pyx-2 and Hyperphagia

Hypothalamic neuropeptide Y (NPY) systems are upregulated during lactation in rats. Because NPY is central to the hypothalamic control of energy balance, the present studies tested the hypothesis that NPY contributes to the marked hyperphagia during lactation. A 4-day infusion of [D-tyr (27,36), D-thr (32)] NPY (27-36) (D-NPY(27-36)), a peptide analogue of NPY that antagonizes NPY-induced feeding, into the third ventricle at 1 microg/h transiently inhibited nocturnal feeding in nonlactating female rats. However, this antagonist had no effect on nocturnal feeding, but did transiently reduce food intake during the light hours, when infused into the third ventricle at the same dose in lactating females. An essentially similar pattern of results was obtained with chronic infusion into the third ventricle of the anorexigenic peptide alpha-melanocyte-stimulating hormone (alpha-MSH, 1 microg/h), in nonlactating and lactating rats. Both D-NPY(27-36) and alpha-MSH transiently reduced nocturnal food intake in lactating rats by approximately 10% when infused at the higher dose of 5 microg/h, and a marked inhibition of approximately 40% of both nocturnal and diurnal feeding was produced by a combined infusion of both at 5 microg/h. These results provide the first pharmacological evidence implicating specific neuromessengers in mediating the hyperphagia of lactation, and suggest that, while an action of NPY may contribute to the increased food intake seen in lactating animals, other systems are also involved. In particular, a reduction in melanocortin signaling during lactation may allow for an increased orexigenic influence of the agouti-related protein (AgRP), which is co-expressed with NPY.

Topics: alpha-MSH; Animals; Body Weight; Darkness; Eating; Female; Hyperphagia; Injections, Intraventricular; Lactation; Light; Neuropeptide Y; Peptide Fragments; Rats; Rats, Sprague-Dawley; Stereotaxic Techniques

A central dysregulation of several neuropeptides could be at the origin of the marked hyperphagia of the obese Zucker rat, a well-known animal model used for the study of obesity. Neuropeptide Y (NPY), which stimulates food intake and increases early in life in obese rats, plays a major role in the development of this hyperphagia. The aim of our experiment was to test a proposed NPY antagonist namely PYX-2 in obese hyperphagic Zucker rats in order to know if it could be an interesting drug for limiting their food intakes. Four doses of PYX-2 (50-1000 pmol) were injected in a counterbalanced order in the lateral brain ventricles of 10 adult male Zucker rats. Food intake was recorded 0.5, 1, 2, 3, 6, and 23 h after PYX-2 injection and compared either to the rat's spontaneous food intake or to the food intake following injection of artificial CSF (vehicle) only. It was not modified by any dose of PYX-2 whatever the time considered (1 h after injection: 4.3 +/- 0.5 (1000 pmol) vs 4.6 +/- 0.8 (CSF) g; 23 h period: 27.0 +/- 1.9 (1000 pmol) vs 26.6 +/- 2.9 (CSF) g; N.S.). Thus, PYX-2, the putative NPY antagonist, totally failed to inhibit food intake in the obese rats. The absence of effect of PYX-2 on food intake can be explained by the structure of PYX-2, a modified 27-36 amino acid sequence that may not be recognized by the Y1-type NPY receptors which are involved in the regulation of feeding behavior.

Topics: Amino Acid Sequence; Animals; Eating; Hyperphagia; Injections, Intraventricular; Male; Neuropeptide Y; Obesity; Peptide Fragments; Rats; Rats, Zucker