Adipose Tissue Hormone Leptin Research Articles

Obesity and thinness: insights from genetics.

Genetic disruption of key molecular components of the hypothalamic leptin-melanocortin pathway causes severe obesity in mice and humans. Physiological studies in people who carry these mutations have shown that the adipose tissue-derived hormone leptin primarily acts to defend against starvation. A lack of leptin causes an intense drive to eat and increases the rewarding properties of food, demonstrating that human appetite has a strong biological basis. Genetic studies in clinical- and population-based cohorts of people with obesity or thinness continue to provide new insights into the physiological mechanisms involved in weight regulation and identify molecular targets for weight loss therapy. This article is part of a discussion meeting issue 'Causes of obesity: theories, conjectures and evidence (Part II)'.

Differential impact of body mass index and leptin on baseline and longitudinal positron emission tomography measurements of the cerebral metabolic rate for glucose in amnestic mild cognitive impairment.

Several studies have suggested that greater adiposity in older adults is associated with a lower risk of Alzheimer's disease (AD) related cognitive decline, some investigators have postulated that this association may be due to the protective effects of the adipose tissue-derived hormone leptin. In this study we sought to demonstrate that higher body mass indices (BMIs) are associated with greater baseline FDG PET measurements of the regional cerebral metabolic rate for glucose (rCMRgl), a marker of local neuronal activity, slower rCMRgl declines in research participants with amnestic mild cognitive impairment (aMCI). We then sought to clarify the extent to which those relationships are attributable to cerebrospinal fluid (CSF) or plasma leptin concentrations. We used baseline PET images from 716 73 ± 8 years-old aMCI participants from the AD Neuroimaging Initiative (ADNI) of whom 453 had follow up images (≥6 months; mean follow up time 3.3 years). For the leptin analyses, we used baseline CSF samples from 81 of the participants and plasma samples from 212 of the participants. As predicted, higher baseline BMI was associated with greater baseline CMRgl measurements and slower declines within brain regions preferentially affected by AD. In contrast and independently of BMI, CSF, and plasma leptin concentrations were mainly related to less baseline CMRgl within mesocorticolimbic brain regions implicated in energy homeostasis. While higher BMIs are associated with greater baseline CMRgl and slower declines in persons with aMCI, these associations appear not to be primarily attributable to leptin concentrations.

Histone deacetylase 6 inhibition restores leptin sensitivity and reduces obesity.

The adipose tissue-derived hormone leptin can drive decreases in food intake while increasing energy expenditure. In diet-induced obesity, circulating leptin levels rise proportionally to adiposity. Despite this hyperleptinemia, rodents and humans with obesity maintain increased adiposity and are resistant to leptin’s actions. Here we show that inhibitors of the cytosolic enzyme histone deacetylase 6 (HDAC6) act as potent leptin sensitizers and anti-obesity agents in diet-induced obese mice. Specifically, HDAC6 inhibitors, such as tubastatin A, reduce food intake, fat mass, hepatic steatosis and improve systemic glucose homeostasis in an HDAC6-dependent manner. Mechanistically, peripheral, but not central, inhibition of HDAC6 confers central leptin sensitivity. Additionally, the anti-obesity effect of tubastatin A is attenuated in animals with a defective central leptin-melanocortin circuitry, including db/db and MC4R-KO mice. Our results suggest the existence of an HDAC6-regulated adipokine that serves as a leptin-sensitizing agent, and reveals HDAC6 as a potential target for the treatment of obesity.

