LH-lesioned Rats Research Articles

Lysine acetylsalicylate modifies aphagia and thermogenic changes induced by lateral hypothalamic lesion.

These experiments test the effect of intraperitoneal injection of lysine acetylsalicylate on 1) food intake and 2) the sympathetic and thermogenic changes induced by lesion of the lateral hypothalamus (LH). Food intake, firing rate of the nerves innervating interscapular brown adipose tissue (IBAT), and IBAT and colonic temperatures (TIBAT and TC) were monitored in male Sprague-Dawley rats lesioned in the LH. These variables were measured before and after intraperitoneal injection of lysine acetylsalicylate. The same variables were also monitored in 1) lesioned rats with intraperitoneal administration of saline, 2) sham-lesioned animals with intraperitoneal injection of lysine acetylsalicylate, and 3) sham-lesioned rats with intraperitoneal injection of saline. The results show that lysine acetylsalicylate modifies the aphagia by increasing food intake and also reduces the enhancements in firing rate, TIBAT, and TC induced by LH lesion. These findings suggest that prostaglandin synthesis plays a key role in the control of eating behavior in LH-lesioned rats by acting on the sympathetic and thermogenic changes induced by LH lesion.

The specific locus and time course of the body protein adjustments produced in rats by lesions of the lateral hypothalamus

Lesions of the lateral hypothalamus (LH) result in a body weight reduction characterized by declines in both lean and adipose tissues. The body fat of LH-lesioned rats can be restored to or above the levels of nonlesioned rats by overfeeding. However, the protein deficit cannot be so reversed, suggesting that the lesion-induced body protein reduction is chronic. To ascertain which specific tissues surrender protein following LH lesions, the present studies measured skeletal muscle and visceral organ weights at 2 weeks and 6 months postlesion. Daily protein losses during the first 2 weeks postlesion were also assessed to determine the temporal pattern of whole-body protein adjustments. The results at 6 months postlesion suggest that LH lesions lead to reductions in the maintained mass of all protein-based tissues. The largest absolute loss was from skeletal muscle, whereas liver sustained the greatest proportional loss. Assessment of daily postlesion protein balance indicate that the majority of body protein losses occurred during the initial 6 days postlesion. Skeletal muscle mass was characterized by large losses at 2 weeks, and proportionally smaller losses at 6 months. Reductions of visceral organ mass were marginal at 2 weeks, but substantial by 6 months postlesion. Thus, whereas all protein-based tissues are reduced by LH lesions, the protein content of specific tissues appears to be altered differentially. Major reductions in total body protein occur in the first 2 weeks of the LH syndrome, with an apparent redistribution of protein later. This redistribution results in the partial restoration of skeletal muscle at the expense of existing visceral organ protein or its subsequent accretion.

Effect of lateral hypothalamic lesion on sleep-waking pattern and EEG power spectra in the rat.

Bilateral, electrolytic lesion of the lateral hypothalamus (LH) in rats produces hyposomnia and qualitative EEG changes which are difficult to assess by conventional visual inspections of electroencephalograms. In the present study the spectral analysis of EEG was applied in LH-lesioned rats and confronted with a standard visual scoring method. One-hour samples of hippocampal and cortical EEG were taken from the light part of the circadian cycle before and after electrolytic or sham LH damage. In half of the LH-lesioned rats a power spectral analysis was performed using a Fast Fourier Transform routine at 1 Hz bands from 0.5 to 25 Hz; in the other half, as well as in the sham-lesioned group, EEG records were visually scored for the amount of waking, slow wave sleep and paradoxical sleep. Significant hyposomnia effects were found in LH-lesioned rats. Power spectral analysis of hippocampal EEG revealed a significant increase in power density at 4-6 Hz and a reduction at 7-10, 14-17, 19-22 and 23-24 Hz. In neocortical EEG there was a significant increase in power density at 5-6 Hz band and a reduction at 7-8 Hz. The results are discussed in the context of the effects of selective destruction of the specific neurotransmitter systems occupying the LH area.

