A role for NPY overexpression in the dorsomedial hypothalamus in hyperphagia and obesity of OLETF rats

Otsuka Long-Evans Tokushima Fatty (OLETF) rats lacking CCK-A receptors are hyperphagic, obese, and diabetic. We have previously demonstrated that thes e rats have a peripheral satiety deficit resulting in increased meal size. To examine the potential role of hypothalamic pathways in the hyperphagia a nd obesity of OLETF rats, we compared patterns of hypothalamic neuropeptide Y (NPY), proopiomelanocortin (POMC), and leptin receptor mRNA expression i n ad libitum-fed Long-Evans Tokushima (LETO) and OLETF rats and food-restri cted OLETF rats that were pair-fed to the intake of LETO controls. Pair fee ding OLETF rats prevented their increased body weight and elevated levels o f plasma insulin and leptin and normalized their elevated POMC and decrease d NPY mRNA expression in the arcuate nucleus. In contrast, NPY expression w as upregulated in the dorsomedial hypothalamus (DMH) in pair-fed OLETF rats . A similar DMH NPY overexpression was evident in 5-wk-old preobese OLETF r ats. These findings suggest a role for DMH NPY upregulation in the etiology of OLETF hyperphagia and obesity.