Repeated hypothalamic stimulation with neuropeptide Y increases daily carbohydrate and fat intake and body weight gain in female rats

Neuropeptide Y (NPY), repeatedly injected in the hypothalamic paraventricular nucleus (PVN), produces dramatic obesity and overeating in female rats maintained on a single nutritionally complete diet. In the present study, we investigated whether these effects could also be obtained in animals with a choice of three pure macronutrients: protein, carbohydrate, and fat. Female rats with indwelling PVN cannulas were injected with NPY (235 pmol) or its saline vehicle every 8 hr for 6 days. A third group was left undisturbed. Consumption of each macronutrient and body weight were measured every 24 hr for 6 days preinjection, 6 days during injections, and 21 days after the injections were terminated. Relative to vehicle or preinjection rates of body weight gain (approximately 1.5 g/day), NPY dramatically enhanced weight gain to a rate of 9.3 g/day and more than doubled total daily food intake. This augmentation was accounted for by increases in carbohydrate intake (+26.4 kcal/day) and fat intake (+48.5 kcal/day), with no significant potentiation of protein consumption. When the NPY injections were terminated, body weight and macronutrient intake returned to control levels within 1 or 2 weeks. These findings are consistent with a role for NPY in hypothalamic mechanisms of macronutrient intake and body weight regulation and suggest that disturbances in brain NPY may contribute to the development of eating and weight disorders.     

Changes in 24-hour fluctuations of feeding behavior during hypothalamic hyperphagia in rats

Lesions were electrolytically placed in the ventromedial hypothalamic area in rats. Bilateral lesions appear to be more effective in producing hyperphagia than unilateral lesions. Changes in the circadian pattern during the hyperphagic phase are mainly brought about by a variable degree of increase in eating during the light periods. The fact whether or not a rhythm is present is determined by the localization of the lesion. Symmetrically placed lesions result in loss of rhythmicity in most cases but this does not correlate with the degree of hyperphagia. A possible role of connections between the suprachiasmatic nucleus and the ventromedial hypothalamic area is suggested.     

Dietary hyperphagia in rats: role of fat, carbohydrate, and energy content

Dietary energy, fat and carbohydrate content were varied to determine the nutritional factors responsible for hyperphagia induced by feeding rats high-fat diets. In the first experiment, rats were fed isoenergetic high-fat or high-carbohydrate diets for 2 weeks. Weight gain and energy intake were lower in rats given the high-fat diet. When some of the rats were switched to a diet that was high in fat, carbohydrate and energy, gram food intake was initially unchanged, resulting in a substantial increase in energy intake and weight gain. Energy intake gradually declined over the 4 weeks following the switch to the high-energy diet. In the second experiment, rats were fed high-fat diets that were either high or low in carbohydrate content and either high or low in energy content (kcal/g). Rats fed a high-fat diet that was high in energy and carbohydrate ate the most energy and gained the most body weight and carcass fat. In the third experiment, rats were fed high-carbohydrate diets varying in fat and cellulose content. Energy intake and body weight gain varied directly as a function of caloric density regardless of the fat or cellulose content of the diets. It is concluded that hyperphagia induced by feeding high-fat diets is not due to the high dietary fat content alone. Rather, high levels of fat, carbohydrate, and energy interact to produce overeating and obesity in rats fed high-fat diets.     

Caloric compensation to gastric loads in rats with hypothalamic hyperphagia

Rats with hypothalamic hyperphagia were treated with gastric loads of an amount of calories in the form of glucose solution or vegetable oil, while daily food intake, weight change, and carcass fat content were used as indices of caloric compensation. This treatment revealed: (a) Rats responded to daily loads of either substance by reducing food intake without affecting weight gain. The suppression of food intake persisted as long as loading continued. However, loads of fat produced more variable results than glucose. (b) Loads of either substance did not enhance fat deposit as compared to the control loads of water or liquid paraffin. Finally, (c) there was no relaxation of caloric compensation even during the acute increase of food intake shortly following the placement of lesions in the ventromedial hypothalamus.     