Effect of lateral hypothalamus lesions on the water and salt intake, and sodium and urine excretion induced by activation of the median preoptic nucleus in conscious rats

In this study we investigated the influence of electrolytic lesion of the lateral hypothalamus (LH) on the water and salt appetite, and the natriuretic, diuretic and cardiovascular effects induced by angiotensinergic, cholinergic and noradrenergic stimulation of the median preoptic nucleus (MnPO) in rats. Male Holtzman rats were implanted with a cannula into the MnPO. Other groups of sham- and LH-lesioned rats received a stainless steel cannula implanted into the MnPO. ANGII injection into the MnPO induced water and sodium intake, and natriuretic, diuretic, pressor and tachycardic responses. Carbachol induced water intake, and natriuretic, pressor and bradycardic responses, whereas noradrenaline increased urine, sodium excretion and blood pressure, and induced bradycardia. In rats submitted to LH-lesion only, water and sodium ixcretion bradycardia. In rats submitted to LH-lesion only, water and sodium intake was reduced compared with sham rats. LH lesion also reduced the sodium ingestion induced by ANGII (12 ng) into the MnPO. In LH-lesioned rats, the dipsogenic, diuretic and pressor responses induced by ANGII (12 ng), carbachol (2 nmol) and noradrenaline (20 nmol) injection into the MnPO were reduced. The same occurred with sodium excretion when carbachol (2 nmol) and noradrenaline (20 nmol) were injected into the MnPO of LH-lesioned rats, whereas ANGII (12 ng) induced an increase in sodium excretion. These data show that electrolytic lesion of the LH reduces fluid and sodium intake, and pressor responses to angiotensinergic, cholinergic and noradrenergic activation of the MnPO. LH involvement with MnPO excitatory and inhibitory mechanisms related to water and sodium intake, sodium excretion and cardiovascular control is suggested.

Cardiovascular effects of central clonidine in conscious rats after hypothalamic lesions

The central injection of clonidine (an α 2-adrenoceptor agonist) in conscious normotensive rats produces hypertensive responses and bradycardia. The present study was performed to investigate the effect of electrolytic lesions in the anteroventral third ventricle (AV3V) region or in the lateral hypothalamus (LH) on the pressor and bradycardic responses induced by central clonidine in rats. Mean arterial pressure and heart rate were recorded in sham or AV3V-lesioned rats with cerebral stainless steel cannulae implanted into the lateral cerebral ventricle (ICV) or LH, and in sham or bilateral LH-lesioned rats with cannulae-implanted ICV. The injection of clonidine (40 nmol) ICV or into the LH of sham rats produced a pressor response (37 ± 2−48 ± 3 mmHg) and bradycardia (−45 ± 10−– 93 ± 6 bpm). After AV3V-lesion (3 and 12 days) or LH-lesion (3 days) the pressor response was abolished and a small hypotensive response was induced by the injection of clonidine (−1 ± 3–−16 ± 3 mmHg). The bradycardia (−27 ± 6–−57 ± 11 bpm) was reduced, but not abolished by the lesions. These results show that the AV3V region and LH are important cerebral structures that participate in the excitatory pathways involved in the pressor response to central clonidine in rats. They also suggest that, in the absence of these pressor pathways, the hypotensive responses to central clonidine may appear in conscious rats.

Thermogenesis following meal feeding, isoproterenol, and cold in rats with LH lesions

Responses to several thermogenic stimuli were measured in rats maintaining stable but reduced body weights following lateral hypothalamic (LH) lesions. Oxygen consumption was monitored in open-circuit respirometers before and after exposure to cold (16.5 degrees C), intubation of a meal, and isoproterenol injection (40 micrograms/kg 0.75). Observations were made in both warm- (28 degrees C) and cold-acclimated (9 degrees C) LH-lesioned rats. Cold exposure, intubation, and drug injection each caused marked increases in heat production in sham- and LH-lesioned rats. This thermogenic response was similar in magnitude and form for both groups. Acclimation to 9 degrees C caused increased baseline levels of heat production when measured at 28 degrees C. Subsequent exposure to thermogenic stimuli revealed an exaggerated response to isoproterenol but not intubation in cold-acclimated groups. The LH-lesioned cold-acclimated rats responded in the same manner as sham-lesioned cold-acclimated rats. These findings are in contrast to the immediate postlesion period when rats show enhanced thermogenic activity. At reduced body weights LH-lesioned rats show normal rates of heat production and make normal responses to thermogenic stimuli. Enhanced thermogenesis does not appear to play a role in the maintenance of chronically reduced body mass in LH-lesioned rats.