BODY COMPONENT COMPOSITION AND STRESS-INDUCED FEATURES OF LEPTIN SECRETION IN FEMALES WITH VARIOUS BODY MASS INDEX

Aim. The article aims to study the dynamics of the adipose tissue hormone leptin in healthy females with different body component composition and body mass index to assess their energy status under stress. Materials and methods. Based on anthropometry and bioimpedancemetry, three groups of girls were formed: the first group included girls with a BMI of less than 18.5 kg/m2, body mass deficiency (BMD), the second – from 18.5 to 24.9 kg/m2, normal body mass (NBM), the third – with a BMI of more than 24.9 kg/m2, which corresponds to overweight (OvBM). The body component composition was determined by bioimpedancemetry. Plasma leptin concentration was evaluated by enzyme-linked immunosorbent assay both in normal conditions and during emotional stress. Results. In the selected subgroups, a significant difference in the body component composition was found with an increase in the series of BMD → NBM → OvBM. When assessing the level of metabolic processes by the magnitude of the phase angle, it was found that 3.41% of females with BMD showed signs of increased protein catabolism. The stress-induced dynamics of the hormone leptin was evaluated. In normal conditions, the concentration of leptin in blood plasma positively correlated with BMI and depended on the component composition of the body. Conclusion. In persons with BMD, the adipose tissue hormone leptin had a negative dynamics under stress conditions, which was an adequate adaptive physiological response to stress. Females with BMD had a significantly high positive dynamics of leptin, while girls with OvBM did not have significant changes in its concentrations, which can be explained by the development of leptin resistance.

The effects of allium sativum on immunity within the scope of COVID-19 infection

The severity of coronavirus disease 2019 (COVID‐19) infection is quite variable and the manifestations varies from asymptomatic disease to severe acute respiratory infection. Fever, dry cough, dyspnea, myalgia, fatigue, loss of appetite, olfactory and gustatory dysfunctions are the most prevalent general symptoms. Decreased immune system cells such as suppressed regulatory T cells, cytotoxic and helper T cells, natural killer cells, monocytes/macrophages and increased proinflammatory cytokines are the characteristic features. Compounds derived from Allium sativum (garlic) have the potential to decrease the expression of proinflammatory cytokines and to reverse the immunological abnormalities to more acceptable levels. Allium sativum is suggested as a beneficial preventive measure before being infected with SARS‐CoV‐2 virus.Allium sativum is a functional food well-known for its immunomodulatory, antimicrobial, antiinflammatory, antimutagenic, antitumor properties. Its antiviral efficiency was also demonstrated. Some constituents of this plant were found to be active against protozoan parasites. Within this context, it appears to reverse most immune system dysfunctions observed in patients with COVID-19 infection. The relations among immune system parameters, leptin, leptin receptor, adenosin mono phosphate-activated protein kinase, peroxisome proliferator activated receptor-gamma have also been interpreted. Leptin’s role in boosting proinflammatory cytokines and in appetite decreasing suggest the possible beneficial effect of decreasing the concentration of this proinflammatory adipose tissue hormone in relieving some symptoms detected during COVID-19 infection.In conclusion, Allium sativum may be an acceptable preventive measure against COVID-19 infection to boost immune system cells and to repress the production and secretion of proinflammatory cytokines as well as an adipose tissue derived hormone leptin having the proinflammatory nature.

A study of the prognostic value of leptin to assess the risk of progression of diabetic retinopathy in patients with type 2 diabetes

Objective — to evaluate the results of applying a mathematical model to determine the prognostic significance of blood leptin in the development and progression of diabetic retinopathy (DRP) in patients with type 2 diabetes mellitus (DM). Materials and methods. The studyincluded 59 patients (137 eyes) with type 2 DM and DRP: men (27—45.76 %) and women (32—54.24 %), mean age (58.20 ± 0.18) [42; 74] years, the average duration of diabetes from the diagnosis was (9.19 ± 0.46) [1; 35] years, the average level of glycated hemoglobin (HbA1C) was (9.10 ± 0.17) [5.1; 15.1] %.Based on the stage of DRP, patients were divided into 3 groups (1st — 42 patients, 2nd — 9 patients, 3rd — 8 patients). The inclusion criteria in the study were the patient’s informed consent to participate in study, age >18 years, the presence of type 2 DM, verified DRP. Exclusion criteria were endocrine and somatic pathologies leading to obesity (Cushing’s syndrome, hypothyroidism, hypogonadism, polycystic ovary syndrome, other endocrinopathies including hereditary, cerebral obesity), type 1 diabetes, acute infectious diseases, oncological diseases (including history of), decompensation of comorbid pathology, mental disorders, current antipsychotics or antidepressants treatment, the presence of proteinuria, clinically significant maculopathy, glaucoma and cataracts. The diagnosis of DRP was made according to the classification of Е. Kohner and М. Porta (1992), in which there are 3 main stages of DRP: non-proliferative, preproliferative and proliferative. Results and discussion. At the non-proliferative stage of DRP, a favorable prognosis (the likely absence of progression) is mainly due to normal leptin levels with a satisfactory lipid profile, subcompensation of DM (according to HbA1C) and the absence of insulin therapy. At the preproliferative stage of DRP, a favorable prognosis is mainly due to the lack of insulin therapy, and unfavorable due to moderate leptin resistance and insulin therapy. At the proliferative stage of DRP, a relatively favorable prognosis is mainly due to normoleptinemia, and the likely further deterioration of DRP is due to insulin therapy with varying degrees of leptin resistance. Conclusions. The developed mathematical model allows taking into account additional factors to evaluate the course of DRP based on blood level of adipose tissue hormone leptin.

