apelin-13-peptide and Obesity

This study compared the effects of nonlinear resistance training (NRT), aerobic interval training (AIT), and detraining on adipokines and cardiometabolic risk factors in middle-aged obese men. Thirty-three obese men were randomly allocated to NRT (n = 12), AIT (n = 10), and control (CON, n = 11) groups. Subjects in experimental groups performed exercise protocols 3 days per week for 12 weeks followed by a 4-week detraining period. The NRT involved 55 min of weight training with flexible periodization. The AIT consisted of running on a treadmill (4 × 4-min intervals at 90% of maximal heart rate, with each interval separated by 3 min at 65%). Peak oxygen consumption increased significantly after training compared with CON (P < 0.01), but it increased more in the AIT group than in the NRT group (P = 0.004). After detraining, peak oxygen consumption decreased significantly in both training groups (P < 0.001); however, the value in the AIT group was still higher than that in the CON group (P = 0.003). No significant changes were observed in serum levels of omentin-1 and interleukin (IL)-18 after training (P > 0.05), but omentin-1 decreased significantly in both training groups and IL-18 increased significantly in the NRT group after detraining (P < 0.05). High-density lipoprotein cholesterol (HDL-C) increased significantly after training in the AIT group compared with the CON group (P < 0.05) and returned to the pre-training level after detraining. Conversely, apelin-13 increased significantly in response to training, compared with baseline (P < 0.05), and remained unchanged after detraining. Both training regimens had similar effects on most markers; however, AIT seems to have stronger anti-coronary disease effects (as indicated by HDL-C and peak oxygen consumption) than NRT.

Topics: Adiposity; Adult; Biomarkers; Body Mass Index; Cardiovascular Diseases; Cholesterol, HDL; Cytokines; GPI-Linked Proteins; High-Intensity Interval Training; Humans; Intercellular Signaling Peptides and Proteins; Interleukin-18; Iran; Lectins; Male; Metabolic Syndrome; Middle Aged; Obesity; Oxygen Consumption; Resistance Training; Risk Factors; Waist Circumference

To investigate the chronic effects of twice-daily administration of stable apelin analogues, apelin-13 amide and pyroglutamyl (pGlu) apelin-13 amide, on metabolic variables in glucose-intolerant and insulin-resistant diet-induced obese mice fed a high-fat diet for 150 days.. Groups of mice received twice-daily (9 am and 5 pm) injections of saline vehicle, apelin-13 amide, (pGlu)apelin-13 amide or exendin-4(1-39) for 28 days (all at 25 nmol/kg). Energy intake, body weight, non-fasting blood glucose, plasma insulin, glucose tolerance, metabolic response to feeding and insulin sensitivity, together with pancreatic hormone content and biochemical variables such as lipids and total GLP-1 were monitored. Dual-energy X-ray absorptiometry analysis and indirect calorimetry were also performed.. Administration of apelin-13 amide, (pGlu)apelin-13 amide or exendin-4 significantly decreased body weight, food intake and blood glucose and increased plasma insulin compared with high-fat-fed saline-treated controls (P < .05 and P < .001), Additionally, all peptide-treated groups exhibited improved glucose tolerance (oral and intraperitoneal), metabolic responses to feeding and associated insulin secretion. (pGlu)apelin-13 amide also significantly improved glycated haemoglobin and insulin sensitivity after 28 days. Both (pGlu)apelin-13 amide and exendin-4 increased bone mineral content and decreased respiratory exchange ratio, whereas only (pGlu)apelin-13 amide increased energy expenditure. All treatment groups displayed reduced circulating triglycerides and increased glucagon-like peptide-1 concentrations, although only (pGlu)apelin-13 amide significantly reduced LDL cholesterol and total body fat, and increased pancreatic insulin content.. These data indicate the therapeutic potential of stable apelin-13 analogues, with effects equivalent to or better than those of exendin-4.