Lateral and medial hypothalamic lesions do not acutely affect brown adipose tissue thermogenesis

The acute effect of lateral (LH) and medial (MH) hypothalamic lesions on mitochondrial GDP binding in brown adipose tissue (BAT) (an index of thermogenic state) was studied one and two days postlesion. Groups of rats were lesioned, sham-lesioned, or unoperated and were all fasting. An additional group of unoperated rats had access to food throughout the study. The objective was to determine whether the hypermetabolic state and rapid weight loss known to be induced by LH lesions were attributable to the activation of BAT thermogenesis, and, if so, whether these effects were specific for LH lesions. No effect of either lesion on BAT thermogenic state could be detected at either time studied. Despite that fact, LH-lesioned rats, but not MH-lesioned rats, were hyperthermic at both times. We conclude that the prolonged hyperthermia which occurs shortly after LH lesions is not due to an activation of BAT thermogenesis. Instead, it can be likened to the febrile state in which an initial and brief activation of both nonshivering thermogenesis in BAT and shivering thermogenesis in muscles occurs only during the rising phase of the fever and is suppressed as soon as a stable hyperthermic state is reached. It thus appears unlikely that substantial and prolonged activation of BAT thermogenesis is a major mechanism that promotes exaggerated short-term weight loss in the LH-lesioned rat.

Long-term effects of lateral hypothalamic lesions on brown adipose tissue in rats

A classic feature of animals with lateral hypothalamic (LH) lesions is their regulation of body weight at sub-normal levels. The present studies were done to determine whether this is associated with enhanced thermogenic activity of their brown adipose tissue (BAT). Three groups of young chow-fed male Holtzman rats were formed: (1) animals receiving bilateral radiofrequency heat lesions of the dorsal LH and then permitted free access to chow (LH rats); (2) non-lesioned animals that were pair-fed (PF) to the lesioned rats during a 2 week post-operative recovery period (Phase 1); (3) non-lesioned, ad lib fed (NORM) controls. After Phase 1, each group was divided and permitted free access to chow alone or an additional selection of palatable, novel food items (a “cafeteria” diet) for 2–3 weeks (Phase 2) to stimulate diet-induced thermogenesis in BAT. Finally, half of each sub-group was exposed to 4°C for 15 hr to stimulate nonshivering thermogenesis in BAT. During Phase 1 LHs and PFs ate 50% less than NORMs. This resulted in a weight deficit of 16% for LHs and 12% for PFs. After the additional period of feeding palatable foods (Phase 2) LHs collectively weighed 14% less than NORMs whereas previously PFs had a weight deficit of only 4%. They gained less weight than NORMs or PFs despite a similar energy intake. LHs had small deposits of gonadal white adipose tissue [both total amount and expressed per metabolic body mass (kg 0.75)]. The weight of interscapular BAT was less in the LHs but its concentration of protein (mg/g) was higher. Total protein in BAT was normal but expressed in terms of metabolic body mass (kg 0.75) was significantly greater in the LHs. LHs grew more BAT protein in response to the cafeteria diet than did NORMs or PFs. The thermogenic state of BAT (as indicated by mitochondrial GDP binding) tended to be slightly higher in the LHs. Normal increases in GDP binding in response to the cafeteria diet and to cold-exposure occurred in the LHs. It is concluded that LH-lesioned rats have more BAT relative to their body size than do normal or previously pair-fed rats, are capable of normal cold-induced nonshivering thermogenesis in BAT and exhibit an exaggerated dietinduced growth of BAT. The LH lesion appears to prevent the atrophy of BAT and suppression of thermogenesis in BAT that would be expected to occur as a response to reduced food intake.

