Defense of a lowered weight maintenance level by lateral hypothamically lesioned rats: Evidence from a restriction-refeeding regimen

Male rats maintained their body weight at approximately 85% that of sham-lesioned controls following lesions of the lateral hypothalamus (LH). One month following surgery, the food intake of half the LH-lesioned animals was restricted until their body weight had declined to 80% that of nonrestricted LH animals. Half the sham-lesioned animals were similarly restricted until their body weight fell to 80% that of nonrestricted control animals. When returned to an ad lib feeding schedule, both restricted groups were initially hyperphagic and quickly restored their body weights to the level of the nonrestricted group from which they were originally selected. In doing so, the LH animals increased their food intake by the same amount and took the same number of days to restore their weight to control levels as the sham-lesioned animals. These observations provide further evidence of the vigor and effectiveness with which LH animals defend their reduced level of maintained body weight.     

Food intake and utilization in lateral hypothalamically lesioned rats

The daily food intake of rats with lateral hypothalamic (LH) lesions was monitored in two experiments. Confirming earlier reports, LH-lesioned animals were found to ingest nearly the same amount of food per day as nonlesioned controls even though their body weights remained substantially below those of the controls. In view of this result, an experiment was conducted to compare the efficiency of food utilization of LH-lesioned and control animals at different body weights. First, the daily food intakes of seven LH-lesioned rats and seven nonlesioned controls were determined. The body weights of these animals were then lowered by restricting food intake in four successive weekly periods to 85%, 70%, 55% and 40% of their ad lib level. Finally, all animals were refed for one week at their prerestriction levels of food intake reduced in proportion to the intervening loss in metabolic mass (body weight_kg^0.75). At each level of caloric restriction, the weight losses observed in the LH-lesioned and control animals were equivalent. Likewise, though given only prerestriction amounts (indexed to their reduced metabolic mass), LH-lesioned and nonlesioned animals both gained weight rapidly and at equivalent rates during refeeding. Thus, LH-lesioned animals appear to utilize food in a normal fashion and, as do controls, adapt to weight loss by increasing their efficiency of food utilizazion. In the case of LH-lesioned animals, however, such adjustments occur around a reduced level of maintained body weight, or set-point.     

Area postrema/nucleus of the solitary tract ablations: Analysis of the effects of hypophagia

The effect of hypophagia following lesions of the area postrema and caudal-medial aspect of the nucleus of the solitary tract (AP/cmNTS) on body-weight, water intake and preference for palatable diets was examined. Following AP/cmNTS ablation, rats reduced pelleted-food intake to a degree which was sufficient to account for the weight loss and increased water:food ratios observed. Restricting food intakes of intact rats to levels taken by lesioned animals resulted in similar weight losses and increased water:food ratios. When offered both pelleted food and milk, lesioned rats took more calories as milk than did previously food-restricted intact rats. Thus, the hypophagia of AP/cmNTS lesioned rats does not account for their increased preference for milk diets. Lesioned rats ate less high-fat diet than did intact or sham-lesioned controls and did not increase their intakes when this diet was sweetened. At autopsy, retroperitoneal and epididymal fat-pad weights accounted for less of the total body weight of lesioned animals than controls suggesting that body-fat levels are reduced following AP/cmNTS ablation.     

Changes in actual versus defended body weight elicited by a varied, palatable ("supermarket") diet in rats

Male rats fed on a varied, palatable supermarket diet for 11 weeks gained more weight than chow-fed controls. When palatable food was discontinued, their body weights became static, but remained significantly higher than control weights for a further 5 weeks. Hoarding of food was readily elicited by food deprivation in the dietarily obese as well as in the chow-fed rats. Previous studies have shown that the critical body weight at which hoarding appears does not covary with body weight, but appears to reflect a defended level of body weight. In the present study, critical weights were not significantly different between groups before supermarket diet, but were significantly higher in the supermarket rats after obesity had developed. Thus, the increase in body weight brought about by a supermarket diet (unlike that in ventromedial hypothalamic obesity) can be accompanied by an increase in the defended level of body weight as inferred from the critical weight for the onset of hoarding behaviour.     

