comparison of the metabolic and behavioral disturbances following paraventricular- and...

Brcrirl Rr.wcrn~/~ Bu//~~rir~. Vol. 14. pp. S-559. 1985. ” Ankho International Inc. Printed in the U.S.A. 0361-9230185 $3.00 + .OO

Comparison of the Metabolic and Behavioral Disturbances Following Paraventricular- and Ventromedial-Hypothalamic Lesions

HARVEY P. WEINGARTEN,t* PENGKWEI CHANG* AND T. J. MCDONALD*

*Department oj Psychology cmd tlntestinal Diseuse Research Unit, McMaster University

and $Dc)partmrnt Hamilton, Ontario, Canada, L8S 4KI

of Medicinr, University of Western Ontario, London, Ontario, Canadcr N6A 5A5

WEINGARTEN, H P., P. CHANG AND T. J. MCDONALD. Comparison of the mc,tahok and hehaviorcrl disturhuncrs

fi>l/oM’ing paruwntriculnr- und ~rntromPdiu/-hypothalamic, Ic~sions. BRAIN RES BULL 14(6) 551-559, 1985.-Lesions of the ventromedial hypothalamus (VMH) result in an obesity syndrome with several metabolic and behavioral manifestations. It has also been reported that damage to the paraventricular hypothalamus (PVH) leads to changes characteristic of obesity. However, little is known about the consequences of PVH lesions, especially in contrast to the extensive documen- tation of VMH lesion-induced effects. To assess the basic features of the two hypothalamic obesity syndromes, rats underwent VMH, PVH, or sham lesions and, for 15 weeks, were maintained ad lib on a series of test diets. Both lesion groups were hyperphagic and showed similar weight gains. Although both lesion groups became obese (measured by % carcass fat), VMH rats were fatter than PVH animals. Similarly, only VMH rats were hyperinsulinemic. Further tests were conducted in PVH and VMH rats restricted to control body weights. VMH, but not PVH, rats developed a persisting elevation in basal gastric acid secretion. As well, only VMH, and not PVH, animals developed an obesity when restricted to normal weights. These data indicate similarities in PVH and VMH rats maintained ad lib but experiments on restricted animals reveal fundamental differences in the two obesities and point to different etiologies.

Ventromedial hypothalamus Paraventricular hypothalamus Obesity Lesions

IN a series of landmark papers in the early 1940’s, Hetherington and Ranson [19, 20, 21, 221 established that lesions of the ventromedial hypothalamus led to excessive levels of food intake and adiposity. Because of the collection of metabolic and behavioral disturbances accompanying VMH lesions, this experimentally-induced syndrome (termed the VMH syndrome) has been studied extensively by researchers of physiological and psychological orienta- tions and has become a model for the study of obesity (e.g., [4,26]) and motivated behavior (e.g., [39]). From experiments localizing the hypothalamic areas involved with the control of body weight and eating, Hetherington suggested that damage to only a circumscribed area of the hypothalamus, the ventromedial hypothalamic area, resulted in obesity; lesions of other hypothalamic sites were reported not to result in hyperphagia or excessive weight gain. Specifically, Hetherington [22] wrote that “. . cell groups rostra1 or dorsal to the ventromedial hypothalamic nuclei make little if any contribution to the regulation of fat metabolism . . .” (p. 38) and that “. . . two of the animals . . underwent complete elimination of the paraventricular nuclei without becoming fat” (p. 40). In spite of a dissenting report indicating that paraventricular hypothalamic (PVH) lesions produced hyperphagia in dogs [23], for approximately 30 years researchers appeared to ignore the possibility that lesions in areas other than the VMH could result in obesity or overeating.

