Circulating levels of urocortin neuropeptides are impaired in children with overweight

Objective The corticotropin-releasing factor neuropeptides (corticotropin-releasing hormone [CRH] and urocortin [UCN]-1,2,3) and spexin contribute to the regulation of energy balance and inhibit food intake in mammals. However, the status of these neuropeptides in children with overweight has yet to be elucidated. This study investigated the effect of increased body weight on the circulating levels of these neuropeptides. Methods A total of 120 children with a mean age of 12 years were enrolled in the study. Blood samples were collected to assess the circulating levels of neuropeptides and were correlated with various anthropometric, clinical, and metabolic markers. Results Plasma levels of UCNs were altered in children with overweight but less so in those with obesity. Furthermore, the expression pattern of UCN1 was opposite to that of UCN2 and UCN3, which suggests a compensatory effect. However, no significant effect of overweight and obesity was observed on CRH and spexin levels. Finally, UCN3 independently associated with circulating zinc-alpha-2-glycoprotein and UCN2 levels, whereas UCN1 was strongly predicted by TNF alpha levels. Conclusions Significant changes in neuropeptide levels were primarily observed in children with overweight and were attenuated with increased obesity. This suggests the presence of a compensatory mechanism for neuropeptides to curb the progression of obesity.Peer reviewe

Cardiovascular effects of the sirtuin and urocortin systems in humans

Background Cardiovascular disease continues to remain a leading cause of morbidity and mortality in both developing and developed worlds. The sirtuin and urocortin systems are novel hormone systems in humans with an emerging role in cardiovascular physiology and pathophysiology. Through a series of studies, this thesis examines the cardiovascular effects of SRT2104 (a novel small molecule SIRT1 activator) in otherwise healthy cigarette smokers and in patients with type 2 diabetes mellitus, and of urocortins 2 and 3 in healthy volunteers and in patients with heart failure. Methods Twenty-four otherwise healthy cigarette smokers and 15 subjects with stable type 2 diabetes participated in a randomised, double blind, placebo controlled, crossover trial and received 28 days of oral SRT2104 (2.0 g/day) or matched placebo. Plasma SRT2104 concentrations, serum lipid profile, plasma fibrinolytic factors, markers of platelet and monocyte activation and pulse wave analysis and velocity were measured at baseline and the end of each treatment period together with an assessment of forearm blood flow during intra-arterial bradykinin, acetylcholine and sodium nitroprusside infusions. The pharmacodynamic profile of urocortins 2 and 3 were assessed in 18 healthy male volunteers recruited into a series of randomised, double blind, placebo controlled, crossover studies. Bilateral forearm venous occlusion plethysmography was performed during incremental intra-arterial infusions of urocortin 2 (3.6-120 pmol/min), urocortin 3 (1.2-36 nmol/min) and substance P (2-8 pmol/min) in the presence or absence of inhibitors of cyclooxygenase (aspirin), cytochrome P450 metabolites of arachidonic acid (fluconazole) and nitric oxide synthase (L-NG-monomethyl-arginine (L-NMMA)). Finally, 12 patients with stable heart failure (New York Heart Association (NYHA) II-IV) and 10 age- and sex-matched healthy volunteers were recruited to attend once each. Bilateral forearm arterial blood flow was measured using forearm venous occlusion plethysmography during incremental intra-arterial infusions of urocortin 2 (3.6-36 pmol/min), urocortin 3 (360-3600 pmol/min) and substance P (2-8 pmol/min). Results SRT2104 was safe and well tolerated in otherwise healthy cigarette smokers and subjects with type 2 diabetes mellitus. There were no significant differences in fibrinolytic or blood flow parameters between placebo and SRT2014. Treatment with SRT2104 was associated with a significant reduction in augmentation pressure (P=0.0273) and a trend towards improvement in the augmentation index (AIx) and corrected augmentation index (0.10>P>0.05 for both) without significant changes in pulse wave velocity (PWV) and time to wave reflection (Tr) (P>0.05). Administration of SRT2104 had a favourable effect on lipid profile in otherwise healthy cigarette smokers in comparison to placebo. Urocortins 2 and 3 evoked arterial vasodilatation (P0.05). Neither aspirin nor fluconazole affected vasodilatation induced by any of the infusions (P>0.05 for all). In the presence of all three inhibitors, urocortin 2- and urocortin 3-induced vasodilatation were attenuated (P<0.001 for all) to a greater extent than with L-NMMA alone (P≤0.005). The vasodilatory effects of urocortins 2 and 3 were preserved in patients with heart failure. Conclusion Activation of SIRT1 through SRT2104 improved lipid profile but did not produce demonstrable differences in vascular or platelet function with some effect on measures of arterial stiffness. Urocortins 2 and 3 appear to be potent arterial vasodilators whose vasomotor responses remained preserved in patients with heart failure and were at least partly mediated via the endothelium. Both hormone systems hold potential in their role in cardiovascular disease in man but require further studies to help translate findings of this thesis to clinical practice

Controversies about a common etiology for eating and mood disorders.