Acute exposure to a high-fat diet alters meal patterns and body composition

Weight gain and adiposity are often attributed to the overconsumption of unbalanced, high-fat diets however, the pattern of consumption can also contribute to associated body weight and compositional changes. The present study explored the rapid alterations in meal patterns of normal-weight rats given continuous access to high-fat diet and examined body weight and composition changes compared to chow fed controls. Ten Long-Evans rats were implanted with subcutaneous microchips for meal pattern analysis. Animals were body weight matched and separated into two groups: high-fat or chow fed. Each group was maintained on their assigned diet for nine days and monitored for 22 h each day for meal pattern behavior. Body weight was evaluated every other day, and body composition measures were taken prior and following diet exposure. High-fat fed animals gained more weight and adipose tissue than chow fed controls and displayed a reduced meal frequency and increased meal size. Furthermore, meal size was significantly correlated with the gain of adipose tissue. Together, these results suggest that consumption of a high-fat diet can rapidly alter meal patterns, which in turn contribute to the development of adiposity.     

Lateral hypothalamic lesions and fenfluramine increase thermogenesis in brown adipose tissue

The effects of treatment with fenfluramine or electrolytic lesions in the lateral hypothalamus (LH) on binding of guanosine 5-diphosphate (GDP) by mitochondria from brown adipose tissue have been compared in 4 experiments. In 2 experiments the lesions were lateral to the anterior hypothalamic nucleus and in the other two they were lateral to the ventromedial hypothalamic nucleus. Binding of GDP to mitochondria was significantly increased 18 hours after an electrolytic lesion in either LH site. d,1-Fenfluramine, 20 mg/kg, also increased GDP binding in both acute experiments. In the other 2 experiments GDP binding was measured 11 days after the LH lesion or after 11 daily injections of fenfluramine. When the chronic lesions were lateral to the VMN, there was a transient drop in food intake and body weight. With more anterior lesions, body weight remained significantly lower than in sham-operated rats although food intake returned slowly to control levels. Fenfluramine-treated rats had lower body weights in both chronic experiments even after food intake returned to normal. GDP-binding to mitochondria from interscapular brown adipose tissue was elevated in both of the chronically-treated fenfluramine groups but was only increased in the LH-lesioned rats whose body weight remained below normal.     

Digestibility in male rats with lateral hypothalamic lesions

The body weight of male rats with lateral hypothalamic lesions remained approximately 20% below that maintained by nonlesioned controls. One month following surgery, both food intake and energy losses in feces and urine were measured in all animals for five days. The percentage of ingested food absorbed by the gut (“digestibility”) was determined from calorimetric analysis of the feces to be slightly, though significantly, higher for the lesioned animals (79.7% vs 77.4%). Resorptive capacity, as indicated by the percentage of absorbed energy lost in the urine, was determined to be the same for the lesioned and control animals (4.8% vs 4.5%). These results indicate that the digestive, absorptive, and resorptive processes of LH-lesioned animals are at least as efficient as those of nonlesioned animals maintaining normal body weights. Thus, though LH-lesioned animals are reported to display various gastrointestinal dysfunctions, alterations in digestive or resorptive efficiency are apparently not responsible for their chronically-reduced body weights.     