Interest in the PVH was renewed in the mid and late 1970’s as a result of several findings which caused researchers to focus on the PVH as a site involved potentially in the control of eating and fat stores. First, the exact anatomical locus mediating the VMH obesity had not been determined. Lesions of the ventromedial nucleus itself did not mediate the syndrome [13] and a variety of knife cut experiments suggested that destruction of a longitudinal fibre pathway running rostra1 and lateral to the ventromedial nucleus was responsible for VMH obesity [ 14,351. The involvement of the PVH in the control of feeding was implicated, second, by the demonstration that the paraventricular hypothalamus pos- sessed the lowest threshold for noradrenergically-elicited eating [24]. Finally, anatomical studies implicated the PVH in the control of eating with demonstrations of anatomical connections between this area and autonomic ganglia such as the dorsal motor nucleus of the vagus [34, 42, 431. Since it was believed that autonomically-controlled disturbances in viscera1 events contributed to, or caused, the VMH syndrome (e.g., [4,31]), the anatomical links of the PVH to the autonomic nervous system suggested that this area contributed to regulation as well. A role for the PVH in feeding was established conclusively in the early 1980’s with demonstrations that bilateral damage to the PVH resulted in increased levels of food intake and excessive weight gain in adult male and female rats [I, 25, 371.

In contrast to the many reports detailing the VMH syn-

WEINGARTEN, CHANG AND MCDONALD

drome, relatively little is known about PVH obesity. Some have suggested that the two hypothalamic obesities are es- sentially identical in that both lesions are viewed as disrupt- ing a common (hitherto unidentified) fibre system coursing through the medial hypothalamus involved with the inhibi- tion of feeding. This suggestion is reinforced by reported similarities in the nature of hyperphagia produced by VMH and PVH lesions [ 11. However, the relationship between the PVH and VMH syndromes is difficult to assess since so few data are available on PVH lesion rats. For example, although percent carcass fat is the defining characteristic of an obesity, and there are numerous carcass analysis studies in VMH rats (see [30] for review), there is no concensus about the body compartment changes which follow PVH lesions. There is a single report of an elevated percent carcass fat in adult PVH rats maintained ad lib [l] but this is based on Lee Index which may provide an inaccurate measure of body fat compartment [38]. Weanling rats with PVH lesions show no elevation of fat stores [2]. Further, in contrast to the extensive data on the metabolic profile of the VMH rat, there are few data on metabolic changes following PVH lesions. Steves and Lorden [40] report, in abstract form, that PVH lesions increase glucose-stimulated insulin levels in a manner similar to VMH lesions. However, it is unclear whether PVH lesions induce alterations in basal insulin levels 11,411, a defining trait of the VMH syndrome.

Particularly noteworthy by their absence are data on PVH animals restricted to control body weight levels. Obesities can be classified according to their etiologies [27]. A “regulatory” obesity is one in which a primary disturbance in the regulation of feeding causes an excessive level of intake which leads, secondarily, to increased adiposity. A “metabolic” obesity is one in which a primary metabolic disturbance leads to excessive fat levels; the hyperphagia characteristic of these latter obesities is viewed as secondary to the primary metabolic dysfunction. Classification of an obesity into a regulatory or metabolic type involves exam- ination of physiological and body compartment changes in animals prevented from hyperphagia and thus maintained at control body weight levels. The obesity induced by electrolytic lesions of the VMH is of the metabolic type as changes such as enhanced fat stores [18] and hyperinsulinemia [ 12,171 develop even in the absence of hyperphagia or weight gain. The classification of PVH obesity is unclear. The purpose of the presently-described experiments is to evaluate the metabolic and behavioral changes in PVH- lesion animals and to compare these disturbances to those seen in VMH animals.

GENERAL METHOD

Subjects

Subjects were male Long-Evans hooded rats weighing approximately 350 g at the beginning of the experiments. They were housed individually in a room maintained on a 14: 10 1ight:dark cycle. Water was available continuously and food was present according to the experimental require- ments.

