Neurosctence& BmbehavtoralRewews.Vol 15. pp 341-347 ¢ PergamonPress plc, 1991 Fhantedm the U S A

014~7634/91 $3 00 + 00

Ventromedial Hypothalamic Obesity: A Reexamination of the Irritative Hypothesis B R U C E M. K I N G

Department o f Psychology, University o f New Orleans, New Orleans, LA 70148 R e c e i v e d 17 O c t o b e r 1990

KING, B M. Ventromedtal hypothalamlc obesay" A reexamination of the trntatlve hypothesis. NEUROSCI BIOBEHAV REV 15(3) 341-347, 1991.--The basic assumption of brain research utahzmg lesions is that any observed changes in behavior or physiological responses must be the result of tissue destruction. Reynolds suggested 25 years ago that m the case of electrolytic ventromedial hypothalamlc lesions, the observed hyperphagla and obesity were due instead to metallic ion deposits from the electrode np tmtatmg adjacent tissue. His 'qmtatwe hypothesis" was largely ignored after others reported obesity in rats given nomrritative (i e., no deposits) VMH lesions. However, recent studies have shown that the experimental observations by both Reynolds and his cnncs were correct and that the early discrepancies were largely due to the sex of the animals used in the experiments Obesity can be produced with nonlrntative VMH lesions, but the weight gmn is only about 60% of that observed with imtatlve VMH lesions and the animals do not display the charactenstac lesion-reduced elevations in basal insulin levels. A new combination ablauon-imtative hypothesis is proposed in which electrolytic VMH lesion obesity is attributed in part to tissue ablation and in part to metallic ion deposits stimulating (rather than dlsmhibltmg) vagally mediated msuhn responses Ventromedlal hypothalamus

Brain lesions

Feeding behavior

WHEN the Horsley-Clarke (50) stereotaxlc instrument was finally adapted for use with rats in 1939 (20), one of the first studies to result from its use was by Hethenngton and Ranson (46,47), who reported marked weight gains in animals with electrolytic lesions at the base of the hypothalamus. The critical locus for producing obesity was determined to be in the area of the ventromedial hypothalamus (VMH) [(45) but see (34)], but it was not untal later that investigators noted that such lesions markedly increased food intake as well (16,48). Rats with VMH lesions often begin eating voraciously even before fully recoverlng from the effects of anesthesia (16,18). The overeating and obesity have traditionally been divided into two stages (18): a dynamic phase of marked hyperphagia and rapid weight gain followed by declining food intake as body weight first levels off and is then maintained during the static phase of obesity [but see (63)]. VMH leston-mduced obesity has been found in a wide variety of species including mice (72), ground squirrels (74), rabbits (87), cats (2), dogs (89), pigs (56), goats (5), chickens (69), sparrows (66), monkeys (2,17), and humans (13). In the last five decades, there have been hundreds of studies published on the etiology of ventromedial hypothalanuc lesion obesity. Explanations have ranged from the purely behavioral (e.g., the VMH viewed as a "satiety center") (1,104) to the purely metabolic (i.e., obesity and/or hyperphagm attributed to a lesion-induced metabolic deficit) (76). Of all the various hypotheses, perhaps the most controversial was that proposed over 25 years ago by Robert Reynolds (82,83). Beginning with Hetherington and Ranson (46), nearly all studies of VMH obesity had produced lesions by passing direct current (referred to as electrolytic lesions) through a stainless steel electrode used as the anode. This procedure erodes the electrode tip and leaves depos-