Role of Glucagon-Like Peptide-1 in Appetite Regulation in Patients with Morbid Obesity and Leptin Resistance

To contribute to the outstanding discussion of suggested reasons of obesity, including the hormonal disorders, and how to deal and avoid them, this research attempts to investigate and control the energy balance disturbances resulting from hormonal disorders that may cause obesity by dysregulating appetite. A total of 88 participants are recruited, among whom 50 and 38 were allocated to the control and patients groups, respectively. Venous blood samples are collected from the participants at different time points for the quantification of the pre-prandial and 2, 6 and 12 h postprandial levels of lipid markers, including total cholesterol, high density lipoproteins, low density lipoproteins, very low density lipoproteins, and triacylglycerol, and the appetite-related hormones leptin and intestinal hormones glucagon-like peptide (GLP-1). In healthy controls, leptin levels increased prior to eating, decreased after eating, and then increased to induce hunger at several hours after eating. By contrast, the pre-prandial and postprandial leptin levels of the patients group did not show statistically significant differences. Healthy controls had moderate GLP-1 levels, whereas patients with obesity and leptin resistance had high GLP-1 levels. The GLP-1 was found to be secreted in response to high postprandial energy levels as an adaptation to leptin resistance. This study elucidates the relationship between the adipose tissue hormone leptin and GLP-1 in patients with morbid obesity. Findings of using GLP-1 as an appetite regulator for the morbidly obese patients and have leptin resistance (resistance to its action in appetite regulation), presented here, should provide a valuable information for further experimental investigations.

Modulation of the transcriptomic profile of the R2C tumor Leydig cell line by the adipose tissue derived hormone leptin

Leptin is an important adipose derived hormone being secreted by adipocytes and involved in appetite regulation. Disruption of normal plasma levels of leptin has been associated with the pathogenesis of obesity. It is now well established that obesity is associated to an increased risk of cancer development, including testicular cancers. Recently, we have shown that high levels of leptin have inhibitory effects on cAMP-dependent steroidogenic genes expression in MA-10 Leydig cells. Hence, we examined if leptin could alter the transcriptome of the constitutively steroidogenic rat tumor Leydig cell line R2C. These cells were treated with high levels of leptin (1000 ng/ml) for 4 h, followed by mRNA extraction and RNA-Seq analysis. Interestingly, leptin had no effect on steroidogenic gene expression or pathways promoting tumorigenesis of this cell line. Genes being upregulated or downregulated by leptin were enriched in biological processes that were non-relevant to Leydig cell function. Surprisingly, lepr isoforms were weakly expressed in R2C cells and may explain in part the low levels of leptin’s response for tumor Leydig cells. Hence, the current findings suggest that acute treatments of tumor Leydig cells with high levels of leptin have negligible effects on transcriptomics and rather supports that leptin would have a central effect on the hypothalamus to influence testicular function.

Abstract 4919: Preclinical activity of SDX-7320 in mouse models of obesity and obesity-driven cancer

