The Effects of Neuropeptide B on Proliferation and Differentiation of Porcine White Preadipocytes into Mature Adipocytes.

Neuropeptide B (NPB) affects energy homeostasis and metabolism by binding and activating NPBWR1 and NPBWR2 in humans and pigs. Recently, we reported that NPB promotes the adipogenesis of rat white and brown preadipocytes as well as 3T3-L1 cells. In the present study, we evaluated the effects of NPB on the proliferation and differentiation of white porcine preadipocytes into mature adipocytes. We identified the presence of NPB, NPBWR1, and NPBWR2 on the mRNA and protein levels in porcine white preadipocytes. During the differentiation process, NPB increased the mRNA expression of PPARγ, C/EBPß, C/EBPα, PPARγ, and C/EBPß protein production in porcine preadipocytes. Furthermore, NPB stimulated lipid accumulation in porcine preadipocytes. Moreover, NPB promoted the phosphorylation of the p38 kinase in porcine preadipocytes, but failed to induce ERK1/2 phosphorylation. NPB failed to stimulate the expression of C/EBPß in the presence of the p38 inhibitor. Taken together, we report that NPB promotes the differentiation of porcine preadipocytes via a p38-dependent mechanism.

PuraStat in gastrointestinal bleeding: results of a prospective multicentre observational pilot study.

BACKGROUND: A recently developed haemostatic peptide gel for endoscopic application has been introduced to improve the management of gastrointestinal bleeding. The aim of this pilot study was to evaluate the feasibility, safety, efficacy and indication profiles of PuraStat in a clinical setting. METHODS: In this prospective observational multicentre pilot study, patients with acute non-variceal gastrointestinal bleeding (upper and lower) were included. Primary and secondary application of PuraStat was evaluated. Haemoglobin, prothrombin time, platelets and transfusion behaviour were documented before and after haemostasis. The efficacy of PuraStat was assessed during the procedure, at 3 days and 1 week after application. RESULTS: 111 patients with acute gastrointestinal bleeding were recruited into the study. 70 percent (78/111) of the patients had upper gastrointestinal bleeding and 30% (33/111) had lower gastrointestinal bleeding. After primary application of PuraStat, initial haemostatic success was achieved in 94% of patients (74/79, 95% CI 88-99%), and in 75% of the patients when used as a secondary haemostatic product, following failure of established techniques (24/32, 95% CI 59-91%). The therapeutic success rates (absence of rebleeding) after 3 and 7 days were 91% and 87% after primary use, and 87% and 81% in all study patients. Overall rebleeding rate at 30 day follow-up was 16% (18/111). In the 5 patients who finally required surgery (4.5%), PuraStat allowed temporary haemostasis and stabilisation. CONCLUSIONS: PuraStat expanded the therapeutic toolbox available for an effective treatment of gastrointestinal bleeding sources. It could be safely applied and administered without complications as a primary or secondary therapy. PuraStat may additionally serve as a bridge to surgery in order to achieve temporary haemostasis in case of refractory severe bleeding, possibly playing a role in preventing immediate emergency surgery.

Daily Treatment of Mice with Type 2 Diabetes with Adropin for Four Weeks Improves Glucolipid Profile, Reduces Hepatic Lipid Content and Restores Elevated Hepatic Enzymes in Serum.

Adropin is a peptide hormone encoded by Energy Homeostasis Associated gene. Adropin modulates energy homeostasis and metabolism of lipids and carbohydrates. There is growing evidence demonstrating that adropin enhances insulin sensitivity and lowers hyperlipidemia in obese mice. The aim of this study was to investigate the effects of daily administration of adropin for four weeks in mice with experimentally induced type 2 diabetes (T2D). Adropin improved glucose control without modulating insulin sensitivity. Adropin reduced body weight, size of adipocytes, blood levels of triacylglycerol and cholesterol in T2D mice. T2D mice treated with adropin had lower liver mass, reduced hepatic content of triacylglycerol and cholesterol. Furthermore, adropin attenuated elevated blood levels of hepatic enzymes (ALT, AST, GGT and ALP) in T2D mice. In T2D mice, adropin increased the circulating adiponectin level. Adropin had no effects on circulating insulin and glucagon levels and did not alter pancreatic islets morphology. These results suggest that adropin improves glucose control, lipid metabolism and liver functions in T2D. In conjunction with reduced lipid content in hepatocytes, these results render adropin as an interesting candidate in therapy of T2D.