Obesity without overeating in golden hamsters

When male golden hamsters were switched from a diet of Purina rodent chow to a calorically-dense high-fat diet or were given ad lib access to a 32% sucrose solution in addition to chow, they adjusted their food intakes rapidly (within 24 hr) and did not overeat. Nevertheless, the fat-fed hamsters tripled their rate of weight gain and nearly doubled their carcass fat content after one month on the diet. Resting oxygen consumption (animals awake but quiet) was significantly lower in fat-fed animals than in chow-fed controls. Sucrose feeding had no effect on food intake, body weight gain, carcass composition or oxygen consumption. Thus, whereas rats exhibit dietary obesity in spite of increases in energy expenditure (diet-induced thermogenesis), fat-fed hamsters seem to become obese because of decreases in energy expenditure. However, although actual energy expenditure is reduced, fat-fed hamsters exhibit an enhanced thermogenic capacity. Interscapular brown adipose tissue mass, protein content, and DNA content as well as norepinephrine-stimulated oxygen consumption were all significantly elevated in fat-fed hamsters. The significance of these concurrent diet-induced decreases in energy expenditure and increases in thermogenic capacity is not clear, but they could be of some value in preparing the hamster for winter.     

Effects of age,sex, and prior body weight on the development of dietary obesity in adult rats

Adult male and female rats were fed either lab chow (Groups 2 and 3) or lab chow and an assortment of palatable supermarket foods (Group 1) during Days 1–60 of the experiment. All rats were maintained on only lab chow during Days 61–90. Group 1 and 3 rats were then given the supermarket diet during Days 91–150, while Group 2 rats continued on lab chow only. The rats fed the supermarket diet significantly more body weight than did the lab chow fed rats, and this dietary obesity was greater in the older rats (i.e., during the Days 91–150 of the experiment) than in the younger rats (Days 1–60). Male rats gained as much or more weight on the supermarket diet as did the females, but compared to the same-sexed chow fed rats females displayed greater weight gains than did males. Finally, during Days 91–150 Group 1 and 3 rats gained similar amounts of weight on the supermarket diet despite the fact that the Group 1 rats had previous experience with the diet and had been overweight as a result. The findings demonstrate that age and sex, but not prior experience with palatable foods and overweight, are important factors in the development of dietary obesity in adult rats. The similarity between dietary obesity and hypothalamic obesity with respect to these three factors is discussed.     

Lack of diet-induced thermogenesis following lesions of paraventricular nucleus in rats

The effects of electrolytic lesions in the hypothalamus paraventricular nucleus were studied in adult male and female Sprague-Dawley rats, fed different diets, consisting of either palatable human food plus chow (cafeteria diet) or chow alone. The results showed that both cafeteria diet and lesions induced an increase in energy intake and weight gain in rats of both sexes. Oxygen consumption rate and colonic temperature were significantly decreased by lesions, while cafeteria diet increased the same parameters only in intact animals. The lesion decreased weight, protein and DNA, and temperature of brown adipose tissue, while cafeteria diet increased the values considered in brown adipose tissue of sham-injured rats, but not in lesioned animals. The response to norepinephrine administration was significantly greater in intact rats and those fed cafeteria diet. The results suggest that the larger body weight gain observed in lesioned rats, particularly evident in rats fed cafeteria diet, is partly due to the disappearance of diet-induced thermogenesis that depends on the reduced mass and functional activity of brown adipose tissue.     

Effects of LH kainic acid infusions on ingestion and autonomic activity

The effects of lateral hypothalamic (LH) infusions of kainic acid (KA) were determined on ingestive behavior, body weight, and motor and autonomic activity. In Experiment 1 male hooded rats received bilateral LH infusions of isotonic saline in volumes of 0.5 or 1.0 μl, 3.0 μg KA in volumes of 0.5 or 1.0 μl, or 6.0 μg of KA in a volume of 1.0 μl. All animals receiving 6.0 μg/1.0 μl of KA died. The 3.0 μg/0.5 μl dose resulted in transient decreases in food and water consumption and body weight. Animals receiving this dose no longer drank in response to 2 cc/kg 15% NaCl injections, exhibited attenuated drinking in response to 24 hr water and food deprivation, exhibited a transient decrease in eating following food deprivation and decreased eating following 750 mg/kg injections of 2-deoxy-D-glucose. Minimal effects on these measures were observed following the 3.0 μg/1.0 μl dose. In Experiment 2 rats received unilateral infusions of KA and the effects on motor and autonomic activity and ingestive behavior and body weight were compared to unilateral saline infused animals and animals with radiofrequency lesions. Only transient decreases in food consumption lasting 1–2 days were observed for both unilateral KA LH infused and lesioned animals. In KA infused rats contralateral exophthalamus, rapid shallow breathing, bilateral mydriasis, no contralateral pupillary constriction response, excessive salivation, body tremors, seizures, convulsions, teeth chattering, contralateral tail suspension induced spinning and turning, and elevated body temperature were observed for up to 6 hr following the infusion. Results are discussed in terms of lateral ventral diencephalic neurons involved in the more permanent deficits associated with bilateral LH damage.     

