Tissue-Specific Effects of Leptin on Glucose and Lipid Metabolism

Abstract The discovery of leptin was intrinsically associated with its ability to regulate body weight. However, the effects of leptin are more far-reaching and include profound glucose-lowering and anti-lipogenic effects, independent of leptin’s regulation of body weight. Regulation of glucose metabolism by leptin is mediated both centrally and via peripheral tissues and is influenced by the activation status of insulin signaling pathways. Ectopic fat accumulation is diminished by both central and peripheral leptin, an effect that is beneficial in obesity-associated disorders. The magnitude of leptin action depends upon the tissue, sex, and context being examined. Peripheral tissues that are of particular relevance include the endocrine pancreas, liver, skeletal muscle, adipose tissues, immune cells, and the cardiovascular system. As a result of its potent metabolic activity, leptin is used to control hyperglycemia in patients with lipodystrophy and is being explored as an adjunct to insulin in patients with type 1 diabetes. To fully understand the role of leptin in physiology and to maximize its therapeutic potential, the mechanisms of leptin action in these tissues needs to be further explored.

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The Potential Association between the Risk of Post-Surgical Adhesion and the Activated Local Angiotensin II Type 1 Receptors: Need for Novel Treatment Strategies

Gastrointestinal Tumors ◽

10.1159/000514614 ◽

2021 ◽

pp. 1-8

Author(s):

Mahmood Tavakkoli ◽

Saeed Aali ◽

Borzoo Khaledifar ◽

Gordon A. Ferns ◽

Majid Khazaei ◽

...

Keyword(s):

Angiotensin Ii ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Therapeutic Potential ◽

Angiotensin Receptor Blockers ◽

Surgical Techniques ◽

Treatment Strategies ◽

Transforming Growth Factor Β

Background: Post-surgical adhesion bands (PSABs) are a common complication after abdominal or pelvic surgeries for different reasons like cancer treatment. Despite improvements in surgical techniques and the administration of drugs or the use of physical barriers, there has only been limited improvement in the frequency of postoperative adhesions. Complications of PSAB are pain, infertility, intestinal obstruction, and increased mortality. The most important molecular mechanisms for the development of PSAB are inflammatory response, oxidative stress, and overexpression of pro-fibrotic molecules such as transforming growth factor β. However, questions remain about the pathogenesis of this problem, for example, the causes for individual differences or why certain tissue sites are more prone to post-surgical adhesions. Summary: Addressing the pathological causes of PSAB, the potential role of local angiotensin II/angiotensin II type 1 receptors (AngII/AT1R), may help to prevent this problem. Key Message: The objective of this article was to explore the role of the AngII/AT1R axis potential to induce PSAB and the therapeutic potential of angiotensin receptor blockers in the prevention and treatment of PSAB.

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How glucagon-like peptide 1 receptor agonists work

Endocrine Connections ◽

10.1530/ec-21-0130 ◽

2021 ◽

Author(s):

Christine Rode Andreasen ◽

Andreas Andersen ◽

Filip Krag Knop ◽

Tina Vilsbøll

Keyword(s):

Body Weight ◽

Therapeutic Potential ◽

Clinical Effects ◽

Glucose Lowering ◽

Receptor Agonists ◽

Reduce Body Weight ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1 ◽

Clinical Utilisation

Recent years, glucagon-like peptide 1 receptor agonists (GLP-1RAs) have become central in the treatment of type 2 diabetes (T2D). In addition to their glucose-lowering properties with low risk of hypoglycaemia, GLP-1RAs reduce body weight and show promising results in reducing cardiovascular risk and renal complications in high-risk individuals with T2D. These findings have changed guidelines on T2D management over the last years, and GLP-1RAs are now widely used in overweight patients with T2D as well as in patients with T2D and cardiovascular disease regardless of glycaemic control. The currently available GLP-1RAs have different pharmacokinetic profiles and differ in their ability to improve glycaemia, reduce body weight and in their cardio- and renal protective potentials. Understanding how these agents work, including insights into their pleiotropic effects on T2D pathophysiology, may improve their clinical utilisation and be useful for exploring other indications such as non-alcoholic steatohepatitis and neurodegenerative disorders. In this review, we provide an overview of approved GLP-1RAs, their clinical effects and mode of actions, and we offer insights into the potential of GLP-1RAs for other indications than T2D. Finally, we will discuss the emerging data and therapeutic potential of using GLP-1RAs in combinations with other receptor agonists.

