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1.
Rev Diabet Stud ; 8(3): 355-68, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-22262073

RESUMEN

It is estimated that 347 million people worldwide have diabetes and that over 1.5 billion adults worldwide are overweight. Predictions suggest these rates are increasing. Diabetes is a common complication in overweight and obese subjects, and in 2004, an estimated 3.4 million people died from consequences of high blood sugar. Thus, there is great interest in revealing the physiological systems that regulate body weight and blood sugar. Several peptidergic systems within the central nervous system and the periphery regulate energy homeostasis. A number of these systems have been investigated as potential treatments for obesity and the metabolic syndrome. However, manipulation of peptidergic systems poses many problems. This review discusses the peptidergic systems currently attracting research interest for their clinical potential to treat obesity. We consider first neuropeptides in the brain, including the orexigenic neuropeptide Y and melanin-concentrating hormone, and anorectic factors such as the melanocortins, ciliary neurotrophic factor, and neuromedin U. We subsequently discuss the utility of targeting peripheral gut peptides, including pancreatic polypeptide, peptide YY, amylin, and the gastric hormone ghrelin. Also, we analyze the evidence that these factors or drugs based on them may be therapeutically useful, while considering the disadvantages of using such peptides in a clinical context.


Asunto(s)
Diabetes Mellitus/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Péptidos/uso terapéutico , Animales , Humanos
2.
Diabetes ; 59(2): 397-406, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19933997

RESUMEN

OBJECTIVE: Prokineticin 2 (PK2) is a hypothalamic neuropeptide expressed in central nervous system areas known to be involved in food intake. We therefore hypothesized that PK2 plays a role in energy homeostasis. RESEARCH DESIGN AND METHODS: We investigated the effect of nutritional status on hypothalamic PK2 expression and effects of PK2 on the regulation of food intake by intracerebroventricular (ICV) injection of PK2 and anti-PK2 antibody. Subsequently, we investigated the potential mechanism of action by determining sites of neuronal activation after ICV injection of PK2, the hypothalamic site of action of PK2, and interaction between PK2 and other hypothalamic neuropeptides regulating energy homeostasis. To investigate PK2's potential as a therapeutic target, we investigated the effect of chronic administration in lean and obese mice. RESULTS: Hypothalamic PK2 expression was reduced by fasting. ICV administration of PK2 to rats potently inhibited food intake, whereas anti-PK2 antibody increased food intake, suggesting that PK2 is an anorectic neuropeptide. ICV administration of PK2 increased c-fos expression in proopiomelanocortin neurons of the arcuate nucleus (ARC) of the hypothalamus. In keeping with this, PK2 administration into the ARC reduced food intake and PK2 increased the release of alpha-melanocyte-stimulating hormone (alpha-MSH) from ex vivo hypothalamic explants. In addition, ICV coadministration of the alpha-MSH antagonist agouti-related peptide blocked the anorexigenic effects of PK2. Chronic peripheral administration of PK2 reduced food and body weight in lean and obese mice. CONCLUSIONS: This is the first report showing that PK2 has a role in appetite regulation and its anorectic effect is mediated partly via the melanocortin system.


Asunto(s)
Ingestión de Energía/efectos de los fármacos , Hormonas Gastrointestinales/farmacología , Hormonas Gastrointestinales/fisiología , Neuropéptidos/farmacología , Neuropéptidos/fisiología , Obesidad/fisiopatología , Animales , Relación Dosis-Respuesta a Droga , Hormonas Gastrointestinales/genética , Regulación de la Expresión Génica , Hipotálamo/fisiología , Inyecciones Intraventriculares , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Neuropéptidos/genética , ARN Mensajero/genética , Ratas , Ratas Wistar
3.
Endocrinology ; 150(8): 3513-20, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19359390

RESUMEN

Ghrelin is a gastric peptide that regulates appetite and GH secretion. Circulating ghrelin levels are elevated by fasting and suppressed postprandially. However, the mechanisms regulating circulating ghrelin levels are unclear. Oxyntomodulin is an anorexic peptide hormone released from L cells in the gut. We investigated the effects of intracerebroventricular (icv) administration of oxyntomodulin on circulating ghrelin levels. The icv administration of 1, 3, or 10 nmol oxyntomodulin reduced circulating acylated and total (acylated and des-acylated) ghrelin 60 min after icv injection. Administration of 1 nmol oxyntomodulin directly into the arcuate nucleus of the hypothalamus significantly reduced total and acylated ghrelin levels, and administration of 3 nmol oxyntomodulin into the lateral ventricle induced c-fos mRNA expression in arcuate nucleus neurons expressing the glucagon-like peptide-1 (GLP-1) receptor. In a final study, the reduction in total ghrelin observed after icv injection of 3 nmol oxyntomodulin was blocked by coadministration of the GLP-1 receptor antagonist exendin (9-39). These studies suggest oxyntomodulin reduces peripheral ghrelin levels via GLP-1 receptor-dependent hypothalamic pathways. Postprandial release of anorexic gut hormones may thus act centrally to contribute to the postprandial reduction in circulating ghrelin.


Asunto(s)
Ghrelina/sangre , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Oxintomodulina/farmacología , Animales , Glucemia/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Expresión Génica/efectos de los fármacos , Receptor del Péptido 1 Similar al Glucagón , Inyecciones , Insulina/sangre , Masculino , Ratones , Oxintomodulina/administración & dosificación , Fragmentos de Péptidos/farmacología , Proteínas Proto-Oncogénicas c-fos/genética , Radioinmunoensayo , Ratas , Ratas Wistar , Receptores de Glucagón/antagonistas & inhibidores , Receptores de Glucagón/metabolismo
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