The Role of Neuropeptide B and Its Receptors in Controlling Appetite, Metabolism, and Energy Homeostasis.

Neuropeptide B (NPB) is a peptide hormone that was initially described in 2002. In humans, the biological effects of NPB depend on the activation of two G protein-coupled receptors, NPBWR1 (GPR7) and NPBWR2 (GPR8), and, in rodents, NPBWR1. NPB and its receptors are expressed in the central nervous system (CNS) and in peripheral tissues. NPB is also present in the circulation. In the CNS, NPB modulates appetite, reproduction, pain, anxiety, and emotions. In the peripheral tissues, NPB controls secretion of adrenal hormones, pancreatic beta cells, and various functions of adipose tissue. Experimental downregulation of either NPB or NPBWR1 leads to adiposity. Here, we review the literature with regard to NPB-dependent control of metabolism and energy homeostasis.

Adropin stimulates proliferation but suppresses differentiation in rat primary brown preadipocytes.

Adropin is a peptide hormone encoded by Energy Homeostasis Associated (Enho) gene. Adropin modulates glucose and lipid metabolism, and adiposity. Recently, we found that adropin suppresses differentiation of rodent white preadipocytes into mature fat cells. By contrast, the role of adropin in controlling brown adipogenesis is largely unknown. Therefore, in the present study we evaluated the effects of adropin on proliferation and differentiation of adipocyte precursor cells in rats. Brown adipocyte precursor cells were isolated from male Wistar rats. Cell replication was measured by BrdU incorporation. Gene expression was studied using real time PCR. Protein phosphorylation and production was assessed by Western blot. Lipid accumulation was evaluated by Oil Red O staining. Colorimetric kits were used to evaluate glycerol and free fatty acids release. We report here that adropin stimulates proliferation of brown preadipocytes. Moreover, in brown preadipocytes, adropin suppresses mRNA expression of adipogenic genes (C/ebpα, C/ebpß, Pgc1α, Pparγ and Prdm16) during differentiation process. In addition, adropin suppresses UCP1 protein production in brown adipocytes. Finally, adropin reduces intracellular lipid content in brown adipocytes. These results indicate that adropin stimulates proliferation of brown preadipocytes and suppresses their differentiation into mature adipocytes.

FGF-1 modulates pancreatic ß-cell functions/metabolism: An in vitro study.

Fibroblast growth factor 1 (FGF-1), also known as acidic fibroblast growth factor (aFGF), is a growth factor and signaling protein encoded by the Fgf1 gene. Previous studies have shown that FGF-1 may also participate in the regulation of glucose metabolism, both in healthy organisms and in pathological conditions such as diabetes. Because insulin the main regulator of glucose metabolism is secreted from pancreatic beta cells, we investigated whether FGF-1 directly affects the secretion of this hormone and regulates the metabolism of beta cells and isolated pancreatic islets. By using insulin-producing INS-1E cells and isolated pancreatic islets, we investigated the effect of FGF-1 on cell proliferation, viability, apoptosis, and insulin expression and secretion. Our study showed that FGF1 and fibroblast growth factor receptors (FgfRs: FgfR1, FgfR2, FgfR3, and FgfR4) are present on mRNA level in INS-1E cells and isolated rat pancreatic islets. We also proved that FGF1 stimulates the proliferation of INS-1E beta cells and enhances the viability of these cells and that of isolated pancreatic islet cells, and that ERK1/2 kinase is involved in the regulation of INS-1E cell proliferation. Moreover, we found that FGF1 can stimulate insulin secretion from both INS-1E cells and isolated rat pancreatic islets. Thus, the FGF1 peptide increases cell survival and decreases cell death. The obtained results indicate that FGF1 may play a role in controlling the physiology and metabolism of pancreatic beta cells as well as glycemia.