Resting oxygen consumption in rats during food restriction,starvation and refeeding

Oxygen consumption was measured in male rats during starvation and during different regimens of restricted feeding and refeeding after starvation. Changes in oxygen consumption and body mass were mostly parallel, but rats with a very reduced food intake displayed the same reduction in oxygen consumption as starved rats, despite the smaller reduction in body mass. Also, rats fed different amounts of food after starvation had different oxygen consumptions, but displayed the same changes in body mass. Two different refeeding regimens with restricted food amounts either induced a further depression of oxygen consumption (i.e. below starvation oxygen consumption), or a stabilizing of oxygen consumption on the level of starvation. The changes in oxygen consumption during restriction and feeding after starvation indicate that reductions in resting metabolic rate may not always be predicted from either body mass change or food intake.     

Exercise and the development and persistence of dietary obesity in male and female rats

Adult male and female hooded rats were housed in sedentary conditions or were given free access to a running wheel. Exercising and sedentary rats received either a palatable, mixed, high energy diet with chow (experimental group) or only chow (control group). Exercise reduced the weight gain of the males but not of the females. All experimental groups preferentially selected the palatable foods. Both exercising and sedentary females and the sedentary males became obese compared to their controls, but the exercising males did not. The mixed diet was withdrawn after 10 weeks: thereafter the male and female sedentary experimental groups maintained the elevated body weight. The exercising experimental females showed significant weight loss. Analysis of x-ray photographs indicated that elevated body weight in the experimental rats probably reflected increased deposition of fat and not skeletal growth. The results show that the effect of exercise on the development of dietary obesity is different in males and females, and that sedentary male and female rats can both show persistent dietary obesity after withdrawal of the palatable foods.     

Early weight gain and behavioral responsivity as predictors of dietary obesity in rats

Variance in diet-induced weight gain was examined for possible relationships with variations in early weight gain and three tests of behavioral responsivity. Female Sprague-Dawley rats were reared in litters of 4, 8, or 20. When animals reached adulthood, each animal's acoustic startle reflex, tail-pinch feeding responses and activity in an open field containing a palatable food were assessed. After completing these behavioral tests, rats were exposed to either palatable foods or a control diet for 59 days, following which all subjects were maintained on the control diet for 66 days. Body weights, food intakes, and naso-anal lengths were measured. Preweaning body weight gain for all rats correlated positively with later diet-induced weight gain. Rats reared in litters of 4 or 20 both gained less weight after exposure to palatable foods than did rats reared in litters of 8. Diet-induced weight gain correlated positively with magnitude of acoustic startle reflex and with latency to eat in response to tail pinch. These results tentatively identify specific predictive factors which may be useful in future studies of dietary obesity.     

