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Ablation of ghrelin receptor in leptin-deficient ob/ob mice has paradoxical effects on glucose homeostasis when compared with ablation of ghrelin in ob/ob mice.
Ma, Xiaojun; Lin, Yuezhen; Lin, Ligen; Qin, Guijun; Pereira, Fred A; Haymond, Morey W; Butte, Nancy F; Sun, Yuxiang.
Afiliação
  • Ma X; US Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Am J Physiol Endocrinol Metab ; 303(3): E422-31, 2012 Aug 01.
Article em En | MEDLINE | ID: mdl-22669248
The orexigenic hormone ghrelin is important in diabetes because it has an inhibitory effect on insulin secretion. Ghrelin ablation in leptin-deficient ob/ob (Ghrelin(-/-):ob/ob) mice increases insulin secretion and improves hyperglycemia. The physiologically relevant ghrelin receptor is the growth hormone secretagogue receptor (GHS-R), and GHS-R antagonists are thought to be an effective strategy for treating diabetes. However, since some of ghrelin's effects are independent of GHS-R, we have utilized genetic approaches to determine whether ghrelin's effect on insulin secretion is mediated through GHS-R and whether GHS-R antagonism indeed inhibits insulin secretion. We investigated the effects of GHS-R on glucose homeostasis in Ghsr-ablated ob/ob mice (Ghsr(-/-):ob/ob). Ghsr ablation did not rescue the hyperphagia, obesity, or insulin resistance of ob/ob mice. Surprisingly, Ghsr ablation worsened the hyperglycemia, decreased insulin, and impaired glucose tolerance. Consistently, Ghsr ablation in ob/ob mice upregulated negative ß-cell regulators (such as UCP-2, SREBP-1c, ChREBP, and MIF-1) and downregulated positive ß-cell regulators (such as HIF-1α, FGF-21, and PDX-1) in whole pancreas; this suggests that Ghsr ablation impairs pancreatic ß-cell function in leptin deficiency. Of note, Ghsr ablation in ob/ob mice did not affect the islet size; the average islet size of Ghsr(-/-):ob/ob mice is similar to that of ob/ob mice. In summary, because Ghsr ablation in leptin deficiency impairs insulin secretion and worsens hyperglycemia, this suggests that GHS-R antagonists may actually aggravate diabetes under certain conditions. The paradoxical effects of ghrelin ablation and Ghsr ablation in ob/ob mice highlight the complexity of the ghrelin-signaling pathway.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Leptina / Grelina / Receptores de Grelina / Glucose / Obesidade Tipo de estudo: Etiology_studies Limite: Animals Idioma: En Ano de publicação: 2012 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Leptina / Grelina / Receptores de Grelina / Glucose / Obesidade Tipo de estudo: Etiology_studies Limite: Animals Idioma: En Ano de publicação: 2012 Tipo de documento: Article