Granulosa Cells (OGCs) induced by insulin extracted from a mouse model were used in further functional research. RESULTS: Real-time PCR and western blotting indicated that LEP expression was upregulated in GCs induced by insulin, in comparison with that in GCs not induced by insulin. Furthermore, the knockdown of LEP resulted in a reduction in growth and multiplication and an increase in apoptosis and inflammation in GCs induced by insulin. Next, the authors evaluated the effect of LEP on three key pathways of inflammation (MAPK, NF-kB, and JAK1/STAT3); results showed that the JAK1/STAT3 pathway was induced by LEP knockdown, as evidenced by the upregulation of phosphor-JAK1, phosphor-STAT3, and nuclear STAT3 expression. Administration of curcumin, a specific inhibitor of STAT3, counteracted the effect of LEP knockdown on cell inflammation and apoptosis. CONCLUSION: The present data suggest that upregulation of LEP expression in the PCOS granulosa cell model is essential for reducing apoptosis and inflammation by modulating the JAK1/STAT3 pathway axis.

[Leptin-mediated ERK Signaling Pathway Promotes the Transformation 
of Rat Alveolar Type II Epithelial Cells Induced by Yunnan Tin Mine Dust].

BACKGROUND: Currently, a significant number of miners are involved in mining operations at the Gejiu tin mine in Yunnan. This occupational setting is associated with exposure to dust particles, heavy metals, polycyclic aromatic hydrocarbons, and radioactive radon, thereby significantly elevating the risk of lung cancer. This study aims to investigate the involvement of leptin-mediated extracellular regulated protein kinase (ERK) signaling pathway in the malignant transformation of rat alveolar type II epithelial cells induced by Yunnan tin mine dust. METHODS: Immortalized rat alveolar cells type II (RLE-6TN) cells were infected with Yunnan tin mine dust at a concentration of 200 µg/mL for nine consecutive generations to establish the infected cell model, which was named R200 cells. The cells were cultured normally, named as R cells. The expression of leptin receptor in both cell groups was detected using the Western blot method. The optimal concentration of leptin and mitogen-activated protein kinase kinase (MEK) inhibitor (U0126) on R200 cells was determined using the MTT method. Starting from the 20th generation, the cells in the R group were co-cultured with leptin, while the cells in the R200 group were co-cultured with the MEK inhibitor U0126. The morphological alterations of the cells in each group were visualized utilizing hematoxylin-eosin staining. Additionally, concanavalin A (ConA) was utilized to detect any morphological differences, and an anchorage-independent growth assay was conducted to assess the malignant transformation of the cells. The changes in the ERK signaling pathway in epithelial cells after the action of leptin were detected using the Western blot method. RESULTS: Both the cells in the R group and R200 group express leptin receptor OB-R. Compared to the R200 group, the concentration of leptin at 100 ng/mL shows the most significant pro-proliferation effect. The proliferation of R200 cells infected with the virus is inhibited by 30 µmol/L U0126, and a statistically significant divergence was seen when compared to the control group (P<0.05). Starting from the 25th generation, the cell morphology of the leptin-induced R200 group (R200L group) underwent changes, leading to malignant transformation observed at the 30th generation. The characteristics of malignant transformation became evident by the 40th generation in the R200L group. In contrast, the other groups showed agglutination of P40 cells, and the speed of cell aggregation increased with an increase in ConA concentration. Notably, the R200L group exhibited faster cell aggregation compared to the U0126-induced R200 (R200LU) group. Additionally, the cells in the R200L group were capable of forming clones starting from P30, with a colony formation rate of 2.25‰±0.5‰. However, no clonal colonies were observed in the R200LU group and R200 group. The expression of phosphorylated extracellular signal-regulated kinase (pERK) was enhanced in cells of the R200L group. However, when the cells in the R200L group were treated with U0126, a blocking agent, the phosphorylation level of pERK decreased. CONCLUSIONS: Leptin can promote the malignant transformation of lung epithelial cells infected by mine dust, and the ERK signaling pathway may be necessary for the transformation of alveolar type II epithelial cells induced by Yunnan tin mine dust.

Leptin exacerbates sepsis-mediated morbidity and mortality.

The adipose-derived hormone leptin is well known for its contribution to energy metabolism and satiety signaling in the hypothalamus. Previous studies suggested that obesity is an independent risk factor for sepsis morbidity and mortality, and it is associated with elevated baseline levels of circulating leptin in normal, nonseptic patients. In mouse endotoxemia and cecal ligation puncture models of sepsis, we observed elevated levels of leptin and soluble leptin receptor (sLR). Exogenously administered leptin increased mortality in endotoxemia and cecal ligation puncture models and was associated with increased expression of adhesion and coagulation molecules, macrophage infiltration into the liver and kidney, and endothelial barrier dysfunction. Conversely, longform leptin receptor-deficient mice were protected from sepsis morbidity and mortality and had less endothelial dysfunction. Furthermore, an in vitro study revealed that leptin-induced endothelial dysfunction is likely mediated, at least in part, by monocytes. Moreover, administration of an sLR conferred a survival benefit. Human septic patients have increased circulating sLR concentrations, which were correlated with disease severity indices. Together, these data support a pathogenic role for leptin signaling during sepsis.

Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis.

Whereas in most cases a fatty liver remains free of inflammation, 10%-20% of patients who have fatty liver develop inflammation and fibrosis (nonalcoholic steatohepatitis [NASH]). Inflammation may precede steatosis in certain instances. Therefore, NASH could reflect a disease where inflammation is followed by steatosis. In contrast, NASH subsequent to simple steatosis may be the consequence of a failure of antilipotoxic protection. In both situations, many parallel hits derived from the gut and/or the adipose tissue may promote liver inflammation. Endoplasmic reticulum stress and related signaling networks, (adipo)cytokines, and innate immunity are emerging as central pathways that regulate key features of NASH.

Metreleptin treatment of non-HIV lipodystrophy syndromes.

Lipodystrophy syndromes (LS) constitute a group of rare diseases of the adipose tissue, characterized by a complete or selective deficiency of the fat mass. These disorders are associated with important insulin resistance, cardiovascular and metabolic comorbidities that impact patient's survival and quality of life. Management is challenging and includes diet, physical activity, and specific pharmacological treatment of LS-associated comorbidities. Because of a common pathophysiology involving decreased concentration of the adipokine leptin, efforts have been made to develop therapeutic strategies with leptin replacement therapy. Metreleptin, a recombinant human leptin analogue, has been proposed in hypoleptinemic patients since the beginning of 2000's. The treatment leads to an improvement in metabolic parameters, more important in generalized than in partial LS forms. In this review, the current knowledge about the development of the drug, its outcomes in the treatment of lipodystrophic patients as well as the peculiarities of its use will be presented.

Leptin Contributes to Neuropathic Pain via Extrasynaptic NMDAR-nNOS Activation.

Leptin is an adipocytokine that is primarily secreted by white adipose tissue, and it contributes to the pathogenesis of neuropathic pain in collaboration with N-methyl-D-aspartate receptors (NMDARs). Functional NMDARs are a heteromeric complex that primarily comprise two NR1 subunits and two NR2 subunits. NR2A is preferentially located at synaptic sites, and NR2B is enriched at extrasynaptic sites. The roles of synaptic and extrasynaptic NMDARs in the contribution of leptin to neuropathic pain are not clear. The present study examined whether the important role of leptin in neuropathic pain was related to synaptic or extrasynaptic NMDARs. We used a rat model of spared nerve injury (SNI) and demonstrated that the intrathecal administration of the NR2A-selective antagonist NVP-AAM077 and the NR2B-selective antagonist Ro25-6981 prevented and reversed mechanical allodynia following SNI. Administration of exogenous leptin mimicked SNI-induced behavioral allodynia, which was also prevented by NVP-AAM077 and Ro25-6981. Mechanistic studies showed that leptin enhanced NR2B- but not NR2A-mediated currents in spinal lamina II neurons of naïve rats. Leptin also upregulated the expression of NR2B, which was blocked by the NR2B-selective antagonist Ro25-6981, in cultured dorsal root ganglion (DRG) neurons. Leptin enhanced neuronal nitric oxide synthase (nNOS) expression, which was also blocked by Ro25-6981, in cultured DRG cells. However, leptin did not change NR2A expression, and the NR2A-selective antagonist NVP-AAM077 had no effect on leptin-enhanced nNOS expression. Our data suggest an important cellular link between the spinal effects of leptin and the extrasynaptic NMDAR-nNOS-mediated cellular mechanism of neuropathic pain.

Role of Leptin in the Association Between Body Adiposity and Persistent Asthma: A Longitudinal Study.

OBJECTIVE: Obesity is a likely risk factor for asthma. However, underlying mechanisms by which obesity affects asthma activity remain poorly understood. This study aimed to investigate the role of leptin, an adipocyte-derived proinflammatory protein, as a mediator in the association between body adiposity (assessed using BMI, waist circumference, and body fat percentage) and persistent asthma. METHODS: A causal approach to mediation analysis was used to disentangle total and direct effects and the indirect effect mediated by leptin, using data from the French prospective French Epidemiological Study on the Genetics and Environment of Asthma (EGEA) (baseline: 2003-2007; follow-up: 2011-2013; mean follow-up time: 7 years). A total of 331 participants with current asthma at baseline were included. RESULTS: Per 1-SD increment in BMI, waist circumference, and body fat percentage, the adjusted odds ratios of the total effect were 1.59 (95% CI: 0.95-2.97), 2.06 (1.06-4.00), and 3.25 (1.01-9.41), respectively; the odds ratios of the indirect effect mediated by leptin were 1.68 (1.09-2.46), 1.55 (0.99-2.57), and 1.99 (0.94-4.83), respectively. CONCLUSIONS: Leptin partly (> 60%) mediated the association between high body adiposity and persistent asthma over time. Using a newly developed analytic approach, this longitudinal study brought new insight into one mechanism by which obesity may affect asthma activity.