Carlos R. Plata-Salamán

Tumor necrosis factor and interleukin-1β: suppression of food intake by direct action in the central nervous system

Abstract Intracerebroventricular microinfusion of recombinant human tumor necrosis factor (rhTNF) and recombinant human interleukin-1β (rhIL-1β) suppressed food intake in rats. Central infusion of heat-inactivated rhTNF and rhIL-1β, bovine serum albumin, heparin or transforming growth factor-β had no such effect. Central infusion of rhIL-1β did not affect the dipsogenic response to central administration of angiotensin II. Peripheral administration of rhTNF and rhIL-1β in doses equivalent to or higher than those administered centrally had no effect. Electrophoretically applied rhTNF and rhIL-1β specifically suppressed the activity of glucose-sensitive neurons in the lateral hypothalamic area. Glucose-insensitive neurons were little affected. The results suggest that TNF and IL-1β act directly in the central nervous system to suppress feeding, and this effect may be operative during acute and chronic disease.

Hyperphagia and obesity in rats with bilateral ibotenic acid-induced lesions of the ventromedial hypothalamic nucleus.

Macro-electrophoretic applications of the cellular neurotoxin ibotenic acid into the ventromedial hypothalamic nucleus (VMH) resulted in hyperphagia and obesity in male rats. Histological examination showed a reduction in the number of neuronal VMH cell bodies with glial proliferation without evidence of non-specific damage. This supports the hypothesis that hyperphagia and obesity after VMH lesions are related to destruction of neurons intrinsic to the VMH.

Dependence of food intake on acute and chronic ventricular administration of insulin

Several lines of evidences indicate that insulin affords short- and long-term neuroendocrine signals to modulate ingestive behavior. To further study a possible role of insulin in the control of food intake, male Wistar rats were subjected to various intra-third cerebro-ventricular applications of saline and insulin. Infusion of 2.0 mIU/rat of insulin at 1100 and 1900 decreased food intake in a 23.5 hr test period. Infusion of 0.5 mIU/rat of insulin between 1100 and 1200 decreased nighttime food intake during the 1st and 2nd days. Infusion of 2.0 mIU/rat/24 hr of insulin from osmotic minipumps decreased nighttime food intake throughout the active pump period and the effect persisted into the post-pump period. The results support the notion that insulin is involved in the regulation of food intake in the rat.

Effect of intra-third ventricular administration of insulin on food intake after food deprivation

It has been suggested that insulin may participate as a signal in the overall control of feeding. To further study this possible role of insulin, food-deprived male Wistar rats were subjected to intra-third cerebro-ventricular infusions of insulin. Infusion of 0.5 and 2.0 mIU/rat at 0745 hr, and 2.0 mIU/rat of insulin at 1900 hr in 24.5 hr food-deprived rats, and 2.0 mIU/rat of insulin at 2200 hr in 4 hr food-deprived rats did not significantly affect food intake. Infusion of the high dose of 8.0 mIU/rat of insulin at 2200 hr in 4 hr food-deprived rats significantly decreased food intake with a long-delayed and long-lasting effect. This and previous evidence suggest that intra-third ventricular administration of small amounts of insulin induce a decrease of food intake only in non-food-deprived rats.

Endogenous sugar acid derivative acting as a feeding suppressant

Evidence suggests that endogenous sugar acids 3,4-dihydroxybutanoic acid (2-deoxytetronic acid, 2-DTA) and 2,4,5-trihydroxypentanoic acid (3-deoxypentonic acid, 3-DPA) may participate in the regulation of feeding. To study the effect of 2-buten-4-olide, a 2-DTA synthetic derivative, on food intake, male Wistar rats were subjected to various applications. Intraperitoneal administration of 2-buten-4-olide in doses of 30 to 100 mg/kg, decreased food intake dose-dependently by reducing meal frequency, meal size and eating rate, and prolonging meal duration, latency to eat the first meal after injection and post-prandial intermeal intervals. Drinking patterns and locomotor activity were not significantly affected. Administration of 2-buten-4-olide intragastrically in doses of 50 to 300 mg/kg, and intra-third cerebroventricularly in doses of 1.2 to 5.0 mumol/rat, dose-dependently reduced food intake. This and previous evidence suggest that: 2-DTA and its derivatives that share its bioactive components suppress food intake in the rat; They might represent a new category of potential therapeutic agents for hyperphagia and obesity.