Surgery

Using standard stereotaxic procedures, rats sustained bilateral electrolytic lesions of the VMH (2.3 mm posterior to bregma, 0.6 mm lateral to midline sutures, 8.5 mm below the skull-l milliampere for 17 seconds), PVH (1.8, 0.2, 7.2-l milliampere for 12 seconds), or sham lesionsI_Lesion elec-

trodes were made from No. 00 stainless steel insect pins insulated with epoxylite except for 0.4 mm at the tip.

Sacrifice

At the termination of the study, rats were fasted for 24 hr and injected with a large dose of sodium pentobarbital (65 mg/kg). Ten minutes after the anesthesia was administered, five ml of blood were collected through the heart into a heparinized tube. The blood was centrifuged and the plasma frozen and stored for subsequent insulin and glucose assay. Animals were perfused intracardially with 0.15 M saline fol- lowed by buffered formalin. Brains were removed, stored in formalin, and eventually sectioned at 40 p for histological analysis.

To prepare the body for carcass analysis, the carcass was shaved, the tail removed, the gastrointestinal tract cleaned, and the body frozen until the time of fat estimation. To analyze body fat content, the carcass was thawed, weighed, and dessicated at 60°C. Body fat content was determined from a regression equation correlating percent body fat with percent water (Cox, Laughton and Powley, unpublished ob- servations) .

Plasma levels of immunoreactive insulin and glucose were assayed by T. J. McDonald at the University of Western Ontario according to procedures described previously [28].

Srledon of Animals

Animals were included into the two lesion groups based solely upon an assessment of histological damage by an ob- server blind to the experimental results. The aim of this study was to compare the effects of damage restricted to the PVH or VMH. Thus, to be included in the VMH group, VMH animals had to sustain extensive bilateral lesions of the classically-defined ventromedial hypothalamic area without damage to the PVH area. These lesions began caudal to the PVH, extended to the premammilary bodies and, in the medial-lateral dimension, extended from the third ventricle lateral to the fomix. To be included into the PVH group, animals had to exhibit complete sparing of the VMH, or at worst (in the case of one animal), minimal damage unilater- ally to the most dorsal aspect of the medial hypothalamus. The typical PVH lesion was centered around the middle of the paraventricular nucleus and totally destroyed this nucleus and adjacent tissue. Figure 1 is a reconstruction of the neural damage characteristic of the VMH- and PVH-lesion animals.

Data Analysis

Data were analyzed with analyses of variance. Multiple comparisons were performed using the Studentized range statistic (q) and evaluated according to the Newman-Keuls procedure.

EXPERIMENT 1: STUDIES IN AD LIB ANIMALS

The first study characterizes some basic behavioral and metabolic effects of PVH and VMH lesions in animals per- mitted to eat ad lib.

Following surgery, PVH, VMH, and sham lesion animals were maintained ad lib on a series of test diets including Purina rat chow powder, mash (65% water, 35% Purina chow powder), and high fat (33% Crisco oil, 67% chow powder) diets. Body weights were monitored daily, and food intake was measured every two days.

The weights of the three groups were similar at surgery,

PVH AND VMH OBESITY 553

MEDIAN LARGEST MEDIAN LARGEST MEDIAN

CONTROL VMH VMH PVH PVH

FINAL BODY WT.(g) 532 042 790 822 735

CARCASS FAT (%) 26.8 53.8 52.4 47.5 46.6

A5910u

A5660u

A5 150~

A4620u

A4230u

A3990u

FIG. 1. Reconstructions of PVH and VMH lesions. Shaded areas indicate extent of neural damage at each of the planes of section (taken from the Kiinig and Klippel atlas). “Largest VMH” refers to animal with highest body weight of all VMH group animals; “median VMH” indicates animal with median body weight in VMH group. Similar labels are used for PVH group. Also shown are the % carcass fat of each of these rats (Abbreviations: F=fomix; HA=anterior hypothalamic area; RE=nucleus reuniens; PVN=paraventricular hypothalamic nucleus; OT=optic tract; VMN=ventromedial hypothalamic nucleus; DMN=dorsomedial nucleus of the hypothalamus).