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Role of the KCNJ Gene Variants in the Clinical Outcome of Type 1 Diabetes

Hormone and Metabolic Research ◽

10.1055/a-1204-5443 ◽

2020 ◽

Vol 52 (12) ◽

pp. 856-860

Author(s):

Annalisa Blasetti ◽

Valeria Castorani ◽

Laura Comegna ◽

Simone Franchini ◽

Giovanni Prezioso ◽

...

Keyword(s):

Pediatric Patients ◽

Therapeutic Potential ◽

Insulin Requirement ◽

Gene Variants ◽

Nucleotide Polymorphisms ◽

Binding Function ◽

Inwardly Rectifying

AbstractDiabetes is considered as a disease with a wide and continuous clinical spectrum, ranging from Type 1 (T1D) and Type 2 Diabetes (T2D) with complex multifactorial causes. In the last years, particular attention has been focused on the predictive value and therapeutic potential of single nucleotide polymorphisms (SNPs). SNPs can alter the seed-sequence in miRNA’s loci and miRNA target sites causing changes in the structure and influencing the binding function. Only few studies have investigated the clinical influence of SNPs, in particular potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ) gene variants in T1D population. The aim of the study is to investigate the occurrence and the possible metabolic significance of KCNJ polymorphism in a group of pediatric patients with T1D. The study was performed in a cohort of 90 Caucasian children and adolescents with T1D and 93 healthy subjects. Rs5210 polymorphism has been analyzed with a prevalence of the GG genotype in the patient group suggesting its association with T1D. Therefore, a relationship was found between GG genotype and body mass index (BMI) at diagnosis and insulin requirement (IR) after 6 months. The study suggested an action for rs5210 in determining the metabolic features of T1D pediatric patients, by showing some clues of insulin resistance in patients carrying that polymorphism.

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Complement activation-related cardiac anaphylaxis in pigs: role of C5a anaphylatoxin and adenosine in liposome-induced abnormalities in ECG and heart function

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00622.2005 ◽

2006 ◽

Vol 290 (3) ◽

pp. H1050-H1058 ◽

Cited By ~ 56

Author(s):

János Szebeni ◽

Lajos Baranyi ◽

Sándor Sávay ◽

Michael Bodó ◽

János Milosevits ◽

...

Keyword(s):

Therapeutic Potential ◽

Heart Function ◽

Cardiac Anaphylaxis ◽

Cardiac Abnormalities ◽

Life Threatening ◽

Amplifying Effect ◽

C5a Anaphylatoxin

Cardiac anaphylaxis is a severe, life-threatening manifestation of acute hypersensitivity reactions to allergens and drugs. Earlier studies highlighted an amplifying effect of locally applied C5a on the process; however, the role of systemic complement (C) activation with C5a liberation in blood has not been explored to date. In the present study, we used the porcine liposome-induced cardiopulmonary distress model for 1) characterizing and quantifying peripheral C activation-related cardiac dysfunction; 2) exploring the role of C5a in cardiac abnormalities and therapeutic potential of C blockage by soluble C receptor type 1 (sCR1) and an anti-C5a antibody (GS1); and 3) elucidating the role of adenosine and adenosine receptors in paradoxical bradycardia, one of the symptoms observed in this model. Pigs were injected intravenously with different liposomes [Doxil and multilamellar vesicles (MLV)], zymosan, recombinant human (rhu) C5a, and adenosine, and the ensuing hemodynamic and cardiac changes (hypotension, tachy- or bradycardia, arrhythmias, ST-T changes, ventricular fibrillation, and arrest) were quantified by ranking on an arbitrary scale [cardiac abnormality score (CAS)]. There was significant correlation between CAS and C5a production by liposomes in vitro, and the liposome-induced cardiac abnormalities were partially or fully reproduced with zymosan, rhuC5a, adenosine, and the selective adenosine A1 receptor agonist cyclopentyl-adenosine. The use of C nonactivator liposomes or pretreatment of pigs with sCR1 or GS1 attenuated the abnormalities. The selective A1 blocker cyclopentyl-xanthine inhibited bradycardia without influencing hypotension, whereas the A2 blocker 4-(2-{7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino}ethyl)phenol (ZM-24135) had no such effect. These data suggest that 1) systemic C activation can underlie cardiac anaphylaxis, 2) C5a plays a causal role in the reaction, 3) adenosine action via A1 receptors may explain paradoxical bradycardia, and 4) inhibition of C5a formation or action or of A1-receptor function may alleviate the acute cardiotoxicity of liposomal drugs and other intravenous agents that activate C.

