抄録
Feeding behavior regulates body weight. Hyperphagia (increased food intake) causes obesity, diabetes and metabolic syndrome. Ghrelin is a potent orexigenic hormone of the stomach origin. Ghrelin increases [Ca2+]i in neuropeptide Y (NPY) neurons isolated from the hypothalamic arcuate nucleus (ARC) of adult rats, and this effect depends on cAMP-PKA pathway. Leptin suppresses ghrelin-induced [Ca2+]i increases via PI3 kinase- and phosphodiesterase 3 (PDE3)-mediated pathway. Stimulation of feeding by intracerebroventricular (icv) ghrelin injection is counteracted by leptin in a PDE3-dependent manner. Thus, leptin signaling via PI3 kinase-PDE3 counteracts cAMP-dependent ghrelin signaling, suppressing ARC NPY neurons and thereby feeding.We found that Goto-Kakizaki (GK) rats, a suitable model of human type-2 diabetes, display young-adult specific hyperphagia at 6-14 weeks, while body weight is unaltered, compared to control Wistar rats. In GK rats at 11 weeks, visceral fat is accumulated and plasma leptin level is elevated. Leptin suppresses food intake and phosphorylates STAT3 in the hypothalamic ARC less potently in GK than Wistar rats. In ARC, mRNA levels for NPY are elevated. Icv injection of NPY Y1 receptor antagonist corrects the hyperphagia. In conclusion, hyperphagia in GK rats is due to the ARC NPY neuron hyperactivity, which may result from and/or cause visceral fat accumulation and leptin resistance. Young-adult GK rats provide an excellent model for elucidating the mechanisms of hyperphagia. [J Physiol Sci. 2008;58 Suppl:S14]