F(2,19)=2.32, pBO.05. Figure 2 presents the average cumulative weight gain and daily caloric intake throughout the study. After surgery, on powder diet, VMH rats gained weight rapidly so that, by the end of this period they weighed significantly more than control (q,=5.45, p~O.01) and PVH (q2=3.85, ~~0.05) rats. There were no significant weight differences between the PVH and control groups (q2= 1.60, p>O.O5). On this diet, the average daily caloric intake of VMH rats exceeded control (q,=6.04, pCO.01) and PVH (q2=3.34, pCO.01) values. On the first exposure to mash, both PVH and VMH rats gained more weight than controls (p’s<O.Ol) but VMH animals continued to significantly out- gain PVH animals (q,=5.02, ~~0.01). On high fat, PVH (q2=5.89, pCO.01) and VMH (q,=7.67, ~~0.01) rats gained more weight than controls; the weight gains of the lesion groups were similar. In the second mash period, PVH and control rats gained similar amounts of weight, but VMH animals showed significant weight losses compared to both groups (p’s<O.Ol). When returned to high fat, both lesion groups significantly outgained controls (p’s<O.Ol).

Figure 3 presents carcass fat measures. Both lesion groups were significantly fatter than controls (PVH: q,=7.72,p<O.O1; VMH: q,=11.98,p<O.O1). VMH rats were significantly fatter than PVH animals (q,=4.26, pCO.01). These carcass fat differences did not arise from group differ-

ences in linear growth. Nose-anus lengths taken at sacrifice indicated that control (27.0*0.3), VMH (26.5*0.4), and PVH (26.4kO.2) groups were not different on this measure.

Because of the procedure used for blood collection, these insulin values do not strictly represent basal levels. In fact, the insulin values assayed are best treated as providing an ordinal ranking of animals in terms of plasma insulin. Statis- tical analysis of the insulin values with a nonparametric Mann-Whitney test indicate that only VMH animals were significantly hyperinsulinemic compared to controls, C/(5,10)=4, ~~0.01. Four of five VMH rats had insulin values beyond the normal range. PVH rats were not hyperinsulinemic, U(7,10)=91, p>O.OS: only 1 of 7 PVH lesion rats had insulin values beyond the range of values exhibited by controls. In spite of differences in degree of insulinemia, the plasma glucose levels of the control (171t9 mg/dl), VMH (201?10), and PVH (192*7) groups were similar, F(2,19)=3.18, p>O.OS.

The data from these experiments replicate previous findings of increased weight gain and caloric intake in PVH- lesion rats maintained ad lib. However, although PVH rats gained as much weight (378% 15 g) as VMH animals (408-c29 g) over the course of the experiment, PVH rats showed a reduced carcass fat compartment and normal insulin levels, in contrast to VMH rats.

554 WEINGARTEN, CHANG AND MCDONALD

CONSECUTIVE Z-DAY BLOCKS

FIG. 2. Upper panels-Group mean cumulative body weight gains in VMH (N=5), PVH (N=7) and control (N= 10) rats maintained ad lib on the diets shown. Lower panels-Group mean ad lib daily caloric intakes for the three groups during the various phases of the experiment.

EXPERIMENTS 2 AND 3: PHYSIOLOGICAL MEASUREMENTS IN PVH AND VMH ANIMALS RESTRICTED TO CONTROL BODY

WEIGHTS

The crux of any obesity study is to document the relative importance of behavioral and metabolic changes in the production of the obesity. Ad lib studies do not permit an assessment of the primacy of metabolic or behavioral changes in the etiology of the obesity and, thus, classification of the obesity into the regulatory or metabolic type. To explore the relationship between the food intake and metabolic changes identified from ad lib experiments, studies were initiated to investigate the physiological changes in PVH and VMH maintained at control body weights.