Adropin as A Fat-Burning Hormone with Multiple Functions-Review of a Decade of Research.

Adropin is a unique hormone encoded by the energy homeostasis-associated (Enho) gene. Adropin is produced in the liver and brain, and also in peripheral tissues such as in the heart and gastrointestinal tract. Furthermore, adropin is present in the circulatory system. A decade after its discovery, there is evidence that adropin may contribute to body weight regulation, glucose and lipid homeostasis, and cardiovascular system functions. In this review, we summarize and discuss the physiological, metabolic, and pathophysiological factors regulating Enho as well as adropin. Furthermore, we review the literature addressing the role of adropin in adiposity and type 2 diabetes. Finally, we elaborate on the role of adropin in the context of the cardiovascular system, liver diseases, and cancer.

Glucagon regulates orexin A secretion in humans and rodents.

AIMS/HYPOTHESIS: Orexin A (OXA) modulates food intake, energy expenditure, and lipid and glucose metabolism. OXA regulates the secretion of insulin and glucagon, while glucose regulates OXA release. Here, we evaluate the role of glucagon in regulating OXA release both in vivo and in vitro. METHODS: In a double-blind crossover study, healthy volunteers and type 1 diabetic patients received either intramuscular glucagon or placebo. Patients newly diagnosed with type 2 diabetes underwent hyperinsulinaemic-euglycaemic clamp experiments, and insulin-hypoglycaemia tests were performed on healthy volunteers. The primary endpoint was a change in OXA levels after intramuscular glucagon or placebo administration in healthy participants and patients with type 1 diabetes. Secondary endpoints included changes in OXA in healthy participants during insulin tolerance tests and in patients with type 2 diabetes under hyperinsulinaemic-euglycaemic conditions. Participants and staff conducting examinations and taking measurements were blinded to group assignment. OXA secretion in response to glucagon treatment was assessed in healthy and obese mice, the streptozotocin-induced mouse model of type 1 diabetes, and isolated rat pancreatic islets. RESULTS: Plasma OXA levels declined in lean volunteers and in type 1 diabetic patients injected with glucagon. OXA levels increased during hyperinsulinaemic hypoglycaemia testing in healthy volunteers and during hyperinsulinaemic euglycaemic conditions in type 2 diabetic patients. Plasma OXA concentrations in healthy lean and obese mice and in a mouse model of type 1 diabetes were lower after glucagon treatment, compared with vehicle control. Glucagon decreased OXA secretion from isolated rat pancreatic islets at both low and high glucose levels. OXA secretion declined in pancreatic islets exposed to diazoxide at high and low glucose levels, and after exposure to an anti-insulin antibody. Glucagon further reduced OXA secretion in islets pretreated with diazoxide or an anti-insulin antibody. CONCLUSIONS/INTERPRETATION: Glucagon inhibits OXA secretion in humans and animals, irrespective of changes in glucose or insulin levels. Through modifying OXA secretion, glucagon may influence energy expenditure, body weight, food intake and glucose metabolism.

A mixed mirror-image DNA/RNA aptamer inhibits glucagon and acutely improves glucose tolerance in models of type 1 and type 2 diabetes.

