Attenuation of Diabetic Hyperphagia in Neuropeptide Y–Deficient Mice

Attenuation of Diabetic Hyperphagia in Neuropeptide Y–Deficient Mice Dana K. Sindelar 1 , Paul Mystkowski 1 , Donald J. Marsh 2 , Richard D. Palmiter 2 and Michael W. Schwartz 1 1 Department of Medicine, University of Washington, and Howard Hughes Medical Institute, University of Washington, Seattle, Washington 2 Department of Biochemistry, University of Washington, Seattle, Washington Abstract The combined effects of increased hypothalamic signaling by neuropeptide Y (NPY) and decreased signaling by melanocortins are hypothesized to stimulate food intake when body fat stores are depleted. To investigate NPY’s role in the hyperphagic response to uncontrolled diabetes, streptozotocin (STZ) (200 mg/kg intraperitoneally) or saline vehicle was given to NPY-deficient ( Npy –/– ) and wild-type ( Npy +/+ ) mice. In Npy +/+ mice, STZ-induced diabetes increased mean daily food intake to plateau values 50% above baseline intake (+2.0 ± 0.6 g/day; P ≤ 0.05), an effect that was not seen in STZ-treated Npy –/– mice (+0.8 ± 0.1 g/day; NS), despite comparably elevated levels of plasma glucose and comparably decreased levels of body weight, fat content, and plasma leptin. Unlike the impaired feeding response to uncontrolled diabetes, Npy –/– mice exhibit intact hyperphagic responses to fasting (Erickson et al. [ 1 ], Nature 381:415–418, 1996). To investigate whether differences in hypothalamic melanocortin signaling can explain this discrepancy, we used in situ hybridization to compare the effects of STZ-diabetes and fasting on pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) mRNA levels in the hypothalamic arcuate nucleus (ARC) of Npy –/– and Npy +/+ mice. AgRP mRNA levels were increased by both fasting and STZ-diabetes, but the increase in STZ-diabetes was small (50–80%) compared with the effect of fasting (∼20-fold increase of AgRP mRNA). STZ-diabetes also lowered POMC mRNA levels by 65% in the ARC of Npy +/+ mice ( P ≤ 0.05) but by only 11% in Npy –/– mice (NS); fasting significantly lowered POMC mRNA levels in both genotypes. We conclude that NPY is required for both the increase of food intake and the decrease of hypothalamic POMC gene expression induced by uncontrolled diabetes. In contrast, NPY is not required for either of these responses when the stimulus is food deprivation. Moreover, fasting is a more potent stimulus to hypothalamic AgRP gene expression than is STZ-diabetes. Therefore, central nervous system melanocortin signaling appears to be su