In Experiment 2, we assessed lesion-induced changes in gastric acid secretion. The contribution of vagally-mediated visceral disturbances in the production or maintenance of VMH obesity has been stressed by several authors [6,31]. In the VMH syndrome, postlesion changes in visceral secretion develop in the absence of hyperphagia. For example, eleva- tions in insulin levels [3,12] and gastric acid secretion [32,44] are apparent in VMH animals restricted to control body weight. Changes in acid secretion following hypothalamic lesions were monitored in this study since the vagus con- tributes greatly to the maintenance of basal acid levels in the rat and alterations in this digestive secretion are considered to reflect altered parasympathetic tone on the viscera.

To assess acid secretion changes in lesion animals, chron- ically indwelling gastric cannulae were implanted into experimental and control animals [46]. Animals were maintained on a chronic 17-hour food deprivation schedule and suff~i- cient food was provided to PVH and VMH animals to main-

tain their weights at normal levels. Acid secretion was monitored on alternate days. Because of the acknowledged var- iability in acid secretion among rats, this study was designed to permit assessment of lesion-induced changes within each animal by obtaining a prelesion estimate of secretion. Thus, acid levels were measured for 3 trials prior to lesions in order to establish a reliable estimate of basal acid secretion in each animal. Once obtained, lesions were produced and acid secretion was measured on days 2, 4, 6, 8, 10, and 12 postlesion. Animals were then placed on ad lib pellets for 4 weeks. After the ad lib period, basal acid levels were reassessed.

Figure 4 shows the acid concentration data (expressed as PEq H+/ml/2 hr). For each animal, the data were corrected for prelesion differences in secretion by assigning prelesion acid concentrations a value of 100%. Acid concentration measures postlesion were expressed as a ratio of this prelesion baseline. Thus, values above 100% indicate hypersecretion relative to prelesion; scores below 100% indicate a de- crease. As shown in Fig. 4, VMH lesions resulted in an im- mediate elevation of acid concentration. On Day 2, the gastric juice of VMH rats was hyperacidic compared to PVH (q,=5.98, p<O.Ol) and control (q,=6.20, pcO.01) animals. The acid concentrations of PVH and VMH rats were not different (q2=0.22, p>O.OS). An analysis of variance comparing acid concentration in the entire postlesion period indicated significant group differences F(2,21)=6.91, pcO.01: VMH rats hypersecreted compared to the other two groups and the acid concentration of PVH animals never deviated from normal. In the ad lib period following Day 12, VMH and PVH animals gained significantly more weight than controls (mean weight gains & 1 SEM were-controls: 119t7; PVH: 181219; VMH: 208535). Acid measures taken at that

PVH AND VMH OBESITY 5.55

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FIG. 3. Average percent carcass fat of VMH (N=S), PVH (N=7) and controt (N = 10) rats maintained ad lib. Vertical bars represent 1 SEM. Numbers under group name indicate group mean (t-1 SEM) weight at sacrifice.

time indicated that VMH animaIs maintained their basal acid hypersecretion relative to PVH and control rats. The acid concentration of PVH animals was normal. The results demonstrate that VMH, but not PVH, lesions result in a primary alteration in a visceral secretion related to digestion.

Experiment 3 was conducted to explore whether the development of VMH and PVH obesities depends on increased food intake. Animals were prepared with bilateral lesions of the PVH, VMH or sham lesions. After surgery, lesion animals were m~nt~ned on restricted feedings to m~ntain their weights equivalent to matched controls. Because of a previous suggestion that manifestations of the PVH obesity may depend on the diet on which animals are maintained [1], one factor varied in this study was maintenance diet. Half the animals were maintained on a Purina rat chow pellet diet, the other half on high fat (67% chow powder, 33% Crisco oil). Thirty days postlesion, rats were sacrificed and their bodies analyzed for percent carcass fat.