Relationship of thyroid hormones and norepinephrine to the lateral hypothalamic syndrome

The role of thyroid hormones and norepinephrine in the elevated thermogenesis seen following lateral hypothalamic (LH) lesions was investigated by measuring serum thyroid hormone levels and urinary norepinephrine excretion during the 24 hours following placement of LH lesions and again one month later when body weight had stabilized at a reduced level. During the first 24 hours following LH lesions, serum thyroxine (T 4) and triiodothyronine (T 3) were significantly depressed. By one month postlesion, both T 4 and T 3 had returned to normal. In contrast, urinary excretion of norepinephrine (NE) was increased 100% during the 24 hours following LH lesions. By one month postlesion, NE had returned to normal levels. These results indicate that the elevated thermogenesis seen shortly following LH lesions does not reflect enhanced thyroid activity, but is probably a consequence of sympathetic nervous system stimulation. The return of NE to normal levels after one month is consistent with the observation that LH-lesioned rats are by one month postlesion no longer hypermetabolic, but display levels of heat production appropriate to the reduced body weight they then maintain.

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.

Resting oxygen consumption in over- and underfed rats with lateral hypothalamic lesions

Rats maintaining stable, reduced body weights following lateral hypothalamic (LH) lesions were given either ad lib amounts of a palatable liquid diet or restricted amounts of a hydrated chow diet. The palatable diet produced weight gains while the diet restriction led to weight reductions in both LH- and sham-lesioned rats. Body composition analysis indicated that these changes in body mass were accounted for largely by changes in carcass fat. Resting oxygen consumption (expressed relative to body weight raised to the 3 4 power) was altered by both dietary regimens. Resting oxygen consumption in sham-lesioned rats increased by 5% following overfeeding and decreased by 13% following food restriction. LH-lesioned rats made similar responses to these dietary challenges. Overfed LH-lesioned rats increased their rate of resting oxygen consumption by 11%. Underfed LH-lesioned rats decreased oxygen consumption by 11%. These findings provide further evidence that rats with LH lesions defend a reduced level of body weight. The changes in energy expenditure that mitigate weight change in sham-lesioned animals are also present in LH-lesioned rats. In the latter, however, these adjustments serve to stabilize body weight at a lower level.

Preoperative experience with insulin enhances glucoprivic feeding in rats with lateral hypothalamic lesions

Adult male Sprague-Dawley rats received either one injection per week of regular insulin (IP, 5 Units) or saline for 4 weeks prior to destruction of the LH or sham-operations. During this preoperative period, animals given insulin consumed significantly more food in a 6-hr test period than animals given saline. Following surgery, animals were given 3 weeks to recover from the acute effects of LH lesions and then tested for responsiveness to glucoprivic challenges. Sham-operated animals from both pre-operative injection groups consumed significantly more food during a 6-hour period when injected with either insulin (5 and 7.5 Units) or 2-DG (400 mg/kg) than when given saline injections. Similarly, LH-lesioned rats with preoperative experience with insulin significantly increased food intake when given insulin or 2-DG. In contrast, LH-lesioned rats without preoperative experience with insulin failed to increase feeding in response to the administration of either insulin or 2-DG. Differnnces in feeding responses following glucoprivation between LH-lesioned rats with and without preoperative exposure to insulin were not a function of differences in the extent of central nervous system damage. The present data indicate that experimental conditions play an important role in determining the presence or absence of regulatory deficits following brain damage.

Comparison of deficits in electrical self-stimulation after ibotenic acid lesion of the lateral hypothalamus and the medial prefrontal cortex

The aim of the present study was to compare the self-stimulation deficit produced by a unilateral injection of the neurotoxin, ibotenic acid, in the lateral hypothalamus (LH) to the deficit produced by the same unilateral injection in the medial prefrontal cortex (MPC). Four groups of adult male Sprague-Dawley rats were used: in two control groups, electrodes were bilaterally implanted in the LH (5 rats) or in the MPC (6 rats) and self-stimulation (ICSS) was obtained separately with the right and left electrodes. In the two experimental groups the intrinsic neurons of the LH (8 rats) or of the MPC (10 rats) were destroyed unilaterally by local injection of ibotenic acid (4 μg in 0.5 μl); the other side served as the sham-lesioned control. Ten days later ICSS electrodes were implanted bilaterally, one in the lesioned area, the other in the contralateral region. As in the case of the control rats, ICSS was determined separately for each electrode, first by a rate dependent test (nose-poke) then by a ‘rate-free’ test (shuttle-box). In the LH and MPC control rats, ICSS responses were the same with stimulation on either side. In the LH-lesioned rats, the ICSS rates measured with the nose-poke test were significantly decreased with stimulation on the lesioned side, whereas rates with stimulation of the non-lesioned LH were normal. Likewise, while shuttle responses with stimulation of the non-lesioned LH were normal, the OFF-time was increased and the ON-time was decreased with stimulation of the lesioned LH. In the MPC-lesioned rats, ICSS (nose-poke) was totally suppressed and the shuttle responses were disorganized since neither the ON- nor the OFF-times changed in response to increasing current intensities. Nose-poke responses with stimulation of the non-lesioned MPC were just about normal. These results show that in the two brain regions studied local neurons are involved in ICSS. The difference in the magnitude of the deficit observed suggests, that the neuronal circuits involved in MPC self-stimulation are poorly represented whereas in the LH many neuronal circuits involved in these mechanisms overlap.

