S.G. Gilbey

Increases in Neuropeptide Y Content and Gene Expression in the Hypothalamus of Rats Treated with Dexamethasone Are Prevented by Insulin

The neurotransmitter neuropeptide Y (NPY) is abundant in the hypothalamus where its actions include the potent stimulation of food intake. The peripheral metabolic and hormonal signals involved in its regulation are not clear. The aim of this study was to investigate possible actions of corticosteroids and insulin on hypothalamic NPY synthesis and content in vivo. We measured NPY content in individual hypothalamic nuclei, and hypothalamic NPY mRNA by Northern blotting in whole hypothalamus in rats treated with dexamethasone (0.4 mg/kg/day) and dexamethasone plus insulin (60 U/kg/day), compared to controls. The effect of stopping dexamethasone treatment was also studied. Dexamethasone treatment produced significant increases in NPY in the paraventricular (11.0 +/- 1.3 vs. 7.1 +/- 0.4 fmol/micrograms protein, p < 0.05) and arcuate (6.2 +/- 0.3 vs. 3.8 +/- 0.2 fmol/microgram protein, p < 0.001) nuclei of the hypothalamus, paralleled by a 38% increase in total hypothalamic NPY mRNA (p < 0.05). These changes were not seen in the group treated with dexamethasone plus insulin. In the group in whom dexamethasone was stopped, NPY mRNA was unchanged compared to controls, but peptide content remained increased in the arcuate but not the paraventricular nucleus (arcuate 7.7 +/- 0.7 vs. 5.5 +/- 0.7, PVN 4.9 +/- 1.0 vs. 4.7 +/- 0.9 fmol/microgram protein). Thus hypothalamic NPY and its mRNA were increased by corticosteroid administration, and this effect was prevented by systemic insulin treatment. This dual regulatory system for hypothalamic NPY may be important in the control of food intake by corticosteroids and insulin.

High-Dose Porcine Galanin Infusion and Effect on Intravenous Glucose Tolerance in Humans

The neuropeptide galanin inhibits glucose-stimulated insulin release in dogs and rodents and has been proposed as having a role in the control of insulin release in humans. The effect of infused galanin on intravenous glucose tolerance in humans was investigated by giving an intravenous glucose tolerance test (0.5 g glucose/kg body wt) alone and with infusions of synthetic porcine galanin at high-dose levels (80 and 160 pmol · kg−1 · min−1) to seven healthy male volunteers. The results showed no effect of galanin infusion on plasma glucose or serum insulin, although a rise in serum growth hormone even in the face of the intravenous glucose load confirmed the potent growth hormone-stimulating effect of galanin. These results suggest that caution should be exercised in extrapolating a physiological role for galanin in humans from the results of animal studies.

The effect of central blockade of kappa-opioid receptors on neuropeptide Y-induced feeding in the rat

Neuropeptide Y (NPY) and the endogenous kappa-opioid receptor ligand, dynorphin (dyn), stimulate feeding when injected centrally in the rat. Norbinaltorphimine (norBNI, 25 nmol) reduced the feeding response to NPY (2.4 nmol) by 67% (P < 0.02). An additive effect of dynorphin and NPY was seen on food intake (saline 0.8 +/- 0.1, dyn 1.9 +/- 0.4, NPY 6.1 +/- 1.4, dyn and NPY 9.7 +/- 2.2). A component of NPY-induced feeding may be mediated by kappa-opioid neuronal systems.

Naloxone-induced anorexia increases neuropeptide Y concentrations in the dorsomedial hypothalamus: Evidence for neuropeptide Y-opioid interactions in the control of food intake

We measured neuropeptide Y (NPY) concentration in microdissected hypothalamic nuclei, by radioimmunoassay, and NPY mRNA in the hypothalamus in rats treated systemically with the nonspecific opioid antagonist, naloxone, to produce mild anorexia. Twenty rats were treated with daily SC injections of naloxone (7.5 mg/kg); 20 were treated with vehicle alone. Naloxone produced a 7% reduction in food intake (p < 0.01) and a reduction in weight gain (p < 0.002). Neuropeptide Y concentrations were increased specifically in the dorsomedial nucleus of the hypothalamus (DMN) in rats treated with naloxone (6.8 +/- 0.7 fmol/micrograms protein vs. 3.1 +/- 1.0 fmol/micrograms protein, p < 0.05, n = 10 per group). Total hypothalamic NPY mRNA was unchanged. Neuropeptide Y-opioid interactions may be important in the control of food intake.

Dexfenfluramine treatment and hypothalamic neuropeptides in diet-induced obesity in rats

Neuropeptide Y (NPY) is a powerful appetite stimulant, and hypothalamic concentrations rise after food deprivation and in experimental diabetes. Serotonergic drugs such as dexfenfluramine are inhibitors of feeding. We measured hyothalamic NPY and NPY mRNA, along with galanin, neurotensin, and somatostatin in chow-fed rats and in rats with dietary obesity, and examined the effect of dexfenfluramine on these peptides in this model. Sixty-five rats were fed a palatable diet (condensed milk, sucrose and chow) for 6 weeks, which produced significant weight gain compared to twenty fed standard chow (145.1 +/- 2.3 g vs. 113.4 +/- 3.2 g, p less than 0.001). Groups of animals were treated for 7 days or 28 days with dexfenfluramine (1.8 mg/kg/day) or saline intraperitoneally via miniosmotic pumps. Hypothalami were dissected into medial and lateral blocks, and NPY, galanin, neurotensin, and somatostatin were measured by radioimmunoassay. Neuropeptide Y mRNA was measured by Northern blotting. Hypothalamic NPY was significantly higher in the palatable diet group compared to chow-fed controls (medial hypothalamus: 86.6 +/- 7.6 vs. 65.7 +/- 4.0 pmol/g tissue, p less than 0.02, lateral hypothalamus 71.2 +/- 6.6 vs. 53.1 +/- 3.6 pmol/g tissue, p less than 0.05), but NPY mRNA was unchanged. Although dexfenfluramine was effective at reducing weight gain in the animals fed the palatable diet, this did not result in any changes in the hypothalamic neuropeptides measured. Neuropeptide Y may be of importance in diet-induced obesity but the weight loss produced by dexfenfluramine in such animals is not mediated by changes in hypothalamic NPY.