Hyperinsulinemia in rats with ventromedial hypothalamic lesions: role of hyperphagia

The relation of hyperinsulinemia to hyperphagia was examined in rats with lesions of the ventromedial hypothalamus (VMH). Plasma insulin and glucose levels were assayed after a 4-hr fast and 17 min after the initiation of a meal (6 ml of sweetened milk in 7 min) in animals with sham lesions, VMH animals maintained at preoperative body weight by food restriction, and VMH animals fed ad lib. Both VMH groups displayed basal and postabsorptive hyperinsulinemia, compared with the sham-operated control group, but insulin levels were greatest under the ad lib feeding condition. It is suggested that VMH hyperinsulinemia is due both to a primary effect of the lesion and to hyperphagia and that marked obesity can result in the absence of basal hyperinsulinemia as a result of hyperphagia with consequent postabsorptive hyperinsulinemia.     

Sham feeding in rats after ventromedial hypothalamic lesions and vagotomy

Sham feeding was examined in female rats with ventromedial hypothalamic (VMH) lesions with or without abdominal vagotomy. In Experiment 1, intact rats consumed more than twice as much sweet milk during 1-hr tests of sham feeding (M = 13.0 ml) as they did when feeding normally (M = 5.5 ml). Rats with VMH lesions showed exaggerated sham feeding, which was elevated almost fourfold (M = 56.6 ml) over their already high normal feeding baseline (M = 15.1 ml). In Experiment 2, vagotomy substantially reduced sham feeding in rats with VMH lesions. After vagotomy, VMH rats sham fed half as much (M = 23.7 ml) as nonvagotomized VMH rats did (M = 46.8 ml). Vagotomy did not, however, reduce sham feeding to control levels (M = 13.1 ml). These results are consistent with the hypothesis that VMH hyperphagia arises from exaggeration of orosensory responsiveness, which is, in part, a consequence of perturbed vagal function.     

Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats

We investigated the role of hypothalamic insulin signaling in the regulation of energy balance and insulin action in rats through selective decreases in insulin receptor expression in discrete hypothalamic nuclei. We generated an antisense oligodeoxynucleotide directed against the insulin receptor precursor protein and administered this directly into the third cerebral ventricle. Immunostaining of rat brains after 7-day administration of the oligodeoxynucleotide showed a selective decrease of insulin receptor protein within cells in the medial portion of the arcuate nucleus (decreased by approximately 80% as compared to rats treated with a control oligodeoxynucleotide). Insulin receptors in other hypothalamic and extra-hypothalamic areas were not affected. This selective decrease in hypothalamic insulin receptor protein was accompanied by rapid onset of hyperphagia and increased fat mass. During insulin-clamp studies, physiological hyperinsulinemia decreased glucose production by 55% in rats treated with control oligodeoxynucleotides but by only 25% in rats treated with insulin receptor antisense oligodeoxynucleotides. Thus, insulin receptors in discrete areas of the hypothalamus have a physiological role in the control of food intake, fat mass and hepatic action of insulin.     

2-deoxy-D-glucose inhibits food intake in rats after ventromedial hypothalamic lesions

Changes in food induced by 2 deoxy-D-glucose (2 DG) have been investigated in newly lesioned rats during the two parts of the diurnal cycle. In a first experiment rats were injected with saline or 2 DG (250, 500, 750 mg/kg) at the beginning of the light or the dark period. In a second experiment rats were injected with saline or 2 DG (250 mg/kg) in the middle of the two periods after 0, 2, 4 or 6 hr of fasting. Results show that 2 DG exerts an inhibitory effect on food intake at night, as it does in intact rats, under ad lib conditions or after a short deprivation time. The stimulating effects of 2 DG on diurnal food intake observed in intact rats is not replicated in VMH rats. On the contrary an inhibition of intake follows a short food deprivation. The data suggest that 2 DG stimulates food intake only under metabolic and feeding conditions characteristic of the diurnal phase in intact rats. Since lipogenesis and hyperphagia are observed 24 hr a day in VMH animals, only inhibition could follow 2 DG.     