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Role of Cannabinoid Receptor Type 1 in Insulin Resistance and Its Biological Implications

International Journal of Molecular Sciences ◽

10.3390/ijms20092109 ◽

2019 ◽

Vol 20 (9) ◽

pp. 2109 ◽

Cited By ~ 6

Author(s):

Arulkumar Nagappan ◽

Jooyeon Shin ◽

Myeong Ho Jung

Keyword(s):

Insulin Resistance ◽

Body Weight ◽

Insulin Sensitivity ◽

Hepatic Steatosis ◽

Cannabinoid Receptor ◽

Inflammatory Responses ◽

Hepatic Insulin Resistance ◽

Leptin Resistance ◽

Peripheral Tissues

Endogenous cannabinoids (ECs) are lipid-signaling molecules that specifically bind to cannabinoid receptor types 1 and 2 (CB1R and CB2R) and are highly expressed in central and many peripheral tissues under pathological conditions. Activation of hepatic CB1R is associated with obesity, insulin resistance, and impaired metabolic function, owing to increased energy intake and storage, impaired glucose and lipid metabolism, and enhanced oxidative stress and inflammatory responses. Additionally, blocking peripheral CB1R improves insulin sensitivity and glucose metabolism and also reduces hepatic steatosis and body weight in obese mice. Thus, targeting EC receptors, especially CB1R, may provide a potential therapeutic strategy against obesity and insulin resistance. There are many CB1R antagonists, including inverse agonists and natural compounds that target CB1R and can reduce body weight, adiposity, and hepatic steatosis, and those that improve insulin sensitivity and reverse leptin resistance. Recently, the use of CB1R antagonists was suspended due to adverse central effects, and this caused a major setback in the development of CB1R antagonists. Recent studies, however, have focused on development of antagonists lacking adverse effects. In this review, we detail the important role of CB1R in hepatic insulin resistance and the possible underlying mechanisms, and the therapeutic potential of CB1R targeting is also discussed.

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UCP1-independent glucose-lowering effect of leptin in type 1 diabetes: only in conditions of hypoleptinemia

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00253.2019 ◽

2020 ◽

Vol 318 (1) ◽

pp. E72-E86

Author(s):

Petr Zouhar ◽

Günaj Rakipovski ◽

Muhammad Hamza Bokhari ◽

Oliver Busby ◽

Johan F. Paulsson ◽

...

Keyword(s):