Obesity

Insulin

Vagus nerve

its of metallic ions (see next section). Reynolds (82) did not observe abnormal weight gains m rats given VMH lesions that left no deposits (produced by electrocautenzauon with radio-frequency current through platinum electrodes). The " t m t a t l v e hypothesis," as Reynolds called it, stated that the hyperphagia and obesity that follow electrolytic VMH leslons were not the result of tissue ablation, but instead resulted from the metallic ~on deposits irritating (i.e., sttmulating) adjacent tissue involved in the regulation of feeding behavior. When subsequent studies reported marked obesity in rats given radio-frequency or other "nonirritative" VMH lesions (49,75), Reynolds' hypothesis was largely ignored, as evidenced by the large number of researchers, including myself, who continued to use electrolytic lesions to study hypothalam~c obesity. However, results of recent studies have shown that Reynolds' expenmental observations were prematurely dismissed and that his conclusions were at least partially correct. PRODUCTION OF IRRITATIVE AND NONIRRITATIVE LESIONS There is no question that passing anodal electrolytic current through a stainless steel electrode results in erosion of the electrode tip. It can be easily demonstrated in a saline bath (70) and it is safe to assume that brain tissue acts as an electrolyte in a similar manner. The deposits in brain tissue can be seen with the naked eye as a brown discoloration and can be verified by a Perls' stain for iron deposition (51). The degree of electrode erosion depends on the electrode matenal and the polarity and type of current. When used as the anode, electrodes with a potential less positive than the hydroxyl ion (e.g., iron, copper, nickel) go into solution as the corresponding metallic ions, while those with a potential greater than

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the hydroxyl ion (e.g., platinum) cause a reaction favoring hydroxyl tons (83). Thus, with dtrect current, platinum electrodes leave fewer deposits than do stainless steel electrodes (35). Destruction of tissue w~th platinum electrodes occurs primarily as a result of generation of oxygen bubbles (35). W~th the same current, twice the volume of gas ~s generated when a platinum electrode ~s used as the cathode, whereas steel, copper, or nickel electrodes destroy t~ssue less effectively when used as the cathode (because of fewer deposits) (88) A few early stu&es that cla~med to have thscredited Reynolds' hypothes~s used anodal current with platinum electrodes or cathodal current w~th stainless steel electrodes to produce "nonirdtatlve" les~ons, but &d not histologically confirm the absence of deposits (7,9). However, it must be emphasized that the use of platinum electrodes and/or cathodal current does not guarantee deposit-free lestons. It only lessens the chances Deposits are often found even with the combination of platinum electrodes and cathodal current (24,61) Another possible ~rntat~ve focus is scar tissue (111), which can result from e~ther a ghal reaction to metallic ions or from hemorrhaging blood vessels. To produce nonL'ntative lesions, radio-frequency current is preferred over cathodal or anodal electrolytic current because the biphas~c sine-wave not only minimizes the chances of metalhc ion deposits (4), but the heat cauterizes blood vessels as well. This would be especially important m a highly vascularized area like the basal hypothalamus. Again, however, deposits are sometimes found with radiofrequency current (62,71), even when used m combination with a platinum electrode (82). Thus, without histological verification, ~t should not be assumed as was done by one early study that attempted to disprove Reynolds' hypothes~s (49), that radiofrequency les~ons are nomrntat~ve THE RISE AND FALL OF REYNOLDS' HYPOTHESIS

Reynolds was not the first to suggest that les~on-mduced metalhc Ion deposits rmght affect behavior (88), nor were the putatwe effects limited to VMH feeding behavior. Everett and colleagues (28,29) reported that ovulation m anovulatory pentobarbital-treated rats could be reduced by anodal electrolytic lesions of the preoptic area or by direct apphcatlon of 5% FeCI 3, but not by ra&o-frequency lesions. In later stu&es, Simons (86,99) reported that a short-term poly&psm could be produced m food-deprived, nephrectomized rats by anodal electrolytic les~ons, but not by ra&o-frequency lesions, of the median eminence of the tuber cinereum. The excessive dnnlong was not observed ff water was withheld for 6 to 7 hours after the lesions. She concluded that the dnnklng was due to deposit-reduced irritation of the lateral hypothalamus, where very small electrolytic lesions had the same effect [also see (26)] Large electrolytic les~ons of the medml hypothalamus were actually found to cause death by water intoxication shortly after surgery (114). It was Reynolds, however, more so than anyone else, who by formalizing it in a review article (83), came to be associated with the hypothesis that the effects of some lesions were due not to removal of t~ssue, but to metalhc ~on deposits irritating adjacent tissue [see also (78)] The focus of his research was the ventromedial hypothalamus. Rats w~th anodal electrolytic VMH lesions often displayed signs of pulmonary edema shortly after surgery (possibly related to the transient polydipsia cited previously) (73), displayed marked hyperphagia, and became obese (82) Very few animals wtth radio-frequency lesions &splayed these changes, and those that &d were found during histology to have metallic ~on deposits. Although no objective measurements were taken, Reynolds (82) also noted that rats with ra&o-fre-

