RESUMO
Body weight is regulated by complex neurohormonal interactions between endocrine signals of long-term adiposity (e.g., leptin, a hypothalamic signal) and short-term satiety (e.g., amylin, a hindbrain signal). We report that concurrent peripheral administration of amylin and leptin elicits synergistic, fat-specific weight loss in leptin-resistant, diet-induced obese rats. Weight loss synergy was specific to amylin treatment, compared with other anorexigenic peptides, and dissociable from amylin's effect on food intake. The addition of leptin after amylin pretreatment elicited further weight loss, compared with either monotherapy condition. In a 24-week randomized, double-blind, clinical proof-of-concept study in overweight/obese subjects, coadministration of recombinant human leptin and the amylin analog pramlintide elicited 12.7% mean weight loss, significantly more than was observed with either treatment alone (P < 0.01). In obese rats, amylin pretreatment partially restored hypothalamic leptin signaling (pSTAT3 immunoreactivity) within the ventromedial, but not the arcuate nucleus and up-regulated basal and leptin-stimulated signaling in the hindbrain area postrema. These findings provide both nonclinical and clinical evidence that amylin agonism restored leptin responsiveness in diet-induced obesity, suggesting that integrated neurohormonal approaches to obesity pharmacotherapy may facilitate greater weight loss by harnessing naturally occurring synergies.
Assuntos
Amiloide/agonistas , Amiloide/química , Leptina/metabolismo , Tecido Adiposo/metabolismo , Amiloide/metabolismo , Amiloide/farmacologia , Animais , Peso Corporal , Restrição Calórica , Modelos Animais de Doenças , Hormônios/metabolismo , Hipotálamo/metabolismo , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Leptina/análogos & derivados , Leptina/farmacologia , Modelos Biológicos , Obesidade/genética , Obesidade/terapia , Consumo de Oxigênio , RatosRESUMO
Circulating amylin inhibits food intake via activation of the area postrema (AP). The aim of this study was to identify the neurochemical phenotype of the neurons mediating amylin's hypophagic action by immunohistochemical and feeding studies in rats. Expression of c-Fos protein was used as a marker for neuronal activation and dopamine-beta-hydroxylase (DBH), the enzyme-catalyzing noradrenaline synthesis, as a marker for noradrenergic neurons. We found that approximately 50% of amylin-activated AP neurons are noradrenergic. To clarify the functional role of these neurons in amylin's effect on eating, noradrenaline-containing neurons in the AP were lesioned using a saporin conjugated to an antibody against DBH. Amylin (5 or 20 microg/kg s.c.)-induced anorexia was observed in sham-lesioned rats with both amylin doses. Rats with a lesion of > 50% of the noradrenaline neurons were unresponsive to the low dose of amylin (5 microg/kg) and only displayed a reduction in food intake 60 min after injection of the high amylin dose (20 microg/kg). In a terminal experiment, the same rats received amylin (20 microg/kg) or saline. The AP and nucleus of the solitary tract (NTS) were stained for DBH to assess noradrenaline lesion success and for c-Fos expression to evaluate amylin-induced neuronal activation. In contrast to sham-lesioned animals, noradrenaline-lesioned rats did not show a significant increase in amylin-induced c-Fos expression in the AP and NTS. We conclude that the noradrenergic neurons in the AP mediate at least part of amylin's hypophagic effect.
Assuntos
Fibras Adrenérgicas/metabolismo , Amiloide/metabolismo , Regulação do Apetite , Área Postrema/metabolismo , Comportamento Animal , Ingestão de Alimentos , Norepinefrina/metabolismo , Fibras Adrenérgicas/patologia , Amiloide/administração & dosagem , Amiloide/toxicidade , Animais , Anorexia/induzido quimicamente , Anorexia/metabolismo , Área Postrema/patologia , Dopamina beta-Hidroxilase/metabolismo , Imuno-Histoquímica , Injeções Subcutâneas , Polipeptídeo Amiloide das Ilhotas Pancreáticas , Masculino , Fenótipo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
Amylin receptor agonism is emerging as part of an integrated neurohormonal therapeutic approach for managing diabetes mellitus (DM) and body weight. Pramlintide acetate, an analogue of the pancreatic hormone amylin, has been studied in the United States as an antihyperglycemic agent in patients with type 1 or type 2 DM treated with mealtime insulin(1). Further clinical testing of pramlintide in subjects with obesity demonstrated that pramlintide monotherapy induced significant, sustained, and dose-dependent weight loss(2). Recent clinical observations point to its compatibility as a combination therapy with the hormone leptin, eliciting double-digit weight loss in patients with overweight and obesity(3). Herein, we link amylin activation of central neural circuits to these therapeutic effects, and we speculate on other potential therapeutic applications of amylin receptor agonism.