Figure 5 presents the results of this experiment. Regard- less of whether they were maintained on pellets or high fat, VMH lesion animals were significantly fatter than both PVH and control animals (for all comparisons to VMH group, p’s<O.Ol). Percent fat of PVH animals was equivalent to that of controls in both the pellet (qZ= 1.10. ~10.05) and high fat fyz=0.61, p>O.O5) conditions.

In concert with the results of the previous study, these data indicate that the development of visceral hypersecretion and obesity following PVH lesions depend critically on the opportunity for an increased level of caloric intake. In contrast. acid hypersecretion and obesity deveiop in VMH rats even in the absence of hy~~hagia. These differences suggest fundamentally different etiologies of the PVH and VMH obesities.

EXPERIMENT 4: SHAM FEEDING

If the PVH obesity is caused by lesion-induced disturbance in the control of feeding, one might predict feeding- related changes even in PVH animals restricted to control weights. As an initial exploration in this direction, we

- VMH

- PVH

- CONT

I I I I I I I

2 4 6 8 10 12

POSTLESION DAY POSTTEST

FIG. 4. Average acid concent~tion scores for VMH (N=4), PVH (N= IO), and control (CONT; N=lO) groups on Days 2-12 postlesion and after a 4 week ad lib period. Acid concentrations were corrected for prelesion baselines by expressing postlesion values as a ratio of prelesion levels X 100.

analyzed the sham feeding responses of PVH and VMH animals restricted to control body weights. A previous study [45] shows that VMH rats display altered profiles of sucrose consumption in a sham feeding paradigm. This observation is interpreted as indicating an altered reactivity to the taste properties of food following VMH lesions (i.e., ~nickiness). Based upon analyses of intake in animals eating normally, it has been suggested that the PVH rat is also finicky 111. As has been argued previously [46], taste reactivity in normally-eating rats is contaminated by postingestive consequences of food, factors which are minimized in the sham feeding preparation. In this study, we compare the sham feeding responses of PVH and VMH animals ingesting liq- uids varying in sucrose concentration.

Animals were implanted with chronic gastric cannulae and maintained throughout the experiment at control body weights. All animals were 3 hr deprived at testing. This level of deprivation was ensured by providing all animals with an opportunity to eat a liquid diet meal immediateIy prior to the initiation of the 3 hr deprivation period. Animals were trained to sham feed 18% (w/v) sucrose and once the behavior had stabilized were tested at 6%, 18%, and 36% sucrose. Figure 6 indicates the average cumulative 30-minute sham fed intake for the groups. As reported previously [45,46], normal animals increased consumption with ascending sucrose concentration. However, VMH animals showed dis- propo~ionately large increases in consumption with increased sucrose. PVH animals, even when restricted to con-


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VMH PVH CONT FIG. 5. Percent carcass fat of groups of VMH (N=6 for both pellet and high fat), PVH (N=8, pellet: N=9, high fat), and control (N=8 for both pellet and high fat) animals maintained for 30 days postlesion on pellet or high fat diet. Numbers above bars indicate mean (21 SEM) weight of group at sacrifice. Vertical bars represent 1 SEM.

trol weights, showed a disturbance similar to VMH animals. Specifically, at 6% sucrose, there were no significant ditfer- ences in consumption among the groups (for all pairwise comparisons, ~~0.05). At 18% sucrose, both VMH (q,=7.68,p<O.O1) and PVH (q,=3.11,p<O.O5) animals sham fed more than controls. At this level, VMH animals were also hyperphagic compared to PVH rats, (q,=4.87,p<O.O1). At 36% sucrose, both lesion groups continued to exhibit significantly elevated consumption relative to controls (VMH: q,(19)=7.67, ~~0.01; PVH: q,(19)=5.26, p~O.01). At this concentration, no significant differences existed between the two lesion groups (q,=2.41, p>O.O5), although this may reflect an asymptotic level of ingestion.