quency lesions thd not display the vicious response to handling that is typical of animals with electrolytic lesions (101,113) Normal reactivity to handhng was subsequently reported for a variety of other nomrntative techniques as well, including VMH suction lesions (75), electrolytic lesions with platinum electrodes (35), and parasaglttal knife cuts between the ventromedial and lateral hypothalamus (91) The different results with electrolyttc and depostt-free, ra&ofrequency lesions were not due to les~on size, and the two types of lesions were found to produce identical effects in the septum (septal rage) (84) and lateral hypothalamus (aphagm and a&psia) (81). It was the presence of deposits in the basomedial hypothalamus that was critical. Two other stu&es conducted dunng thin same time period also reported that VMH hyperphagia was observed only when lesions produced metalhc ion deposits (24,79). Reynolds (83) attributed the results w~th electrolytic lesions to Lrritation of the lateral hypothalamlc "feeding center." The irntatwe effects of deposits were used to explain the several hours of continuous feeding that follows electrolytic VMH lesions (43), s~mflar to that which is observed after electrical st~mulauon of the lateral hypothalamus (103) Reynolds concluded his studies by demonstrating that hyperphagia and obesity could be obtained by direct deposition of iron ions (as FeCI3.6H20) to the VMH (27). Reynolds review article had no sooner appeared m pnnt when it was rebutted by Hoebel (49), who reported marked hyperphagla and obesity m rats given radio-frequency lesions. Reynolds (85) attempted to counter by stating that the ~mportant point was not whether one could produce hyperphagia with ra&o-frequency les~ons, but whether one could destroy the VMH w~thout producmg hyperphag~a as he had done. Hoebel's results, however, were not easdy explained away and the Zettgetst was not ready to reevaluate 25 years of lesion stu&es with any assumption other than that the effects of lesions must be due to the removal of tissue. Even though a few stu&es replicated Reynolds' findrags (24,79), the fate of the irritatwe hypothesis was sealed when additional studies reported hyperphagm m rats given radio-frequency les~ons (44,71), suction lesions (75), or parasagittal knife cuts lateral to the VMH (93), all presumably nomrritatwe techmques. Reynolds' hypothesis soon suffered the worse fate that can happen in science, 1 e., ~t was ~gnored. The majority of researchers continued to produce VMH lesions using anodal electrolytic current through a stainless steel electrode. RESURRECTION OF THE HYPOTHESIS

In the years that followed Hoebel's rebuttal, major advances were made in the understanding of hypothalamic obesity. A sex difference was noted, i.e., female rats with electrolytic lesions often gained significantly more weight than male rats with lesions (23,102). Weanhng rats with VMH lesions were found to display significant increases m body fat content despite the fact that they did not overeat (31,40). Adult rats with VMH lesions were also found to have greater body fat content and/or greater weight gain when pa~r-tube-fed with normal control animals (37,38,41). The latter results demonstrated that the obesity that results from electrolytic VMH lesions is at least partially due to a primary metabolic dysfunction 0 . e , lesion induced rather than feeding induced). When pair-fed and weanling VMH rats were found to have greatly elevated plasma msuhn levels (22, 31, 39), it suggested a possible mechanism by which such animals could develop excess carcass hpld content m the absence of hyperphagta. Powley (76) proposed that VMH obesity was the result of a lesion-induced dismhib~tion of parasympathetic responses, most notably vagally mediated insuhn responses Obese rats with VMH lesions were observed to lose all of their excess body