Dorsomedial hypothalamic lesions at weaning and ovariectomy after maturity: Somatic and metabolic changes

Weanling Sprague-Dawley rats received lesions in the dorsomedial hypothalamic nuclei or sham operations. Analysis of variance revealed a significant lesion-induced depression of body weight (BW) and food intake (FI). After sexual maturity, bilateral ovariectomy (OVX) and/or sham-ovariectomy (S-OVX) were performed in each of the above groups. OVX produced a significant increase in BW in both lesioned and non-lesioned rats without changes in food intake. Following DMN lesions efficiency of food utilization (EFU) was greater than normal and OVX caused a further significant increase, irrespective of hypothalamic manipulation. DMN lesions, as previously shown, were followed by a reduction in linear growth; subsequent OVX exerted a growth-promoting effect in both DMN-lesioned and sham-lesioned rats. However, OVX did not alter plasma growth hormone or insulin levels. When calculated on the basis of per gram tissue protein, DMN lesions significantly diminshed the incorporation of glucose into lipids of diaphragm and fat pad, but not of liver. DMN lesions had no effect on the incorporation of glucose into glycogen of diaphragm, fat pad or liver. OVX did not produce significant changes in lipogenesis from glucose or incorporation of glucose into glycogen in either sham-lesioned OVX or DMN-lesioned OVX rats. The data support the concept that increased weight gain following OVX can be attributed to factors other than increased food intake. They also support previous findings that DMN lesions lower the BW “settling point” (i.e., both lean body mass and fat commensurately). The data also suggest that the DMNL rat is responsive to various manipulations—in this case OVX—of the adipose tissue mass “settling point”.     

Chronic food restriction and reduced dietary fat: risk factors for bouts of overeating

The purpose of this study was to determine the effect of chronic food restriction and reduced dietary fat on feeding behavior and body weight. Young female rats were fed ad lib or food restricted on a low-fat (LF) or a fat-free (FF) diet for 4 weeks. Rats then received 24-h free access to 2 diets, the maintenance diet (LF or FF) plus a novel high-fat (HF) diet (24-h intake test). After the test, all the rats were allowed chronic free access to the HF diet until body weight was stable. During the 24-h test, the restricted groups ate significantly more calories than the ad lib groups, and the FF-restricted rats ate significantly more total food, carbohydrate and protein than the LF-restricted rats; there were no differences between the two ad lib groups. During chronic free access to the HF diet, the formerly restricted rats achieved and defended lower body weights than the formerly non-restricted rats. Throughout the experiment, the ad lib groups had more body fat than the restricted groups independent of the dietary subgroup. Hence, a history of chronic food restriction predisposes to consuming more food in acute feeding situations, particularly when dietary fat is reduced, and lowers the level of body weight maintained and defended. Chronic food restriction accompanied by reduced dietary fat may increase risk for bouts of overeating.     

Pregnancy and lactation in the obese rat: Effects on maternal and pup weights

Lister hooded female rats, fed palatable high energy foods and chow, weighed significantly more than chow-fed control rats before mating. A smaller proportion of the obese rats became pregnant, and they lost more litters in lactation. When litters survived (7±1 pups), maternal weight changes differed between groups during lactation. The controls gained 6.2±3.2 g, whereas the obese rats lost variable amounts of weight despite the continued availability of the palatable diet. The rats that were heaviest at mating and parturition and which showed the largest non-fetal weight gains in pregnancy (i.e., the “large weight loss group”) lost 60.6±4.8 g, while less obese rats which showed similar non-fetal gains to controls (i.e., the “small weight loss group”) lost 24.6±3.2 g. Thus the weights of all groups converged and were similar after three weeks of lactation, but diverged again after weaning. During lactation the total energy intakes and amounts of protein consumed by the obese rats were significantly below those of controls, and total fat intake was significantly elevated. Although litter size and pup weights did not differ significantly at birth, pups of obese mothers weighed significantly less than those of controls at weaning. Maternal obesity in lactation appears to influence both body weight regulation and lactational performance.     