Type 1 Diabetes ◽

Therapeutic Potential ◽

Uncoupling Protein ◽

Leptin Resistance ◽

Diabetic Mice ◽

High Fat ◽

Glucose Lowering ◽

Lowering Effect ◽

Glucose Lowering Effect

The possibility to use leptin therapeutically for lowering glucose levels in patients with type 1 diabetes has attracted interest. However, earlier animal models of type 1 diabetes are severely catabolic with very low endogenous leptin levels, unlike most patients with diabetes. Here, we aim to test glucose-lowering effects of leptin in novel, more human-like murine models. We examined the glucose-lowering potential of leptin in diabetic models of two types: streptozotocin-treated mice and mice treated with the insulin receptor antagonist S961. To prevent hypoleptinemia, we used combinations of thermoneutral temperature and high-fat feeding. Leptin fully normalized hyperglycemia in standard chow-fed streptozotocin-treated diabetic mice. However, more humanized physiological conditions (high-fat diets or thermoneutral temperatures) that increased adiposity — and thus also leptin levels — in the diabetic mice abrogated the effects of leptin, i.e., the mice developed leptin resistance also in this respect. The glucose-lowering effect of leptin was not dependent on the presence of the uncoupling protein-1 and was not associated with alterations in plasma insulin, insulin-like growth factor 1, food intake or corticosterone but fully correlated with decreased plasma glucagon levels and gluconeogenesis. An important implication of these observations is that the therapeutic potential of leptin as an additional treatment in patients with type 1 diabetes is probably limited. This is because such patients are treated with insulin and do not display low leptin levels. Thus, the potential for a glucose-lowering effect of leptin would already have been attained with standard insulin therapy, and further effects on blood glucose level through additional leptin cannot be anticipated.

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Update on the Role of Cannabinoid Receptors after Ischemic Stroke

Mediators of Inflammation ◽

10.1155/2012/824093 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 24

Author(s):

Luciano S. A. Capettini ◽

Silvia Q. Savergnini ◽

Rafaela F. da Silva ◽

Nikos Stergiopulos ◽

Robson A. S. Santos ◽

...

Keyword(s):

Ischemic Stroke ◽

Cannabinoid Receptors ◽

Inflammatory Diseases ◽

Receptor Activation ◽

Protective Effects ◽

Peripheral Tissues ◽

Transmembrane Receptors ◽

Anti Inflammatory

Cannabinoids are considered as key mediators in the pathophysiology of inflammatory diseases, including atherosclerosis. In particular, they have been shown to reduce the ischemic injury after acute cardiovascular events, such as acute myocardial infarction and ischemic stroke. These protective and anti-inflammatory properties on peripheral tissues and circulating inflammatory have been demonstrated to involve their binding with both selective cannabinoid type 1 (CB1) and type 2 (CB2) transmembrane receptors. On the other hands, the recent discoveries of novel different classes of cannabinoids and receptors have increased the complexity of this system in atherosclerosis. Although only preliminary data have been reported on the activities of novel cannabinoid receptors, several studies have already investigated the role ofCB1andCB2receptors in ischemic stroke. WhileCB1receptor activation has been shown to directly reduce atherosclerotic plaque inflammation, controversial data have been shown on neurotransmission and neuroprotection after stroke. Given its potent anti-inflammatory activities on circulating leukocytes, theCB2activation has been proven to produce protective effects against acute poststroke inflammation. In this paper, we will update evidence on different cannabinoid-triggered avenues to reduce inflammation and neuronal injury in acute ischemic stroke.

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Mediation of Endogenous β-Endorphin in the Plasma Glucose-Lowering Action of Herbal Products Observed in Type 1-Like Diabetic Rats

Evidence-based Complementary and Alternative Medicine ◽

10.1093/ecam/nen078 ◽

2011 ◽

Vol 2011 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

I. M. Liu ◽

J. T. Cheng

Keyword(s):

Adrenal Gland ◽

Glucose Homeostasis ◽

Plasma Glucose ◽

Biological Effects ◽

Diabetic Rats ◽

Herbal Products ◽

Peripheral Tissues ◽

Glucose Lowering ◽

Stimulation Of

Recently, there have been advances in the development of new substances effective in managing diabetic disorders. Opioid receptors couple multiple systems to result in various biological effects, although opioids are best known for analgesia. In the present review, we used our recent data to describe the advance in plasma glucose-lowering action of herbal products, especially the mediation of β-endorphin in glucose homeostasis of insulin-deficient diabetes. In type 1-like streptozotocin-induced diabetic rats, we identified many products purified from herbs that show a dose-dependent plasma glucose-lowering action. Increase in β-endorphin secretion from the adrenal gland may activate peripheral opioid μ-receptors (MOR) to enhance the expression of muscle glucose transporters and/or to reduce hepatic gluconeogenesis at the gene level, thereby leading to improved glucose utilization in peripheral tissues for amelioration of severe hyperglycemia. It has also been observed that stimulation of α1-adrenoceptors (α1-ARs) in the adrenal gland by some herbal products is responsible for the increase in β-endorphin secretion via a phospholipase C-protein kinase dependent pathway. However, an increase in β-endorphin secretion from the adrenal gland by herbal products can function via another receptor. New insights into the mediation of endogenous β-endorphin activation of peripheral MOR by herbal products for regulation of glucose homeostasis without the presence of insulin have been established. Therefore, an increase in β-endorphin secretion and/or direct stimulation of peripheral MOR via an insulin-independent action might serve as the potential target for development of a therapeutic agent or promising adjuvant in intensive plasma glucose control.