Heat production and body weight changes following lateral hypothalamic lesions

Factors causing rats with lateral hypothalamic (LH) aphagia to lose weight at a faster rate than food deprived controls were investigated in two experiments. In Experiment 1, the heat production of LH-lesioned and control rats was measured by indirect calorimetry for four days following surgery. A higher rate of energy expenditure was shown to account for the greater weight loss of the LH-lesioned rats. In Experiment 2, the heat production of rats receiving LH lesions either at normal or reduced body weights was measured continuously for 24 hours following surgery. Reducing body weight prior to lesioning attenuated postlesion heat production. It was also found that, though the heat production of LH-lesioned rats was consistently higher than that of nonlesioned rats of similar body weight, the fundamental relationship between body weight and heat production was unchanged by the lesion. These findings of higher rates of energy expenditure when at the same weight as nonlesioned animals, accompanied by normal adjustments in expenditure in response to weight change, are consistent with the view that LH-lesioned rats, both behaviorally and metabolically, regulate body weight at a reduced level. Their elevated rate of heat production following lesioning can be seen as an adaptive metabolic adjustment which, coupled with LH aphagia, leads to the rapid decline in body weight to a lower maintenance level.

Body composition and adiposity in LH-lesioned and pair-fed obese Zucker rats.

It has been reported previously that lateral hypothalamic (LH) lesions alter body composition including reducing adipocyte cellularity in lean and obese Zucker rats. The present experiment was designed to determine whether these alterations in body composition and adipose cell number are secondary to the reduced energy consumption of LH-lesioned rats or to a direct effect of the hypothalamic lesion. Groups of lean and obese Zucker rats, sustaining lesions of the lateral hypothalamus at 10 wk of age, maintained body weight at 72% that of nonlesioned controls until killed at 32 wk. Pair-feeding nonlesioned rats to the intakes of lean and obese LH-lesioned rats produced a reduction in adipocyte number similar to that caused by lesions. However, neither the lean nor obese LH-lesioned rats displayed an increase in cell number when fed a palatable diet that markedly increased carcass lipids. This finding suggests that adipocyte number may be constrained in LH-lesioned rats. These and further observations that 1) lean control rats maintained a higher body weight than the LH-lesioned rats to which they were pair fed and 2) in obese rats, food restriction further reduced protein deposition and elevated plasma insulin relative to comparably fed LH-lesioned obese rats suggest that the LH syndrome is mimicked by simple food restriction.

Developmental study of adipose cellularity in lateral hypothalamic-lesioned Zucker obese rats.

Ten-week-old lean and obese Zucker rats were sham lesioned or received bilateral, electrolytic lesions of the lateral hypothalamus (LH). They were maintained on a wet mash diet until killing at 15 or 32 wk of age; control lean and obese rats were also killed at 6 and 10 wk. Body composition analyses were performed and adipocyte cellularity of epididymal, retroperitoneal, and subcutaneous depots were calculated. Changes in body composition of LH-lesioned rats, though similar in the two genotypes on an absolute basis, differed on a percentage basis due to the extreme adiposity of the obese rats. Retarded development of protein depots in both lesioned lean and obese rats was apparent at 15 but not 32 wk. Relative to genotypic controls, lesioned lean and obese rats had smaller adipose depots by 32 wk due to decreased adipocyte size in lean rats and reduced adipocyte number in the obese. This genotype-specific response was probably due to the chronic hyperplasia of adipocytes unique to the obese rats. This distinctive developmental pattern of the epididymal depot is discussed.

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.