Release of hypothalamic norepinephrine during MSG intake in rats fed normal and nonprotein diet

Effects of monosodium L-glutamate (MSG) solution (0.06 M) on interstitial levels of norepinephrine (NE) were measured in the lateral hypothalamus (LH). Wistar male rats, housed in standard operant boxes, were fed either normal or nonprotein diet for 3 days. Beside a daily bar-mediated drinking session (75 min), animals were without access to fluids. Microdialysates, collected from the LH during the 75 min of drinking, were analyzed using high-pressure liquid chromatography. No significant responses of the LH NE to the drinking of distilled water, MSG, NaCl (0.06 M), and glucose solution (0.6 M) were found in normally fed rats. However, a specific decline in LH NE release was detected during MSG solution-drinking in rats fed nonprotein diet. As MSG preference indicates protein intake, it is possible that LH NE is, at least partially, one of the brain signals that relate MSG preference to dietary protein intake.     

Meal size as a determinant of food intake in normal and hypothalamic obese rats

Size of meals taken by normal rats was greatly increased by following each spontaneously initiated meal with gastric infusion of additional diet. In a second experiment, rats in the dynamic phase of hypothalamic obesity were limited to meals much smaller than the unusually large ones they usually take. In both experiments rats made precise adjustments in meal frequency which maintained daily food intakes at or close to pre-experimental levels.     

Delayed or precocious hyperphagia after symmetrical or asymmetrical hypothalamic knife cuts in male and female weanling rats

Hypothalamic knife cuts were made in weanling rats. Following bilateral parasagittal knife cuts in either sex there was an initial 1– weeks of marginally excessive weight gain followed by 1–2 weeks of no gain or even weight loss followed finally by a sustained excessive weight gain. Following asymmetrical knife cuts (unilateral parasagittal cut + contralateral coronal cut) in either sex the obesity was also delayed. With these asymmetrical cuts, however, there was no initial excessive gain and subsequent loss. With both types of knife cuts the onset of the delayed excessive weight gain did not coincide with puberty. For a few rats with either type of cut there was no delay at all, the knife cut weanlings gaining excessively and continuously beginning from the day of surgery.     

Salt and water intake in Brattleboro rats with hypothalamic diabetes insipidus

Brattleboro rats lacking vasopressin have an elevated plasma osmolality and a stimulated renin-angiotensin system relative to Long-Evans rats (LE). The current studies were performed to elucidate the factors controlling water and salt intake in the Brattleboro rat with diabetes insipidus (DI). DI and LE rats were given the choice of water and saline solutions ranging from 0.1-1.0% to assess palatability, dialyzed with isotonic glucose to test for sodium appetite after sodium depletion, and infused intracranially with an angiotensin II analogue (saralasin) to assess the role of angiotensin II in spontaneous salt and water intake. DI rats exhibited spontaneous salt intake which was not significantly different from LE rats and increased their intake of 3.0% NaCl following sodium depletion, although less reliably than LE rats. A significant proportion of those DI rats not developing a sodium appetite showed attenuation of their diabetes following dialysis. No evidence for involvement of angiotensin II in spontaneous salt and water intake was found.     

Reduced salivation in rats following ventromedial hypothalamic lesions

Salivation was assessed in normal rats and rats with bilateral lesions of the ventromedial hypothalamus (VMH). VMH lesioned rats demonstrated a reliable reduction of salivation. This hyposalivation occurred during a one month period that animals were maintained on dry rat chow and for a 16 day period that animals were maintained on a palatable liquid diet. VMH rats did not differ from control rats in the amount of saliva secreted in response to Prostigmin or wintergreen solution. Thus, while the VMH rat shows a reduced basal salivation level, such animals salivate normally in response to a strong taste substance.     

Reappearance of dynamic hyperphagia during the static phase in medial hypothalamic lesioned rats

Female rats overate and became obese following electrolytic lesions of the medial hypothalamus. While every animal displayed the characteristic dynamic-static hyperphagic syndrome, not all of them maintained a permanent static phase. After many weeks or months of maintaining body weight at an elevated obese plateau with near-normal food consumption, several of the rats which had at least doubled their preoperative body weight displayed a spontaneous renewal of hyperphagia that was longer lasting and nearly equal in amplitude to the initial dynamic phase. Only one of the less obese animals displayed the phenomenon. The sudden increases in food intake and body weight were not due to a change in diet or any of the other variables which are known to influence the eating habits of obese lesioned rats.