Excessive secretion of glucagon, a functional insulin antagonist, significantly contributes to hyperglycemia in type 1 and type 2 diabetes. Accordingly, immunoneutralization of glucagon or genetic deletion of the glucagon receptor improved glucose homeostasis in animal models of diabetes. Despite this strong evidence, agents that selectively interfere with endogenous glucagon have not been implemented in clinical practice yet. We report the discovery of mirror-image DNA-aptamers (Spiegelmer®) that bind and inhibit glucagon. The affinity of the best binding DNA oligonucleotide was remarkably increased (>25-fold) by the introduction of oxygen atoms at selected 2'-positions through deoxyribo- to ribonucleotide exchanges resulting in a mixed DNA/RNA-Spiegelmer (NOX-G15) that binds glucagon with a Kd of 3 nm. NOX-G15 shows no cross-reactivity with related peptides such as glucagon-like peptide-1, glucagon-like peptide-2, gastric-inhibitory peptide, and prepro-vasoactive intestinal peptide. In vitro, NOX-G15 inhibits glucagon-stimulated cAMP production in CHO cells overexpressing the human glucagon receptor with an IC50 of 3.4 nm. A single injection of NOX-G15 ameliorated glucose excursions in intraperitoneal glucose tolerance tests in mice with streptozotocin-induced (type 1) diabetes and in a non-genetic mouse model of type 2 diabetes. In conclusion, the data suggest NOX-G15 as a therapeutic candidate with the potential to acutely attenuate hyperglycemia in type 1 and type 2 diabetes.

Neuronostatin regulates proliferation and differentiation of rat brown primary preadipocytes.

Neuronostatin suppresses the differentiation of white preadipocytes. However, the role of neuronostatin in brown adipose tissue remains elusive. Therefore, we investigated the impact of neuronostatin on the proliferation and differentiation of isolated rat brown preadipocytes. We report that neuronostatin and its receptor (GPR107) are synthesized in brown preadipocytes and brown adipose tissue. Furthermore, neuronostatin promotes the replication of brown preadipocytes via the AKT pathway. Notably, neuronostatin suppresses the expression of markers associated with brown adipogenesis (PGC-1α, PPARγ, PRDM16, and UCP1) and reduces cellular mitochondria content. Moreover, neuronostatin impedes the differentiation of preadipocytes by activating the JNK signaling pathway. These effects were not mimicked by somatostatin. Our results suggest that neuronostatin is involved in regulating brown adipogenesis.

Sex-specific cytotoxicity of ostarine in cardiomyocytes.

Ostarine is the most popular compound in the selective androgen receptor modulator group (SARMs). Ostarine is used as a physical performance-enhancing agent. The abuse of this agent in higher doses may lead to severe side effects. Here, we evaluate the effects of ostarine on the heart. We utilized a cardiomyocyte H9C2 cell line, isolated primary female and male cardiac fibroblast cells, as well as hearts obtained from rats. Ostarine increased the accumulation of two fibrosis protein markers, αSMA and fibronectin (p < 00.1) in male, but not in female fibroblast cells. Ostarine increased the expression of the cardiomyopathy marker ßMhc in the H9C2 cell line (p < 0.05) and in the heart in rats (p < 0.01). The unfavorable changes were observed at high ostarine doses. Moreover, a decrease in viability and an increase in cytotoxicity marker LDH were observed already at lowest dose (1 nmoL/l). Taken together, our results suggest that ostarine is cardiotoxic which may be more relevant in males than in females.

GIP_HUMAN [22-51] Peptide Encoded by the Glucose-Dependent Insulinotropic Polypeptide (GIP) Gene Suppresses Insulin Expression and Secretion in INS-1E Cells and Rat Pancreatic Islets.