Abstract Cancer patients who are obese face a greater risk of dying from cancer compared to nonobese patients (Calle, 2003). Obesity is believed to contribute to metastasis and progression of cancer via multiple mechanisms: increased secretion of the adipose tissue hormone leptin, decreased secretion of adiponectin, increased production of estrogen in adipose tissue, and elevated insulin (secondary to peripheral insulin resistance) as well as the local effects of inflammatory cytokines (Gucalp, 2016). Small-molecule inhibitors of methionine aminopeptidase type 2 (MetAP2) have previously demonstrated clinical activity in oncology (Kudelka, 1998) as well as obesity/type 2 diabetes (Hughes, 2013; Kim, 2015). However, development of some small-molecule MetAP2 inhibitors has been hampered by CNS side effects (Bhargava, 1999). SDX-7320 is a copolymer-drug conjugate of a novel fumagillin-derived MetAP2 inhibitor (SDX-7539) attached via a cleavable linker to a hydroxypropylmethacrylamide (HPMA) backbone, intended to limit CNS penetration and therefore reduce CNS toxicity. In vitro MetAP2 binding assays showed that SDX-7320 was unable to bind to MetAP2 while SDX-7539 was a potent binder (apparent IC50 = 0.13 nM), indicating that cleavage of SDX-7320 is required for biologic activity. SDX-7539 inhibited proliferation of human umbilical vein endothelial cells (HUVECs) with an apparent IC50 = 0.2 nM. The preclinical efficacy of SDX-7320 was evaluated in mouse models of obesity/insulin resistance and also in syngeneic tumor models coupled with high fat diet-induced obesity (DIO)/metabolic dysfunction. Obesity and insulin resistance were induced in C57Bl/6 mice by feeding them a high-fat diet (HFD) for at least 12 weeks. SDX-7320 was dosed subcutaneously every 4 days (for 28 days) into DIO mice or control mice fed a low-fat diet. SDX-7320 caused significant reduction in body weight and fat mass in obese mice while also reversing insulin resistance relative to controls. In addition, SDX-7320 caused greater reduction in body weight in obese mice relative to lean mice. Circulating levels of leptin and insulin were reduced while levels of adiponectin were increased in response to SDX-7320. In mouse models of obesity-accelerated tumor growth, SDX-7320 was more efficacious in obese relative to lean mice harboring subcutaneous B16F10 melanoma or EO771 mammary gland tumors. These effects occurred without any signs of neurotoxicity. SDX-7320, currently in phase I (solid tumors; all-comers; NCT02743637), is being developed for the treatment of cancers whose progression is accelerated in the setting of obesity and host metabolic dysfunction, termed “metabo-oncology.” Citation Format: Peter Cornelius, John S. Petersen, Benjamin Mayes, David Turnquist, Kimberly Sullivan, Alfred Anderson-Villaluz, Robert Lutz, Sara Little, Andrew Slee, Bradley J. Carver, James Shanahan. Preclinical activity of SDX-7320 in mouse models of obesity and obesity-driven cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4919.

Regulation of the activins-follistatins-inhibins axis by energy status: Impact on reproductive function

BackgroundWe have previously demonstrated that the adipose tissue derived hormone leptin controls reproductive function by regulating the hypothalamic-pituitary-gonadal axis in response to energy deficiency. Here, we evaluate the activins-follistatins-inhibins (AFI) axis during acute (short-term fasting in healthy people) and chronic energy deficiency (women with hypothalamic amenorrhea due to strenuous exercise [HA]) and investigate their relation to leptin and reproductive function in healthy subjects and subjects with HA. MethodsThe AFI axis was investigated in: a) A double-blinded study in healthy subjects having three randomly assigned admissions, each time for four days: in the isocaloric fed state, complete fasting with placebo treatment, complete fasting with leptin replacement, b) A case-control study comparing women with HA vs healthy controls, c) An open-label interventional study investigating leptin treatment in women with HA over a period of up to three months, d) A randomized interventional trial investigating leptin treatment vs placebo in women with HA for nine months. ResultsThe circulating levels of activin A, activin B, follistatin and follistatin-like 3 change robustly in response to acute and chronic energy deficiency. Leptin replacement in acute energy deprivation does not affect the levels of these hormones suggesting an independent regulation by these two hormonal pathways. In chronic energy deficiency, leptin replacement restores only activin B levels, which are in turn associated with an increase in the number of dominant follicles. ConclusionsWe demonstrate for the first time that the AFI axis is affected both by acute and chronic energy deficiency. Partial restoration of a component of the axis, i.e. activin B only, through leptin replacement is associated with improved reproductive function in women with HA.