Wheel running eliminates high-fat preference and enhances leptin signaling in the ventral tegmental area

Voluntary wheel running (WR) is a form of physical activity in rodents that influences ingestive behavior. This study examined the effects of WR on dietary preference and the potential role of leptin in mediating these effects. In a two-diet choice paradigm in which both palatable high-fat (HF) food and standard laboratory chow were provided ad libitum, rats displayed a strong preference for the former and chose to eat almost exclusively the HF diet over chow in sedentary conditions. With free access to running wheels, however, rats exhibited no preference for the HF food and consumed equal gram amounts of both chow and HF diets. The total daily caloric consumption during WR in the dietary choice protocol was equivalent to the amount of calories consumed daily by WR rats with only chow or only HF diet available, yet significantly less than sedentary chow caloric consumption. Two days after initiating WR, leptin signal transduction was examined in multiple selected brain sites following leptin injection into the third cerebral ventricle. The maximal leptin-stimulated STAT3 phosphorylation was enhanced only in the ventral tegmental area (VTA), but not in the arcuate nucleus, lateral hypothalamus, dorsal medial or ventral medial hypothalamus, or substantia nigra. In conclusion, wheel running appears to act either as an independent reinforcing factor or as a more favored activity to substitute for the consumption of a palatable HF diet, thus eliminating the preference for the HF food. Moreover, WR enhances leptin signaling specifically in the VTA, suggestive of a WR-evoked mechanism of heightened leptin function in the VTA to curb the drive to consume palatable HF foods.     

Effects of lateral hypothalamic lesions on schedule dependent and schedule induced behavior

Rats were reduced to 80 percent body weight and were exposed to an FI 1 min food reinforcement schedule for 30 min daily until lever presses, licks and water consumption stabilized for at least 10 days. Six animals were subjected to bilateral mid lateral hypothalamic (LH) lesions and 6 animals to bilateral posterior LH lesions. Animals were tested for 50 days following the lesions at 80 percent body weight, were permitted to recover body weight, and were tested for an additional 30 days under ad lib feeding and after body weight recovered. Animals were then subjected to the following four home cage tests: food consumption following food deprivation; drinking following water deprivation; insulin induced eating; and salt arousal of drinking. On the basis of the data collected in these tests and lesion locus and size, the 12 experimental animals were divided into 3 groups--asymmetrical, typical and posterior bilateral LH lesion and were compared to a sham lesion control group of 4 animals. The asymmetrical LH lesion group was similar to the sham lesion group except lever pressing was significantly depressed. Typical bilateral lesion animals displayed the usual LH syndrome with prolonged depression of both schedule dependent lever pressing and schedule induced licking and drinking. Posterior bilateral LH lesions produced the most drastic effects on both schedule dependent and schedule induced behavior. Results indicate that the neural mechanism which is involved in schedule induced polydipsia is destroyed by posterior bilateral LH lesions.     

Relationship of dietary intake to the development of glomerulosclerosis in obese Zucker rats

Obese Zucker rats are hyperphagic and develop premature glomerulosclerosis. The purpose of this study was to find out the effects of restriction of dietary intake on this glomerulosclerosis. The obese and lean male Zucker rats were fed with restricted amounts of balanced diet for periods of 40 and 50 weeks, sacrificed, and the body weight, the light and ultrastructural alterations of glomeruli, and the serum levels of blood urea nitrogen, triglyceride, and cholesterol were examined. Obese and lean male rats of identical ages were fed ad libitum with the diet and studied similarly. The dietary restriction significantly lessened the development of the glomerulosclerosis in obese rats, while those on the nonrestricted diet manifested an advanced glomerulosclerosis. The dietary restriction, however, did not normalize the obesity nor correct the elevated serum lipid level to the range of lean control rats. The spontaneous glomerular lesions of the obese rats were characterized by segmental mesangial expansion, disappearance of podocytes and endothelia, and obliteration of capillary lumina. The lean rats maintained essentially normal renal morphology. A similar study on the renal morphology done in female Zucker rats also revealed a preventive effect of dietary restriction on the development of glomerulosclerosis. In conclusion, there is a strong association between the glomerulosclerosis and the hyperphagia of the obese Zucker rats, both in males and females, and the emergence of this lesion is preventable to a significant degree.