GIP_HUMAN [22-51] is a recently discovered peptide that shares the same precursor molecule with glucose-dependent insulinotropic polypeptide (GIP). In vivo, chronic infusion of GIP_HUMAN [22-51] in ApoE-/- mice enhanced the development of aortic atherosclerotic lesions and upregulated inflammatory and proatherogenic proteins. In the present study, we evaluate the effects of GIP_HUMAN [22-51] on insulin mRNA expression and secretion in insulin-producing INS-1E cells and isolated rat pancreatic islets. Furthermore, we characterize the influence of GIP_HUMAN [22-51] on cell proliferation and death and on Nf-kB nuclear translocation. Rat insulin-producing INS-1E cells and pancreatic islets, isolated from male Wistar rats, were used in this study. Gene expression was evaluated using real-time PCR. Cell proliferation was studied using a BrdU incorporation assay. Cell death was quantified by evaluating histone-complexed DNA fragments. Insulin secretion was determined using an ELISA test. Nf-kB nuclear translocation was detected using immunofluorescence. GIP_HUMAN [22-51] suppressed insulin (Ins1 and Ins2) in INS-1E cells and pancreatic islets. Moreover, GIP_HUMAN [22-51] promoted the translocation of NF-κB from cytoplasm to the nucleus. In the presence of a pharmacological inhibitor of NF-κB, GIP_HUMAN [22-51] was unable to suppress Ins2 mRNA expression. Moreover, GIP_HUMAN [22-51] downregulated insulin secretion at low (2.8 mmol/L) but not high (16.7 mmol/L) glucose concentration. By contrast, GIP_HUMAN [22-51] failed to affect cell proliferation and apoptosis. We conclude that GIP_HUMAN [22-51] suppresses insulin expression and secretion in pancreatic ß cells without affecting ß cell proliferation or apoptosis. Notably, the effects of GIP_HUMAN [22-51] on insulin secretion are glucose-dependent.

Small molecule insulin mimetics reduce food intake and body weight and prevent development of obesity.

Obesity and insulin resistance are major risk factors for a number of metabolic disorders, such as type 2 diabetes mellitus. Insulin has been suggested to function as one of the adiposity signals to the brain for modulation of energy balance. Administration of insulin into the brain reduces food intake and body weight, and mice with a genetic deletion of neuronal insulin receptors are hyperphagic and obese. However, insulin is also an anabolic factor; when administered systemically, pharmacological levels of insulin are associated with body weight gain in patients. In this study, we investigated the efficacy and feasibility of small molecule insulin mimetic compounds to regulate key parameters of energy homeostasis. Central intracerebroventricular (i.c.v.) administration of an insulin mimetic resulted in a dose-dependent reduction of food intake and body weight in rats, and altered the expression of hypothalamic genes known to regulate food intake and body weight. Oral administration of a mimetic in a mouse model of high-fat diet-induced obesity reduced body weight gain, adiposity and insulin resistance. Thus, insulin mimetics have a unique advantage over insulin in the control of body weight and hold potential as a novel anti-obesity treatment.

Adropin Slightly Modulates Lipolysis, Lipogenesis and Expression of Adipokines but Not Glucose Uptake in Rodent Adipocytes.

Adropin is a peptide hormone which modulates energy homeostasis and metabolism. In animals with diet-induced obesity, adropin attenuates adiposity and improves lipid and glucose homeostasis. Adropin promotes the proliferation of rodent white preadipocytes and suppresses their differentiation into adipocytes. By contrast, the effects of adropin on mature white adipocytes are unknown. Therefore, we aimed to evaluate the effects of adropin on lipolysis, lipogenesis and glucose uptake in white rodent adipocytes. We assessed the effects of adropin on the mRNA expression of adiponectin, resistin and visfatin. White preadipocytes were isolated from male Wistar rats. Differentiated 3T3-L1 cells were used as a surrogate model of white adipocytes. Lipolysis was measured by the evaluation of glycerol and free fatty acid secretion using colorimetric kits. The effects of adropin on lipogenesis and glucose uptake were measured using radioactive-labelled glucose. The expression of adipokine mRNA was studied using real-time PCR. Our results show that adropin slightly promotes lipolysis in rat adipocytes and 3T3-L1 cells. Adropin suppresses lipogenesis in rat adipocytes without influencing glucose uptake. In addition, adropin stimulates adiponectin mRNA expression and suppresses the expression of resistin and visfatin. These results indicate that adropin may be involved in controlling lipid metabolism and adipokine expression in white rodent adipocytes.