Feed restriction alters lipogenic and adipokine gene expression in visceral and subcutaneous fat depots in lamb

Currently, lipogenic and adipokine gene expression patterns in different fat depots during long-term feed restriction in growing lambs are poorly understood. This study aimed to determine the effects of long-term nutritional deficiency on lipogenic and adipokine gene expression in subcutaneous and visceral fat depots in lambs. Twenty male lambs (4 months old; 21.81±0.75kg body weight) were randomly assigned to either control or feed-restricted groups. After 60 days of maintenance-level feed restriction, femoral, omental, mesenteric, epicardial, and perirenal fat were collected. Gene expressions were estimated by quantitative real-time PCR, and plasma parameters were also determined. The results showed that feed restriction increased the plasma concentration of NEFA (P<0.05) at 30 days, and decreased the plasma concentration of triglycerides, glucose, and insulin (P<0.05) at 30 days and 60 days. Feed restriction decreased lipogenic gene expression (acetyl coenzyme A carboxylase alpha and fatty acid synthase) in all five fat depots. The related key regulating gene PPARγ mRNA decreased (P<0.05) in femoral, omental, and mesenteric fat depots, while sterol regulatory element binding transcription factor 1 decreased (P<0.05) in femoral fat depots. Perilipin, as a barrier to lipolysis, decreased (P<0.05) in femoral, omental and perirenal fat depots of the feed restriction group. Adipose tissue-derived hormone leptin mRNA decreased (P<0.05) in all five fat depots, while adiponectin decreased (P<0.05) only in omental, mesenteric, and epicardial depots. Macrophage marker CD68 mRNA increased (P<0.05) in femoral and mesenteric fat depots. In addition, tumor necrosis factor-α mRNA increased in femoral, omental, and mesenteric depots, whereas IL-1β mRNA increased in femoral and perirenal depots. IL-6 expression decreased in femoral, omental, and epicardial fat depot at the end of feed restriction. Nutritional deficiency induced different changes in lipogenic and adipokine gene expression between visceral and subcutaneous adipose tissue. The decreased leptin, adiponectin, and increased inflammatory factors may inhibit lipogenesis and stimulate lipolysis to protect the body against the threat of starvation.

Gender Specific Association of Serum Leptin and Insulinemic Indices with Nonalcoholic Fatty Liver Disease in Prediabetic Subjects.

Adipose tissue-derived hormone leptin plays a functional role in glucose tolerance through its effects on insulin secretion and insulin sensitivity which also represent the risk factors for nonalcoholic fatty liver disease (NAFLD). The present study explored the gender specific association of serum leptin and insulinemic indices with NAFLD in Bangladeshi prediabetic subjects. Under a cross-sectional analytical design a total of 110 ultrasound examined prediabetic subjects, aged 25–68 years consisting of 57.3% male (55.6% non NAFLD and 44.4% NAFLD) and 42.7% female (57.4% non NAFLD and 42.6% NAFLD), were investigated. Insulin secretory function (HOMA%B) and insulin sensitivity (HOMA%S) were calculated from homeostasis model assessment (HOMA). Serum leptin showed significant positive correlation with fasting insulin (r = 0.530, P = 0.004), postprandial insulin (r = 0.384, P = 0.042) and HOMA-IR (r = 0.541, P = 0.003) as well as significant negative correlation with HOMA%S (r = -0.388, P = 0.046) and HOMA%B (r = -0.356, P = 0.039) in male prediabetic subjects with NAFLD. In multiple linear regression analysis, log transformed leptin showed significant positive association with HOMA-IR (β = 0.706, P <0.001) after adjusting the effects of body mass index (BMI), triglyceride (TG) and HOMA%B in male subjects with NAFLD. In binary logistic regression analysis, only log leptin [OR 1.29 95% (C.I) (1.11–1.51), P = 0.001] in male subjects as well as HOMA%B [OR 0.94 95% (C.I) (0.89–0.98), P = 0.012], HOMA-IR [OR 3.30 95% (C.I) (0.99–10.95), P = 0.049] and log leptin [OR 1.10 95% (C.I) (1.01–1.20), P = 0.026] in female subjects were found to be independent determinants of NAFLD after adjusting the BMI and TG. Serum leptin seems to have an association with NAFLD both in male and female prediabetic subjects and this association in turn, is mediated by insulin secretory dysfunction and insulin resistance among these subjects.

Modulation of cue-induced firing of ventral tegmental area dopamine neurons by leptin and ghrelin.