GENERAL DISCUSSION

The purpose of this study was to characterize the PVH obesity by comparing the metabolic and behavioral disturbances accompanying PVH lesions to those produced by obesity-producing VMH lesions. PVH and VMH lesions produce similar degrees of hyperphagia and weight gain under ad lib conditions, although the effects with PVH lesions are somewhat attenuated. The excessive food intake in these two lesion groups results in the development of obesity

k~ VMH

H PVH

,- CONT I

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6% 18% 36%

SUCROSE CONCENTRATION

FIG. 6. Group average intakes in a 30-minute sham feed of 6%. I%, or 36% sucrose. Vertical bars represent 1 SEM.

TABLE 1 GROUP MEAN IRRITABILITY RESPONSES OF VMH (N=S),

PVH (N=7) AND CONTROL (N=lO) RATS

Irritability Test VMH

Group

PVH Control

Response to pencil 0.1 0 0 Visual presentation of hand 0.4 0 0.1 Biting response to hand 1.4 0.2 0 Vocalization 1.4 0.4 0

identified as an increased body fat compartment relative to controls. In VMH animals, the obesity is accompanied by a significant hyperinsulinemia. Insulin levels of ad lib PVH animals are elevated but are not significantly greater than control values.

When the food intake of the two hypothalamic lesion groups is restricted postlesion to maintain their weights at normal values, VMH, but not PVH, rats develop an obesity. The development of obesity in VMH rats in the absence of hyperphagia is apparent regardless of whether the rats are maintained on a pellet or high fat diet. Furthermore, only VMH animals at control weights, and not PVH rats, display a basal gastric acid hypersecretion. Thus, the development of the obesity and certain visceral secretion changes follow-

PVH AND VMH OBESITY

APPRWCHES TO THE WLYSIS OF THE HYPOTWLMiIC LESION DISORDERr?

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FIG. 7. Schematic representing different approaches which may be taken to an analysis of the hypothalamic lesion disorders. “Single primary cause approaches” are ones in which a single primary disturbance is viewed as precipitating the remainder of the symptoms in the syndrome. Two specific hypotheses of this nature are presented. The “multiple effect approach” suggests that the hypothalamic damage induces a set of independent disturbances.

ing VMH lesions is independent of hyperphagia. In contrast, the development of obesity following PVH lesions depends upon an excessive level of food intake.

As discussed in the Introduction, obesities may be broadly classified into two categories based upon the de- pendence of the obesity on an elevated food intake. The development of obesity in the presence of ~ormophagia is the defining test of a metabolic obesity. The requirement of hyperphagia for the development of an obesity defines a regulatory obesity. The present results replicate the work of others (see 1301 for review) that the VMH syndrome repre- sents a metabolic obesity in that the development of the obesity (see Fig. 5) and certain visceral changes (see Fig. 4) postlesion do not depend upon an excessive level of food intake. Most other animal models of obesity are metabolic in nature including the Zucker rat [lo], dbldb mouse [I I], and ob/ob mouse [8]. Hyperphagia amplifies the anabolic disturbances in these metabolic obesities. In contrast, the PVH obesity appears to be regulatory in nature as its development depends critically on the opportunity for overeating.

lt is unlikely that the differences documented between the PVH and VMH exist simply because of differences in the amount of hypothalamic tissue destroyed by the two lesions. First, although (relative to the VMH) less current is used to produce PVH lesions, the neural damage characteristic of PVH group rats is extensive. The typical PVH animal in this study sustained extensive hypothalamic damage in the ros- tral dorsal hypothalamus including complete destruction of the paraventricular hypothalamic nuclei. Furthermore, in our study there are animals with lesions in the VMH smaller than the typical PVH lesion that did become obese on restricted schedules. Further, if simply the volume of damage

in the hypothalamus contributed to the magnitude of the physiological changes observed, and the locus of damage was unim~~ant, one would expect to observe some level of disturbance in PVH animals even though the amount of change might only approximate VMH effects and might not reach a statistically significant difference from controls. It is noteworthy, however, that the gastric acid and percent carcass fat levels of PVH animals are almost identical to normal values.