The effects of neuronostatin on proliferation and differentiation of rat primary preadipocytes and 3T3-L1 cells.

Neuronostatin is a peptide hormone encoded by the somatostatin gene. Biological effects of neuronostatin are mediated through activation of GPR107. There is evidence indicating that neuronostatin modulates energy homeostasis by suppressing food intake and insulin secretion, while stimulating glucagon secretion. While it was found that neuronostatin receptor is expressed in white adipose tissue, the role of neuronostatin in controlling adipose tissue formation is unknown. The aim of this study is to investigate the effects of neuronostatin on proliferation and differentiation of rat primary preadipocytes and 3T3-L1 cells. We found that neuronostatin receptor GPR107 is expressed in rat preadipocytes and 3T3-L1 cells. Neuronostatin promotes proliferation of preadipocytes via AKT activation. Downregulation of GPR107 mRNA expression and protein production results in an attenuation of neuronostatin-induced stimulation of preadipocyte proliferation. Moreover, neuronostatin reduces intracellular lipid content and the expression of adipogenesis-modulating genes C/ebpα, C/ebpß, Pparγ, and Fabp4. In summary, these results show that neuronostatin, AKT-dependently, stimulates the proliferation of preadipocytes via GPR107. In contrast, neuronostatin inhibits the differentiation of preadipocytes into mature adipocytes.

Neuropeptide B promotes proliferation and differentiation of rat brown primary preadipocytes.

Neuropeptide B (NPB) is reported to regulate energy homeostasis and metabolism via the NPBWR1 and NPBWR2 receptors in various tissues. However, the molecular mechanisms triggered from their interaction are not well investigated in brown adipose tissue. In this study, we specifically analyzed the role of NPB in controlling brown adipogenesis in rat brown preadipocytes. We first detected the expression of NPBWR1 and NPB on mRNA and protein level in brown preadipocytes and observed that NPB increased viability and proliferation of preadipocytes. Moreover, NPB stimulated expression of adipogenic genes (Prdm16, Ucp1) and suppressed the expression of antiadipogenic preadipocyte factor 1 (Pref1) during the differentiation process. Altogether, this led to an increase in intracellular lipid accumulation during preadipocyte differentiation, coupled with an increase in adrenaline-induced oxygen consumption mediated by NPB. Furthermore, Ucp1 expression stimulated by NPB was attenuated by blockade of p38 kinase. In summary, we conclude that NPB promotes proliferation and differentiation of rat brown preadipocytes via p38-dependent mechanism and plays an important role in controlling brown adipose tissue formation.

30-Day spexin treatment of mice with diet-induced obesity (DIO) and type 2 diabetes (T2DM) increases insulin sensitivity, improves liver functions and metabolic status.

Spexin (SPX) is a 14 aa peptide discovered in 2007 using bioinformatics methods. SPX inhibits food intake and regulates lipid, and carbohydrate metabolism. Here, we evaluate the ability of SPX at improving metabolic control and liver function in obese and type 2 diabetic animals. The effects of 30 days SPX treatment of mice with experimentally induced obesity (DIO) or type 2 diabetes (T2DM) on serum glucose and lipid levels, insulin sensitivity and hormonal profile (insulin, glucagon, adiponectin, leptin, TNF alpha, IL-6 and IL-1ß) are characterized. In addition, alterations of hepatic lipid and glycogen contents are evaluated. We report that SPX decreases body weight in healthy and DIO mice, and reduces lipid content in all three animal groups. SPX improves insulin sensitivity in DIO and T2DM animals. In addition, SPX modulates hormonal and metabolic profile by regulating the concentration of adiponectin (concentration increase) and leptin (concentration decrease) in the serum blood of DIO and T2DM mice. Lastly, SPX decreases lipid content as well as IL-6 and TNF-α protein levels in liver of DIO and T2DM mice, and reduces IL-6 and TNF-alpha concentrations in the serum derived from T2DM mice. Based on our results, we conclude that SPX could be involved in the development of obesity and type 2 diabetes mellitus and it can be further evaluated as a potential target for therapy of DIO and T2DM.