Effects of sulphated cholecystokinin octapeptide (CCK-8) on the dorsal motor nucleus of the vagus

Sulphated cholecystokinin octapeptide (CCK-8) was applied by superfusion (2.1 x 10(-7) to 4.2 x 10(-6) M) to neurons of the dorsal motor nucleus of the vagus (DMV) in slice preparations of the rat medulla oblongata. Intracellular recordings show 23 of 54 (43%) neurons to be depolarized and the depolarization to be associated with an increase in membrane input resistance; 6 of 54 (11%) neurons were hyperpolarized and the hyperpolarization was associated with a decrease in membrane input resistance. Both effects were dose-dependent, reversible and persisted after blockade of synaptic transmission by Ca2+ free/high Mg2+ solution. On the other hand, nonsulphated CCK-8, a nonactive analogue of CCK-8, had no effect. These data show that vagal neurons in the DMV have receptors for CCK-8 and that CCK-8 may modulate vagal output mainly by increasing neuronal excitability.

Calcitonin as a feeding suppressant: Localization of central action to the cerebral III ventricle

Calcitonin suppresses food and water intake. To further study this effect of calcitonin, rats were subjected to various intra-cerebroventricular (ICV) applications of calcitonin. The results show: (1) Intra-third ventricular (III-ICV) infusion of calcitonin dose-dependently decreased food intake with short- and long-term effects; (2) Potency was decreased by using non-siliconized materials; (3) Potency decreased with age of rats; (4) Infusion into the aqueduct and cisterna magna decreased short- and long-term food intake less than III-ICV administration; (5) Aqueduct obstruction did not affect feeding suppression by III-ICV calcitonin. Aqueduct obstruction did not affect dipsogenic response to III-ICV infusion of angiotensin II; (6) Results of water intake and food to water intake ratios suggest a greater calcitonin effect on food intake than on water intake. The evidence suggests that the hypothalamus is a main locus for suppression of food intake by ICV administered calcitonin.

Food intake dependence on acute changes in light schedule.

The mechanism of the diurnal eating pattern in the rat (eating much more food at night than in the day) is not entirely clear. To further study the influence of environmental lighting on food intake, male rats were maintained in constant 12:12 light-dark cycle (daytime from 0800 to 2000) and subjected to short-time acute changes in the light schedule. The results show: (1) Lights on during the nighttime (30-min from 2230 to 2300 or from 2258 to 2328) suppress short-term food intake; (2) Lights off during the daytime (2-hr from 1000 to 1200) increase short-term food intake. Both responses (1 and 2) are independent of the age of the rat. These results are consistent with acute regulatory adjustment of feeding to abrupt light shifts, possibly by generation through the retino-hypothalamic pathway to the suprachiasmatic nucleus (supporting its action as a pacemaker in the endogenous circadian feeding rhythm in the rat), although other control mechanisms are not excluded.

Somatomedins (Insulin-Like Growth Factors) and the Nervous System

Somatomedin is a general term which refers to plasma factors that have both growth-promoting (stimulate sulfate incorporation into chondroitin sulfate of cartilage and increase thymidine incorporation into DNA in various tissues) and insulin-like effects (in adipose tissue and diaphragm, not neutralized by anti-insulin serum)1,2. “Somato” relates to somatotropin (growth hormone, GH) and also to the soma which is the target and “medin” to indicate it mediates the action of GH.

Fetal hypothalamic brain grafts to the ventromedial hypothalamic obese rats: An immunohistochemical, electrophysiological and behavioral study

Fetal ventromedial hypothalamic (VMH) tissue was transplanted into or around the third ventricle of adult Fischer 344 rats to determine if transplanted VMH tissue could reverse the hyperphagia and obesity produced by bilateral VMH electrolytic lesions. Host VMH-lesioned rats received stereotaxic implants of 13 to 19 postcoitus fetal VMH tissue from normal Fischer pups. The results show that: 1) Fetal VMH tissue survived in the brain (mainly in the third ventricle) of VMH-lesioned rats. The optimal survival and differentiation was at the gestational age of 13 days; 2) VMH-lesioned rats containing VMH grafts tended to consume less food than the controls, but this was not statistically significant. Neural grafts that could compensate the hyperphagia and obesity produced by the VMH lesions (in comparison to the controls) were those placed into the third ventricle; 3) Electrophysiological evidence demonstrated that VMH grafts contain glucoreceptor neurons in grafts not only located in the third ventricle, but also in the thalamus; 4) Immunohistochemical evidence showed the presence of serotonin, beta-endorphin and substance P immunoreactive fibers in the grafts. These results indicated that transplants of fetal VMH tissue in the brain of bilateral VMH-lesioned adult rats may have some functional effects (depending on the location of the graft).