Obesity and depression represent a growing health concern worldwide. For many years, basic science and medicine have considered obesity as a metabolic illness, while depression was classified a psychiatric disorder. Despite accumulating evidence suggesting that obesity and depression may share commonalities, the causal link between eating and mood disorders remains to be fully understood. This etiology is highly complex, consisting of multiple environmental and genetic risk factors that interact with each other. In this review, we sought to summarize the preclinical and clinical evidence supporting a common etiology for eating and mood disorders, with a particular emphasis on signaling pathways involved in the maintenance of energy balance and mood stability, among which orexigenic and anorexigenic neuropeptides, metabolic factors, stress responsive hormones, cytokines, and neurotrophic factors

The Importance of Intra-Islet Communication in the Function and Plasticity of the Islets of Langerhans during Health and Diabetes

Islets of Langerhans are anatomically dispersed within the pancreas and exhibit regulatory coordination between islets in response to nutritional and inflammatory stimuli. However, within individual islets, there is also multi-faceted coordination of function between individual beta-cells, and between beta-cells and other endocrine and vascular cell types. This is mediated partly through circulatory feedback of the major secreted hormones, insulin and glucagon, but also by autocrine and paracrine actions within the islet by a range of other secreted products, including somatostatin, urocortin 3, serotonin, glucagon-like peptide-1, acetylcholine, and ghrelin. Their availability can be modulated within the islet by pericyte-mediated regulation of microvascular blood flow. Within the islet, both endocrine progenitor cells and the ability of endocrine cells to trans-differentiate between phenotypes can alter endocrine cell mass to adapt to changed metabolic circumstances, regulated by the within-islet trophic environment. Optimal islet function is precariously balanced due to the high metabolic rate required by beta-cells to synthesize and secrete insulin, and they are susceptible to oxidative and endoplasmic reticular stress in the face of high metabolic demand. Resulting changes in paracrine dynamics within the islets can contribute to the emergence of Types 1, 2 and gestational diabetes

Adipopharmacology of inflammation and insulin resistance

Among the rapidly expanding list of factors synthesized and released by white adipose tissue, the range of cytokines, chemokines and other signaling proteins, collectively termed adipokines, are of particular interest to better understand the pathogenesis of low-grade systemic inflammation associated with obesity. An overwhelming body of evidence further links high circulating concentrations of inflammatory biomarkers with the development of insulin resistance and the progression to type 2 diabetes mellitus. The secretory pattern of adipose tissue characteristic of obesity comprises an increase in pro-inflammatory adipokines together with a decrease in adipokines with anti-inflammatory, cardioprotective and insulin sensitizing actions. These molecules exerts local autocrine and paracrine effects on white adipose tissue physiology at the same time as having systemic effects on other organs. A number of factors derived not only from adipocytes but also from infiltrated macrophages and mast cells, which have been shown to accompany morbid adiposity, further contribute to inflammation and insulin resistance. The evolving notion of adipose tissue as an immuno-modulatory organ together with the improving knowledge of how inflammation exerts a (counter)regulatory action on glucose and lipid metabolism are opening up new therapeutic opportunities for applying anti-inflammatory strategies to counterbalance the detrimental consequences of excess adiposity and its comorbidities.Biomedical Reviews 2006; 17: 43-51