Background/objectives:The rewarding value of palatable foods contributes to overconsumption, even in satiated subjects. Midbrain dopaminergic activity in response to reward-predicting environmental stimuli drives reward-seeking and motivated behavior for food rewards. This mesolimbic dopamine (DA) system is sensitive to changes in energy balance, yet it has thus far not been established whether reward signaling of DA neurons in vivo is under control of hormones that signal appetite and energy balance such as ghrelin and leptin.Subjects/methods:We trained rats (n=11) on an operant task in which they could earn two different food rewards. We then implanted recording electrodes in the ventral tegmental area (VTA), and recorded from DA neurons during behavior. Subsequently, we assessed the effects of mild food restriction and pretreatment with the adipose tissue-derived anorexigenic hormone leptin or the orexigenic hormone ghrelin on VTA DA reward signaling.Results:Animals showed an increase in performance following mild food restriction (P=0.002). Importantly, food-cue induced DA firing increased when animals were food restricted (P=0.02), but was significantly attenuated after leptin pretreatment (P=0.00). While ghrelin did affect baseline DA activity (P=0.025), it did not affect cue-induced firing (P⩾0.353).Conclusions:Metabolic signals, such as leptin, affect food seeking, a process that is dependent on the formation of cue-reward outcomes and involves midbrain DA signaling. These data show that food restriction engages the encoding of food cues by VTA DA neurons at a millisecond level and leptin suppresses this activity. This suggests that leptin is a key in linking metabolic information to reward signaling.

Limited impact on glucose homeostasis of leptin receptor deletion from insulin- or proglucagon-expressing cells.

Aims/hypothesisThe adipose tissue-derived hormone leptin plays an important role in the maintenance of body weight and glucose homeostasis. Leptin mediates its effects by interaction with leptin receptors (LepRb), which are highly expressed in the hypothalamus and other brain centres, and at lower levels in the periphery. Previous studies have used relatively promiscuous or inefficient Cre deleter strains, respectively, to explore the roles of LepR in pancreatic β and α cells. Here, we use two newly-developed Cre lines to explore the role of leptin signalling in insulin and proglucagon-expressing cells.MethodsLeptin receptor expression was measured in isolated mouse islets and highly-purified islet cells by RNASeq and quantitative RT-PCR. Mice lacking leptin signalling in pancreatic β, or in α and other proglucagon-expressing cells, were generated using Ins1Cre- or iGluCre-mediated recombination respectively of flox'd leptin receptor alleles. In vivo glucose homeostasis, changes in body weight, pancreatic histology and hormone secretion from isolated islets were assessed using standard techniques.ResultsLeptin receptor mRNA levels were at or below the level of detection in wild-type adult mouse isolated islets and purified cells, and leptin signalling to Stat3 phosphorylation was undetectable. Whereas male mice further deleted for leptin receptors in β cells exhibited no abnormalities in glucose tolerance up to 16 weeks of age, females transiently displayed improved glucose tolerance at 8 weeks (11.2 ± 3.2% decrease in area under curve; p < 0.05), and improved (39.0 ± 13.0%, P < 0.05) glucose-stimulated insulin secretion in vitro. No differences were seen between genotypes in body weight, fasting glucose or β/α cell ratio. Deletion of LepR from α-cells, a minority of β cells, and a subset of proglucagon-expressing cells in the brain, exerted no effects on body weight, glucose or insulin tolerance, nor on pancreatic hormone secretion assessed in vivo and in vitro.Conclusions/interpretationThe use here of a highly selective Cre recombinase indicates that leptin signalling plays a relatively minor, age- and sex-dependent role in the control of β cell function in the mouse. No in vivo role for leptin receptors on α cells, nor in other proglucagon-expressing cells, was detected in this study.

Hydrogen sulfide and endothelium-dependent vasorelaxation.