The Role of Peptide Hormones Discovered in the 21st Century in the Regulation of Adipose Tissue Functions.

Peptide hormones play a prominent role in controlling energy homeostasis and metabolism. They have been implicated in controlling appetite, the function of the gastrointestinal and cardiovascular systems, energy expenditure, and reproduction. Furthermore, there is growing evidence indicating that peptide hormones and their receptors contribute to energy homeostasis regulation by interacting with white and brown adipose tissue. In this article, we review and discuss the literature addressing the role of selected peptide hormones discovered in the 21st century (adropin, apelin, elabela, irisin, kisspeptin, MOTS-c, phoenixin, spexin, and neuropeptides B and W) in controlling white and brown adipogenesis. Furthermore, we elaborate how these hormones control adipose tissue functions in vitro and in vivo.

Effects of adropin on proliferation and differentiation of 3T3-L1 cells and rat primary preadipocytes.

Adropin is a protein encoded by Energy Homeostasis Associated (Enho) gene which is expressed mainly in the liver and brain. There is evidence that biological effects of adropin are mediated via GPR19 activation. Animal studies showed that adropin modulates adiposity as well as lipid and glucose homeostasis. Adropin deficient animals have a phenotype closely resembling that of human metabolic syndrome with are obesity dyslipidemia and impaired glucose production. Animals treated with exogenous adropin lose weight, in addition to having reduced expression of lipogenic genes in the liver and fat tissue. While it was shown that adropin may contribute to energy homeostasis and body weight regulation, the role of this protein in controlling fat tissue formation is largely unknown. Thus, in the present study we investigated the effects of adropin on adipogenesis using 3T3-L1 cells and rat primary preadipocytes. We found a low Enho mRNA expression in 3T3-L1 cells and rat primary preadipocytes. Adropin stimulated proliferation of 3T3-L1 cells and rat primary preadipocytes. Stimulation of 3T3-L1 cell proliferation was mediated via ERK1/2 and AKT. Adropin reduced lipid accumulation as well as expression of proadipogenic genes in 3T3-L1 cells and rat preadipocytes, suggesting that this protein attenuates differentiation of preadipocytes into mature fat cells. In summary, these results show that adropin modulates proliferation and differentiation of preadipocytes.

Phoenixin-14 stimulates proliferation and insulin secretion in insulin producing INS-1E cells.

Phoenixin (PNX) is a recently discovered neuropeptide which modulates appetite, pain sensation and neurons of the reproductive system in the central nervous system. PNX is also detectable in the circulation and in peripheral tissues. Recent data suggested that PNX blood levels positively correlate with body weight as well as nutritional status suggesting a potential role of this peptide in controlling energy homeostasis. PNX is detectable in endocrine pancreas, however it is unknown whether PNX regulates insulin biosynthesis or secretion. Using insulin producing INS-1E cells and isolated rat pancreatic islets we evaluated therefore, whether PNX controls insulin expression, secretion and cell proliferation. We identified PNX in pancreatic alpha as well as in beta cells. Secretion of PNX from pancreatic islets was stimulated by high glucose. PNX stimulated insulin mRNA expression in INS-1E cells. Furthermore, PNX enhanced glucose-stimulated insulin secretion in INS-1E cells and pancreatic islets in a time-dependent manner. Stimulation of insulin secretion by PNX was dependent upon cAMP/Epac signalling, while potentiation of cell growth and insulin mRNA expression was mediated via ERK1/2- and AKT-pathway. These results indicate that PNX may play a role in controlling glycemia by interacting with pancreatic beta cells.