The Influence of Central Insulin Signals on Stress Response in Mice

Stress is an anticipatory or actual disruption of homeostasis which triggers physiological responses to prepare for the threat or to reestablish the system's internal equilibrium. Other than physical stress (e.g. blood loss, infection, pain, and cold) and psychogenic stress (e.g. novel environment (rodent) and immobilization (rodent)), nutrient (metabolic) stress such as high fat diet and fasting can also trigger stress responses. Central to the activation and regulation of the stress response in mammals is the hypothalamus, where signals from the periphery and other regions of the brain are integrated and processed. Insulin and leptin are two important hormones that provide information about the energy status of the body to the hypothalamus. The hypothalamic insulin- and leptin- sensing circuits integrate these signals to coordinate metabolic outcomes such as food intake, energy expenditure, fuel partitioning, etc. Given the tight correlation between stress axis activity and nutrient status, it raises the possibility that hypothalamic insulin- and leptin- sensing circuits may also be involved in coordinating responses of the stress axis, particularly during stress pertaining changes in energy homeostasis. My thesis research focused on understanding the roles and the interactions of hypothalamic insulin and leptin signals in regulating and coordinating metabolic and hypothalamic-pituitary-adrenal (HPA) axis functions. My first project involved understanding the role of hypothalamic insulin signals in hypothalamic leptin receptor deficient animals (L^2.1 KO) in regulating energy metabolism (Chapter 2). We observed an increase in body weight and adiposity in D^2.1 KO mice that lack both hypothalamic insulin receptor (InsR) and leptin receptor (LepRb) signals. These changes were accompanied by reduced energy expenditure, rather than an increase in food intake. Unexpectedly, there was a drastic loss in body temperature in D^2.1 KO during fasting that was significantly exacerbated by single-housing. These results suggest that interactions between hypothalamic insulin and leptin signals are important for regulating energy expenditure and body temperature. Furthermore, this study also highlights the influence of housing conditions on the evaluation of thermogenic defects in mice. My second project involved the study of hypothalamic insulin signals in regulating stress-related functions by using the non-obese hypothalamic InsR-deficient mice (I^2.1 KO)(Chapter 3). We showed that I^2.1 KOs have elevated baseline hypothalamic Avp synthesis, increased activity of the HPA axis after restraint, as well as increased anxiety-like behaviors. This study demonstrated that hypothalamic InsR signals suppress the stress response to restraint, possibly by influencing AVP release to the median eminence and decreasing hypothalamic glucocorticoid receptor (GR) signals, and may also modulate anxiety-like behaviors. My current research focuses are: to remove InsR signals by using more restrictedly expressed Cre lines in order to identify brain nuclei mediating insulin's effect on stress response and/or anxiety-like behaviors; to identify the hypothalamic AVP neuronal population affected by the loss of InsR and potential extra-hypothalamic downstream targets of these neurons; to pinpoint the hypothalamic nuclei where GR signaling is altered in I^2.1 KO. By identifying the critical anatomical and functional components mediating insulin's effects, we hope to provide more understanding of the contribution of central insulin resistance to the development of HPA axis dsyregulation and anxiety disorders in humans