Other differences are apparent between PVH and VMH animals. Prior to sacrifice we assessed the irritability of animals in Experiment 1 using the protocol of Paxinos and Bindra [29]. The results are summarized in Table 1. As others have reported, our VMH lesion animals were irritable. In contrast, no change in affective behavior was evident in PVH lesion animals.

Recently, considerable attention has been devoted to anatomical connections between the hypothalamus and the brain stem autonomic nuclei, especially the dorsal motor nucleus of the vagus. The paraventricular nucleus has been identified as a hypothalamic site with intimate associations with the autonomic nervous system [42,43]. In our experiments, damage to the PVH did not produce a primary alteration in at least one peripheral response, acid secretion, and neither insulin nor basal acid levels are significantly elevated even in obese PVH rats. Although other studies implicate the paraventricular nucleus in control of autonomically- regulated peripheral function [9,33] the absence of measura- ble effects of PVH lesions suggest that the control of the periphery by the PVH is not simple.

Finally, the results of the present study have implications for the analysis and interpretation of the collection of disturbances comprising the hypothalamic lesion syndromes. One traditional approach has been to suggest that the hypothalamic ablation induces a single primary disturbance which leads, secondarily, to the development of other charac- teristics comprising the syndrome (see Fig. 7, Panel A). In the case of the VMH syndrome, the disturbance identified as the primary etiological factor has changed. Originally, to Brobeck et al. [7], hyperphagia was considered as the primary etiological factor. More recently, the primacy of metabolic disturbances, such as an elevation of cephalic phase of digestion, has been championed (e.g., (6,311). The important point is that although these viewpoints differ in identification of the essential etiological mechanism they all agree that a single disturbance is primarily responsible for the production of the entire syndrome and that all other symptoms of the syndrome arise as a secondary conse- quence of this primary disturbance. An alternative interpretation is that large lesions or extensive knife cuts in the hypothalamus induce a series of multiple imfrprndcnr disturbances which, given the appropriate anatomical and behavioral analyses, could be dissociated from one another. Al- though this sentiment has been expressed (e.g., [15, 16,36]), this approach is not usually represented in formal reviews of the VMH syndrome. The results of the experiments described here indicate that lesions of two adjacent areas of the hypothalamus produce obesities with fundamentally different etiologies. Some have argued already for a distinction between a VMH syndrome induced by electrolytic lesions and by parasaggital knife cuts. In contrast to the VMH lesion syndrome, neither the VMH cut [5,36] nor PVH lesion rat are hype~nsuIinemic. The possibility exists, therefore, that two types of obesity can be produced by damage in the hypothalamus. One. represented by the VMH knife cut and PVH lesion,


arises from a primary disturbance in the control of food intake with ensuing changes in adiposity and metabolism. The second, typified by a pure VMH syndrome induced by electrolytic lesions, reflects a primary metabolic disturbance which results in increased adiposity and, secondarily, in hyperphagia. Large electrolytic lesions of the hypothalamus, such as those typically used to produce the VMH syndrome might damage both of the neural systems mediating these two obesity effects. This might account for the more rapid development of the VMH syndrome compared to the PVH one. This perspective suggests the necessity for experiments investigating dissociations between elements of the hypotha-

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lamic obesity syndromes rather than studies oriented towards integrating the host of disturbances associated with these syndromes.

ACKNOWLELIGEMENTS

This research was funded by grants from the Medical Research Council of Canada and Natural Sciences and Engineering Research Council. We thank Cecilia Malinski for technical assistance and Dr. James Cox, Department of Psychology, University of Alabama for providing us wth the regression equation for the calculation of body fat.

REFERENCES

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comparison of the metabolic and behavioral disturbances following paraventricular- and...

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