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The role of AMP-activated protein kinase in the coordination of skeletal muscle turnover and energy homeostasis

AJP Cell Physiology ◽

10.1152/ajpcell.00125.2012 ◽

2012 ◽

Vol 303 (5) ◽

pp. C475-C485 ◽

Cited By ~ 70

Author(s):

Anthony M. J. Sanchez ◽

Robin B. Candau ◽

Alfredo Csibi ◽

Allan F. Pagano ◽

Audrey Raibon ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Energy Homeostasis ◽

Therapeutic Potential ◽

Energy Status ◽

Muscle Plasticity ◽

Glucose And Lipid Metabolism ◽

Muscle Homeostasis ◽

Amp Activated Protein Kinase

The AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that acts as a sensor of cellular energy status switch regulating several systems including glucose and lipid metabolism. Recently, AMPK has been implicated in the control of skeletal muscle mass by decreasing mTORC1 activity and increasing protein degradation through regulation of ubiquitin-proteasome and autophagy pathways. In this review, we give an overview of the central role of AMPK in the control of skeletal muscle plasticity. We detail particularly its implication in the control of the hypertrophic and atrophic signaling pathways. In the light of these cumulative and attractive results, AMPK appears as a key player in regulating muscle homeostasis and the modulation of its activity may constitute a therapeutic potential in treating muscle wasting syndromes in humans.

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Role of endocannabinoid system in the pathogenesis of obesity: how can we help a patient? From theory to practice

Russian Medical Inquiry ◽

10.32364/2587-6821-2020-4-6-382-389 ◽

2020 ◽

Vol 4 (6) ◽

pp. 382-389

Author(s):

V.A. Dudareva ◽

◽

M.L. Maksimov ◽

I.G. Djadikova ◽

A.A. Zveginceva ◽

...

Keyword(s):

Metabolic Syndrome ◽

Cannabinoid Receptors ◽

Cannabinoid Receptor ◽

Endocannabinoid System ◽

Medical Society ◽

Cannabinoid Receptor 1 ◽

Peripheral Tissues ◽

Theory To Practice

Obesity that results in various metabolic disorders is one of the central concerns of modern healthcare system. Only 4% to 5% of patients with metabolic syndrome achieve favorable outcomes without any additional pharmacotherapy. Therefore, many patients require weight-loss drugs in addition to non-pharmacological treatments. The endocannabinoid system and the drugs that affect its functions receive a widespread attention of medical society due to its effects on behavioral and cerebral functions and its potential use as a therapeutic “target” in various peripheral and neurological psychiatric disorders. Among known to date cannabinoid receptors, type 1 receptors play a role in the development of obesity. It was demonstrated that the blockade of these receptors in the hypothalamus reduces appetite, inhibits adipocyte activation in peripheral tissues, prevents lipogenesis, and increases the level of adiponectin. The result is the decreased levels of atherogenic lipoproteins and improved insulin resistance. This article addresses the results of fundamental and clinical studies on Dietressa, a drug composed of affine-purified antibodies to cannabinoid receptor 1. Case report of a patient with obesity that analyzes pharmaceutical and non-pharmaceutical treatment approaches is described.KEYWORDS: obesity, metabolic syndrome, diet, endocannabinoid system, cannabinoids, cannabinoid receptors, affine-purified antibodies.FOR CITATION: Dudareva V.A., Maksimov M.L., Djadikova I.G. et al. Role of endocannabinoid system in the pathogenesis of obesity: how can we help a patient? From theory to practice. Russian Medical Inquiry. 2020;4(6):382–389. DOI: 10.32364/2587-6821-2020-4-6-382-389.

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