In addition to nitric oxide and carbon monoxide, hydrogen sulfide (H2S), synthesized enzymatically from l-cysteine or l-homocysteine, is the third gasotransmitter in mammals. Endogenous H2S is involved in the regulation of many physiological processes, including vascular tone. Although initially it was suggested that in the vascular wall H2S is synthesized only by smooth muscle cells and relaxes them by activating ATP-sensitive potassium channels, more recent studies indicate that H2S is synthesized in endothelial cells as well. Endothelial H2S production is stimulated by many factors, including acetylcholine, shear stress, adipose tissue hormone leptin, estrogens and plant flavonoids. In some vascular preparations H2S plays a role of endothelium-derived hyperpolarizing factor by activating small and intermediate-conductance calcium-activated potassium channels. Endothelial H2S signaling is up-regulated in some pathologies, such as obesity and cerebral ischemia-reperfusion. In addition, H2S activates endothelial NO synthase and inhibits cGMP degradation by phosphodiesterase 5 thus potentiating the effect of NO-cGMP pathway. Moreover, H2S-derived polysulfides directly activate protein kinase G. Finally, H2S interacts with NO to form nitroxyl (HNO)—a potent vasorelaxant. H2S appears to play an important and multidimensional role in endothelium-dependent vasorelaxation.

Molecular Linkages Between Diabetes and Alzheimer&amp;#39;s Disease: Current Scenario and Future Prospects

After the revolutionary Rotterdam study that suggested there was an increased risk of developing Alzheimer's disease (AD) in patients with type-2 diabetes mellitus (T2DM), a number of studies have provided direct evidence for the linkage between AD and T2DM. In recent years, AD is considered as a neuroendocrine disorder, also referred as type-3 diabetes. There is a growing list of evidence to suggest that, in addition to impaired insulin signaling, there are a number of additional factors that may act as mechanistic links between AD and T2DM. These factors mainly include hypercholesterolemia, dyslipidemia, hypercystinemia, inflammation, impaired insulin signaling and impaired central nervous response to the adipose tissue-derived hormone leptin. Increased cholesterol plays a crucial role in the abnormal metabolism of the amyloid precursor protein, leading to the accumulation of β-amyloid. In addition to impaired insulin signaling, diabetes has been found to accelerate the appearance of cerebrovascular inflammation and β-amyloid peptide (Aβ) deposition. Increased oxidative stress and production of advanced glycation end products are other probable marker linkages. However, the details of many of these molecular links still require extensive investigation. It is possible that a number of common molecular linkages exist between T2DM and AD. Understanding and analyzing the various molecular linkages between AD and T2DM may shed light on new tools that can be used for the early diagnosis and treatment of AD and also accelerate the identification of T2DM patients who are at high risk of AD.

Severe Acute Malnutrition in Childhood: Hormonal and Metabolic Status at Presentation, Response to Treatment, and Predictors of Mortality

Malnutrition is a major cause of childhood morbidity and mortality. To identify and target those at highest risk, there is a critical need to characterize biomarkers that predict complications prior to and during treatment. We used targeted and nontargeted metabolomic analysis to characterize changes in a broad array of hormones, cytokines, growth factors, and metabolites during treatment of severe childhood malnutrition. Children aged 6 months to 5 years were studied at presentation to Mulago Hospital and during inpatient therapy with milk-based formulas and outpatient supplementation with ready-to-use food. We assessed the relationship between baseline hormone and metabolite levels and subsequent mortality. Seventy-seven patients were enrolled in the study; a subset was followed up from inpatient treatment to the outpatient clinic. Inpatient and outpatient therapies increased weight/height z scores and induced striking changes in the levels of fatty acids, amino acids, acylcarnitines, inflammatory cytokines, and various hormones including leptin, insulin, GH, ghrelin, cortisol, IGF-I, glucagon-like peptide-1, and peptide YY. A total of 12.2% of the patients died during hospitalization; the major biochemical factor predicting mortality was a low level of leptin (P = .0002), a marker of adipose tissue reserve and a critical modulator of immune function. We have used metabolomic analysis to provide a comprehensive hormonal and metabolic profile of severely malnourished children at presentation and during nutritional rehabilitation. Our findings suggest that fatty acid metabolism plays a central role in the adaptation to acute malnutrition and that low levels of the adipose tissue hormone leptin associate with, and may predict, mortality prior to and during treatment.

