Leptin and neuropeptide Y (NPY) modulate nitric oxide synthase: further evidence for a role of nitric oxide in feeding.

Recent studies have suggested a role for nitric oxide in the regulation of food intake. Neuropeptide Y (NPY) is one of the most potent orexigenic agents. Chronic administration of leptin decreases food intake. This study examined the effects of NPY and leptin on nitric oxide synthase (NOS) in the hypothalamus. Previously it has been demonstrated that obese (ob/ob) mice have elevated NOS levels in the hypothalamus. In this study we demonstrated that the administration of leptin (6 microg/day) subcutaneously (SC) for 3 days decreased body weight (P < 0.001) and food intake P < 0.001) in obese (ob/ob) mice as expected. In addition, leptin decreased NOS in the hypothalamus nu 37% (P < 0.01) and in brown adipose tissue by 69% (P < 0.01) but not in white adipose tissue. NPY was administered intracerebroventricularly to CD-1 mice at doses of 0.25 and 0.50 microg. Mice were sacrificed 15 min after injection and NOS was measured in their hypothalami. NPY at the lower dose increased NOS in the hypothalamus by 147%. These results, taken together, with previously published studies support the concept that nitric oxide may play a role as a mediator of the effects of NPY and leptin on food intake. The alterations of NOS in brown adipose tissue following leptin administration could result in changes in blood flow or metabolism in the brown fat.

Inhibition of feeding by a nitric oxide synthase inhibitor: effects of aging.

Nitric oxide has been demonstrated to play a role in the modulation of food intake. With advancing age, there is a physiological decrease in food intake. The effect of the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) on food intake in C57BL/6Nnia mice aged 3, 12 and 24 months was studied. L-NAME was more effective at decreasing food intake in 12- and 24-month-old mice than in the 3-month-old mice. NO synthase levels in the hypothalamus were increased in 16- and 25-month-old mice compared to 6-month-old mice (P < 0.01). NO synthase mRNA increased in 16- compared to 6-month-old mice, but decreased in 25-month-old mice. Overall, these studies may suggest that nitric oxide may play an increasingly important role in the feeding drive with advancing age.

Effects of localized injections of neuropeptide Y antibody on motor activity and other behaviors.

Neuropeptide Y (NPY) was shown to increase feeding when injected into the hypothalamus. Neuropeptide Y antibody (aNPY) decreased feeding in the ventromedial area of the hypothalamus as well as when it was injected into the ventromedial or ventrolateral areas of the thalamus, but not when injected into other hypothalamic areas. The decrease in feeding produced by aNPY in the hypothalamus was associated with a sterotypic increase in general activity in the hypothalamus, circling in the ventromedial thalamic area, and barrel rolling in the ventrolateral thalamic area. Neuropeptide Y antibody also reduced by 54-73% the time it required for mice to recover from anesthesia. The marked increase in stereotypic activity and enhanced recovery from anesthetic suggest that blocking endogenous NPY released the brain areas from inhibitory control. These studies further confirm a physiological role for NPY in the central nervous system.

An investigation of tolerance to the actions of leptogenic and anorexigenic drugs in mice.

This study compared the effects of chronic administration of anorexigenic drugs on weight loss in mice. Tolerance to the effects of peripheral anorexigenic peptides, viz. cholecystokinin-octapeptide and bombesin, developed rapidly. Morphine, cocaine and dehydroepiandrosterone-sulfate caused weight loss and appeared similar to d-amphetamine in mechanisms of action. A high dose of fluoxetine (25 mg/kg) proved to be a potent leptogenic agent but was also associated with death in some animals. A lower dose of fluoxetine (5 mg/kg) was associated with the development of tolerance. Calcitonin, a potent anorexigenic agent, did not produce weight loss and tolerance to its anorectic effect had developed by 10 days. Animals varied widely in their individual responsiveness to a given drug. Peripheral administration of peptide YY caused weight loss. We conclude that acute or chronic effects of agents on food intake do not necessarily predict effects on body weight. However, neurotransmitters that enhance feeding centrally appear to cause weight loss when administered peripherally.

A comparison of the effects of localized brain administration of catecholamine and protein synthesis inhibitors on memory processing.

Protein synthesis inhibitors disrupt biosynthetic processes thought to control the formation of long-term memory. While the agents used (i.e. puromycin, acetoxycycloheximide, cycloheximide and anisomycin) do not selectively inhibit the synthesis of any particular class of protein, it has generally been hypothesized or assumed that the critical proteins(s) is structural and necessary for modification and/or growth of synapses. Recent reports indicated that all of the protein synthesis inhibitors causing amnesia inhibited tyrosine hydroxylase activity. Tyrosine hydroxylase is needed for the conversion of tyrosine to dopamine (DA) and norpinephrine (NE); altering the level of this enzyme could affect catecholamine (CA) turnover. Since drugs known to inhibit CA synthesis cause amnesia, it is of considerable interest whether amnesia induced by protein synthesis inhibitors depends basically on inhibition of CA synthesis.