Urocortin 3 in obesity and type 2 diabetes : -

Diabesity is a major health burden worldwide, particularly in Kuwait, where several epidemiologic studies reveal the parallel escalation of the prevalence of obesity and diabetes. There is still a lack of complete understanding of the pathways and their interactions triggering the development of obesity-related co-morbidities. Urocortin 3 (UCN3) is a novel neuropeptide implicated in the regulation of food intake, energy homeostasis, cardioprotection, and identified as a regulator of insulin secretion and as a marker for functional pancreatic β-cells. Hence, UCN3 could be a potential therapeutic target for managing metabolic diseases. In this thesis we have assessed UCN3 expression in two cross-sectional populations living in Kuwait: adults with obesity and type 2 diabetes (T2D) and children with overweight and obesity. In addition, we have examined associations of UCN3 with metabolic markers and stressors and assessed the effect of UCN3 overexpression on signaling pathways of insulin, glucose uptake, endoplasmic reticulum (ER) stress, and heat shock response in an adipocyte cell model. In study (I), we investigated the circulating UCN3 levels in the plasma of adults with obesity and T2D. The effect of inflammatory microenvironment in adipose tissue on the expression of UCN3 and the effect of physical exercise training on UCN3 expression was also investigated. We demonstrated that UCN3 expression levels were impaired in response to an inflammatory microenvironment, obesity, and T2D. In study (II), the effect of UCN3 overexpression on apoptotic, ER, and heat-shock stress response pathways was studied in 3T3L1 adipocytes. We showed that the overexpression of UCN3 attenuated markers of apoptosis, inflammation, ER stress, and heat shock response. These events were associated with improved glucose uptake and insulin signaling. We showed that the levels of UCN3 and the other corticotropin-releasing factor (CRF) family are impaired with obesity both in plasma and peripheral blood mononuclear cells obtained from children. In studies (III) and (IV), the circulating levels of UCN3 were assessed in children with different levels of adiposity. Metabolic stressors such as palmitic acid and high glucose concentrations differentially modulated the neuropeptide levels in human monocytic cell line (THP1) cells depending on the duration of the exposure. The homeostasis of energy balance and metabolism is regulated by the central nervous system and peripheral mechanisms. The progression of obesity and T2D is associated with disturbances in this homeostasis, dysregulation of insulin secretion, and alterations in inflammatory and stress response pathways. Most of the thesis findings were shown for the first time and highlighted the role of UCN3 in metabolic dysregulations in obesity and T2D. UCN3 might be a promising marker in future approaches to monitor the progression of obesity, T2D, and related metabolic co-morbidities.Diabetes on merkittävä terveystaakka maailmanlaajuisesti ja erityisesti Kuwaitissa, jossa useat epidemiologiset tutkimukset ovat todenneet lihavuuden ja diabeteksen esiintyvyyden lisääntyvän samanaikaisesti. Tieto lihavuuteen liittyvien sairauksien syntyyn vaikuttavista eri reiteistä sekä niiden vuorovaikutuksista on edelleen puutteellista. Urokortiini 3 (UCN3) on neuropeptidi, joka säätelee ruokailua ja energiatasapainoa sekä suojaa sydäntä. UCN3 säätelee insuliinieritystä ja se on tunnistettu haiman kypsien β-solujen merkkiaineeksi. UCN3 voi olla mahdollinen terapeuttinen kohde hoidettaessa aineenvaihduntasairauksia. Tässä väitöskirjatyössä tutkittin UCN3:n ilmentymistä kahdessa Kuwaitissa asuvassa väestössä: lihavilla ja tyypin 2 diabetesta (T2D) sairastavilla aikuisilla sekä ylipainoisilla ja lihavilla lapsilla. Lisäksi selvitettiin yhteyksiä UCN3:n ja aineenvaihdunnan merkkiaineiden sekä stressitekijöiden välillä. UCN3:n yli-ilmentymisen vaikutusta insuliinin signaalinsiirtoon, glukoosin soluunottoon, endoplasmisen kalvoston stressiin sekä lämpösokkivasteeseen tutkittiin rasvasolumallissa. Tutkimuksessa I tutkimme plasman UCN3 pitoisuuksia lihavilla ja T2D:ta sairastavilla aikuisilla. Tutkimme myös tulehduksellisen mikroympäristön vaikutusta UCN3:n ilmentymiseen sekä liikuntaharjoittelun vaikutusta UCN3:n ilmentymiseen. Osoitimme, että UCN3:n ilmentyminen vähenee vasteena tulehdukselliselle mikroympäristölle, lihavuudelle ja T2D:lle. Liikuntaharjoittelu vaikutti rasvakudoksen UCN3:n ilmentymiseen. Tutkimuksessa II tutkittiin UCN3:n yli-ilmentymisen vaikutusta apoptoosin, endoplasmisen kalvoston stressin sekä lämpösokkivasteen signaalinsiirtoreitteihin 3T3L1-rasvasoluissa. UCN3:n yli-ilmentyminen vähensi apoptoosia, tulehdusta, endoplasmisen kalvoston stressiä sekä lämpösokkivasteen merkkiaineita. Nämä tapahtumat liittyivät parantuneeseen glukoosin soluunottoon ja insuliinin signaalinsiirtoon. Tutkimuksissa III ja IV plasman UCN3 pitoisuuksia arvioitiin ylipainoisilla ja lihavilla lapsilla. Lasten ylipaino ja lihavuus vaikuttivat UCN3:n ja kortikotropiinia vapauttavan tekijän (CRF) ilmentymiseen plasmassa ja perifeerisen veren mononukleaarisoluissa. Metaboliset stressitekijät, kuten palmitaatti ja korkea glukoosipitoisuus, vaikuttivat myös näiden neuropeptidien ilmentymiseen THP1-soluissa altistuksen kestosta riippuvalla tavalla. Sekä keskushermosto että perifeeriset mekanismit säätelevät energiatasapainon ja aineenvaihdunnan homeostaasia. Lihavuuden ja T2D:n eteneminen näyttää liittyvän häiriöihin tässä homeostaasissa, muutoksiin insuliinin erityksessä, sekä poikkeamiin tulehdus- ja stressivasteissa. Väitöskirjatutkimuksessani on useita alkuperäishavaintoja ja se tuo uutta tietoa UCN3:sta lihavuudessa ja T2D:ssa. UCN3 saattaa olla uusi lupaava merkkiaine lihavuuden, T2D:n ja näihin liittyvien sairauksien etenemisen seuraamiseksi