Topics: Adiposity; Amides; Animals; Anti-Obesity Agents; Diabetes Mellitus, Type 2; Diet, High-Fat; Drug Stability; Energy Intake; Energy Metabolism; Exenatide; Glucagon-Like Peptide-1 Receptor; Hyperglycemia; Hypoglycemic Agents; Insulin Resistance; Intercellular Signaling Peptides and Proteins; Male; Mice; Obesity; Weight Loss

Apelin is a peptide ligand of the G-protein-coupled receptor APJ and exhibits anti-diabetes and anti-heart failure activities. However, short serum half-life of the apelin peptide limits its potential clinical applications. This study aimed to develop a long-acting apelin analog.. To extend apelin's in vivo half-life, we made a recombinant protein by fusing the IgG Fc fragment to apelin-13 (Fc-apelin-13), conducted pharmacokinetics studies in mice, and determined in vitro biological activities in suppressing cyclic adenosine monophosphate and activating extracellular signal-regulated kinase signalling by reporter assays. We investigated the effects of Fc-apelin-13 on food intake, body weight, fasting blood glucose and insulin levels, glucose tolerance test, hepatic steatosis, and cardiac function and fibrosis by subcutaneous administration of Fc-apelin-13 in diet-induced obese mice for 4 weeks.. The estimated half-life of Fc-apelin-13 in blood was approximately 33 hours. Reporter assays showed that Fc-apelin-13 was active in suppressing cyclic adenosine monophosphate response element and activating serum response element activities. Four weeks of Fc-apelin-13 treatment in obese mice did not affect food intake and body weight, but resulted in a significant improvement of glucose tolerance, and a decrease in hepatic steatosis and fibrosis, as well as in serum alanine transaminase levels. Moreover, cardiac stroke volume and output were increased and cardiac fibrosis was decreased in the treated mice.. Fc-apelin-13 fusion protein has an extended in vivo half-life and exerts multiple benefits on obese mice with respect to the improvement of glucose disposal, amelioration of liver steatosis and heart fibrosis, and increase of cardiac output. Hence, Fc-apelin-13 is potentially a therapeutic for obesity-associated disease conditions.

Topics: Animals; Diet; Fatty Liver; Heart Failure; Humans; Immunoglobulin Fc Fragments; Intercellular Signaling Peptides and Proteins; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Recombinant Fusion Proteins

Previous studies have shown that modified apelin analogues exhibited enzyme resistance in plasma and improved circulating half-life compared to apelin-13. This study investigated the antidiabetic effects of chronic administration of stable long acting fatty acid modified apelin analogues, namely, (Lys8GluPAL)apelin-13 amide and pGlu(Lys8GluPAL)apelin-13 amide, in high-fat fed obese-diabetic mice. Male NIH Swiss mice (groups n = 8) were maintained either on a high-fat diet (45% fat) from 8 to 28 weeks old, or control mice were fed a normal diet (10% fat). When diet induced obesity-diabetes was established after high-fat feeding, mice were injected i.p. once daily with apelin analogues, liraglutide (25 nmol/kg) or saline (controls). Administration of (Lys8GluPAL)apelin-13 amide and pGlu(Lys8GluPAL)apelin-13 amide for 28 days significantly reduced food intake and decreased body weight. Non-fasting glucose was reduced (p<0.01 to p<0.001) and plasma insulin concentrations increased (p<0.01 to p<0.001). This was accompanied by enhanced insulin responses (p<0.01 to p<0.001) and significant reductions in glucose excursion after oral (p<0.01) or i.p. (p<0.01) glucose challenges and feeding. Apelin analogues also significantly improved HbA1c (p<0.01), enhanced insulin sensitivity (p<0.01), reduced triglycerides (p<0.001), increased HDL-cholesterol (p<0.01) and decreased LDL-cholesterol (p<0.01), compared to high-fat fed saline treated control mice. Cholesterol levels were decreased (p<0.01) by pGlu(Lys8GluPAL)apelin-13 amide and both apelin treated groups showed improved bone mineral content, reduced fat deposits and increased plasma GLP-1. Daily treatment with liraglutide mirrored many of these changes (not on bone or adipose tissue), but unlike apelin analogues increased plasma amylase. Consumption of O2, production of CO2, respiratory exchange ratio and energy expenditure were improved by apelin analogues. These results indicate that long-term treatment with acylated analogues (Lys8GluPAL)apelin-13 amide and particularly pGlu(Lys8GluPAL)apelin-13 amide resulted in similar or enhanced therapeutic responses to liraglutide in high-fat fed mice. Fatty acid derived apelin analogues represent a new and exciting development in the treatment of obesity-diabetes.

