Neuropeptide Y (NPY), one of the most abundant peptide transmitters in the mammalian brain, is assumed to play an important role in feeding and body weight regulation. However, there is little genetic evidence that overexpression or knockout of the NPY gene leads to altered body weight regulation. Previously, we developed NPY-overexpressing mice by using the Thy-1 promoter, which restricts NPY expression strictly within neurons in the central nervous system, but we failed to observe the obese phenotype in the heterozygote. Here we report that in the homozygous mice, overexpression of NPY leads to an obese phenotype, but only after appropriate dietary exposure. NPY-overexpressing mice exhibited significantly increased body weight gain with transiently increased food intake after 50% sucroseloaded diet, and later they developed hyperglycemia and hyperinsulinemia without altered glucose excursion during 1 year of our observation period. Diabetes 50: 1206 -1210, 2001 N europeptide Y (NPY) is a member of the peptide family, which includes the endocrine peptides, pancreatic polypeptide, and peptide YY. A significant body of literature argues that the arcuate nucleus NPY neurons are involved in energy homeostasis (1-5). NPY potently stimulates food intake when introduced into the hypothalamus in the vicinity of the paraventricular nucleus and perifornical area (1-5). NPY alters body temperature and peripheral energy metabolism and increases plasma insulin levels. Many syndromes of obesity in animals are characterized either by an increase in NPY levels in the hypothalamus or by an increase in NPY receptor abundance and sensitivity (3). When NPY was chronically administered into the ventricle or the hypothalamus, it was found to produce an obesity syndrome with salient features of hyperphagia, increased body weight, hyperinsulinemia, hypercorticosteronemia, muscle insulin resistance, and increased fat storage (6). However, because both NPY-overexpressing and knockout mice showed almost normal patterns of food intake and body weight (5,7-9), it is still an open question as to whether NPY has an essential role in increased body weight. Here we show that sucrose feeding renders seemingly normal NPY-overexpressing mice to exhibit part of the obesity syndrome.NPY-overexpressing mice (homozygous) were developed by using the Thy-1 promoter, which localized transgene expression within the central nervous system (7). A modest overexpression of NPY was confirmed in these animals ( Fig. 1), which were housed per group and examined in a less stressful condition than those housed individually. There were no apparent differences in body weight between NPY-overexpressing mice and their littermates when normal diet was provided. However, shortly after 50% sucrose was loaded on the diet, the homozygous mice became heavier than controls and maintained their increased body weight ( Fig. 2A). This was accompanied by an increase in food intake that continued for several weeks after the high-sucrose feeding (Fig. 2B). The increased food i...