Leptin-Induced Endothelium-Dependent Vasorelaxation of Peripheral Arteries in Lean and Obese Rats: Role of Nitric Oxide and Hydrogen Sulfide

Adipose tissue hormone leptin induces endothelium-dependent vasorelaxation mediated by nitric oxide (NO) and endothelium-derived hyperpolarizing factors (EDHF). Previously it has been demonstrated that in short-term obesity the NO-dependent and the EDHF-dependent components of vascular effect of leptin are impaired and up-regulated, respectively. Herein we examined the mechanism of the EDHF-dependent vasodilatory effect of leptin and tested the hypothesis that alterations of acute vascular effects of leptin in obesity are accounted for by chronic hyperleptinemia. The study was performed in 5 groups of rats: (1) control, (2) treated with exogenous leptin for 1 week to induce hyperleptinemia, (3) obese, fed highly-palatable diet for 4 weeks, (4) obese treated with pegylated superactive rat leptin receptor antagonist (PEG-SRLA) for 1 week, (5) fed standard chow and treated with PEG-SRLA. Acute effect of leptin on isometric tension of mesenteric artery segments was measured ex vivo. Leptin relaxed phenylephrine-preconstricted vascular segments in NO- and EDHF-dependent manner. The NO-dependent component was impaired and the EDHF-dependent component was increased in the leptin-treated and obese groups and in the latter group both these effects were abolished by PEG-SRLA. The EDHF-dependent vasodilatory effect of leptin was blocked by either the inhibitor of cystathionine γ-lyase, propargylglycine, or a hydrogen sulfide (H2S) scavenger, bismuth (III) subsalicylate. The results indicate that NO deficiency is compensated by the up-regulation of EDHF in obese rats and both effects are accounted for by chronic hyperleptinemia. The EDHF-dependent component of leptin-induced vasorelaxation is mediated, at least partially, by H2S.

Leptin, blood pressure, and left ventricular mass in obese adolescents

Background Obesity is characterized by an excessive accumulationof body fat and has become a major health problem in industrializedsocieties especially with regards to heart disease. Adipose tissuederived hormone (leptin) can cause obesity. Leptin acts to reducefood consumption and enhance energy expenditure.Objective To assess for a relationship between leptin, bloodpressure, and left ventricular mass in obese adolescents.Methods This was a cross-sectional study conducted fromNovember 2011 to April 2012 in Prof. Dr. RD. Kandou Hospital.This study included obese and healthy adolescents aged 13-18years who attended school in Tuminting District ofManado. Eachsubject underwent measurements of body mass index (BMI), booldpressure, and plasma leptin level. Correlation regression test wasused for data analysis. Results were considered to be statisticallysignificant if P values &lt; 0.05.Results There was a significant relationship between leptin andleft ventricular mass (r=-0.467; P=0.006), as well as leptin andsystolic blood pressure (r=-0.366; P=0.028), but not betweenleptin and diastolic blood pressure (r=-0.261; P=0.09). We alsofound significant relationships between systolic blood pressure andleft ventricular mass (r=0.724; P&lt;0.001), and between diastolicblood pressure and left ventricular mass ( r=0.615; P&lt; 0.001) inobese adolescents.Conclusion Higher leptin levels are associated with lower leftventricular mass and lower systolic blood pressure, but are notassociated with diastolic blood pressure.

At the crossroad of T cells, adipose tissue, and diabetes

The study of how different intracellular metabolic signaling pathways impact the control of self-immune tolerance and how metabolic dysregulation in overweight, obesity, and diabetes is able to alter self-immune tolerance are topics of intensive investigation. Recent evidence suggests that metabolic and autoimmune diseases, both characterized by chronic inflammation and an altered self-immune tolerance, are more common in affluent countries. The reasons for such phenomena are still not completely understood, but the 'metabolic pressure' induced by nutritional overload, typical of more developed countries, seems to play a role. In this context, the discovery of the adipose tissue-derived hormone leptin has shed fundamental insights on how these processes might occur. We believe that there is a strong relationship among leptin, metabolic state, and immunological self-tolerance. We hypothesize that the leptin-induced metabolic pressure sets the basis for an exaggerated immuno-inflammatory response to altered self or non-self, leading to chronic inflammation, metabolic dysregulation, and autoimmunity in subjects with risk factors (i.e. genetic predisposition, environment, sex, infectious agents, etc). Capitalizing on our joint effort and trans-disciplinary expertise in metabolism, self-tolerance, and autoimmune diseases, this review highlights key questions on the basic mechanisms governing immune tolerance in the context of metabolic and autoimmune disease susceptibility.