Topics: Acylation; Amides; Animals; Anti-Obesity Agents; Diabetes Mellitus, Experimental; Diet, High-Fat; Hypoglycemic Agents; Intercellular Signaling Peptides and Proteins; Lipids; Male; Mice; Obesity; Time Factors

Apelin-13, an endogenous ligand for the apelin (APJ) receptor, behaves as a potent modulator of metabolic and cardiovascular disorders. Here, we examined the effects of apelin-13 on myocardial injury in a mouse model combining ischaemia/reperfusion (I/R) and obesity and explored their underlying mechanisms.. Adult male C57BL/6J mice were fed a normal diet (ND) or high-fat diet (HFD) for 6 months and then subjected to cardiac I/R. The effects of apelin-13 post-treatment on myocardial injury were evaluated in HFD-fed mice after 24 h I/R. Changes in protein abundance, phosphorylation, subcellular localization and mRNA expression were determined in cardiomyoblast cell line H9C2, primary cardiomyocytes and cardiac tissue from ND- and HFD-fed mice. Apoptosis was evaluated by TUNEL staining and caspase-3 activity. Mitochondrial ultrastructure was analysed by electron microscopy.. In HFD-fed mice subjected to cardiac I/R, i.v. administration of apelin-13 significantly reduced infarct size, myocardial apoptosis and mitochondrial damage compared with vehicle-treated animals. In H9C2 cells and primary cardiomyocytes, apelin-13 induced FoxO1 phosphorylation and nuclear exclusion. FoxO1 silencing by siRNA abolished the protective effects of apelin-13 against hypoxia-induced apoptosis and mitochondrial ROS generation. Finally, apelin deficiency in mice fed a HFD resulted in reduced myocardial FoxO1 expression and impaired FoxO1 distribution.. These data reveal apelin as a novel regulator of FoxO1 in cardiac cells and provide evidence for the potential of apelin-13 in prevention of apoptosis and mitochondrial damage in conditions combining I/R injury and obesity.

Topics: Animals; Apoptosis; Diet, High-Fat; Forkhead Box Protein O1; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Myocardial Reperfusion Injury; Obesity

The central administration of apelin, a recently identified adipokine, has been shown to affect food and water intake. The present study investigated whether body weight could affect an animal's response to apelin. The effects of centrally-administered apelin-13 on food and water intake, activity and metabolic rate were investigated in adult male diet-induced obese (DIO) rats fed either a high fat (32%) or control diet. Rats were administered i.c.v. apelin-13, 15-30 min prior to lights out, and food and water intake, activity and metabolic rate were assessed. Intracerebroventricular administration of apelin-13 decreased food and water intake and respiratory exchange ratio in DIO rats on the control diet, but had no effect in DIO rats on the high-fat diet. In an effort to identify potential central mechanisms explaining the observed physiological responses, the mRNA level of the apelin receptor, APJ, was examined in the hypothalamus. A high-fat diet induced an up-regulation of the expression of the receptor. Apelin induced a down-regulation of the receptor, but only in the DIO animals on the high-fat diet. In conclusion, we have demonstrated a diminished central nervous system response to apelin that is coincident with obesity.

Topics: Animals; Apelin Receptors; Body Weight; Cytokines; Diet; Dietary Fats; Drinking; Eating; Energy Metabolism; Hypothalamus; Insulin; Intercellular Signaling Peptides and Proteins; Leptin; Male; Obesity; Plasminogen Activator Inhibitor 1; Rats; Receptors, G-Protein-Coupled