REEXAMINATION OF THE IRRITATIVE HYPOTHESIS

weight if given subdiaphragmatic transecuons of the vagus nerve (77). Several others proposed similar hypotheses in which the development of VMH obesity was attributed in all or most part to hyperinsulinemia (52-54, 68). While most of the attention during the 1970's and early 1980's was devoted to showing the importance of elevated insulin levels, a few experimental findings suggested that hyper|nsulinemia was not critical to the development of hypothalamlc obesity Alterations in intermediary metabolism that enhance lipogenesls and lead to excessive fat accumulation were demonstrated in VMH rats made diabetic with streptozotocln (36,42). In fact, diabetic rats with VMH lesions were found to gain more weight than animals without lesions dunng controlled insulin administration (30,110). Several studies reported that vagally transected or scopolamine-treated rats with VMH lesions displayed marked obesity, albeit only to about 60% of that of nontransected or nontreated VMH rats (19, 57, 64, 90). After confirming that their vagotomized-VMH animals displayed no increase in basal insulin levels, King and Frohman (60) concluded that vagally mediated hyperinsullnemla could account for no more than 40% of the weight gain observed in animals with VMH lesions. Like electrolytic lesions, injections of procaine into the VMH were reported to produce overeating in satiated animals (11,67), but procaine anesthetization of the VMH actually induced hyporather than hypennsullnemla (11). Obesity-inducing parasaglttal knife cuts between the ventromedlal and lateral hypothalamus also were found not to result in hyperlnsullnemla during food restriction (15, 92, 109). It appeared, therefore, that only electrolytic lesions of the VMH consistently and rehably produced hypennsuhnemia. It was against this backdrop that King and Frohman and colleagues decided to compare the effects of irritative and nonirntatwe VMH lesions on plasma insulin levels (58-62, 65) Anodal electrolytic VMH lesions produced the usual marked elevations m basal insulin levels during periods when food intake was restricted to that of sham-operated animals. However, histologically confirmed nonirritatwe VMH lesions, whether produced by cathodal electrolytic current through a platinum electrode or by radio-frequency current, resulted in no significant increase in basal insulin levels dunng the same period (59,61). Both groups displayed hyperphagla-induced hyperxnsuhnerma when given food ad lib. Nearly identical results were reported by Coscina (21). Results with radio-frequency and electrolytic-lesioned weanling rats were also similar, w~th only the latter displaying hyperinsullnemia after 30 days of food ad llb (58). The differences between lmtative and nonLrntative VMH lesions were equally clear-cut for emotional reactivity. Using a scale modified from Brady and Nauta (12), King and Frohman (61) observed that rats with nonimtatlve lesions, unlike those with lrntatlve lesions, displayed httle or no hyperreactivity to handling, thus replicating observations from earlier studies that used nomrritatlve techniques (35, 75, 82, 91). The results for weight gain were intermediate between those reported years earlier by Reynolds (82) and Hoebel (49). Both groups with lesions became obese compared to animals with sham lesions, but rats with nonirritative lesions gained significantly less welght than rats with lrrltatlve lesions (59,61) The discrepancies in the earlier studies were attributed to a difference In sex of the animals. A review of these studies revealed that male rats were used m all experiments in which little or no excess weight gain was observed after nonirritative lesions (24, 79, 82) and female rats were used whenever nonlmtatlve procedures resulted in obesity (44, 49, 71, 75) [see (78) for an earher review]. King, Frohman, and colleagues used female rats. When they directly compared the effects of anodal electrolytic and ra-

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dio-frequency VMH lesions m both male and female rats (62), they found that male rats gained less than 80% of the weight gained by female rats regardless of lesion type. Rats with nonlrritative radio-frequency lesions gained only about 60% of the weight gained by rats with electrolytic lesions regardless of sex. Thus, male rats with nomrfitative lesions displayed weight gains that were only slightly greater than normal. The seemingly discrepant results of 25 years ago could now be explained. Neither Reynolds' (82) nor Hoebel's (49) experimental observations had been wrong. Reynolds observed little excess weight gain with nonlrntative lesions because he used male rats A VMH lesion sex difference had not yet been reported (23, 62, 102). Although Hoebel observed obesity in female rats with radio-frequency lesions, an effect of lesion type was not appreciated because he failed to include an electrolytic lesion control group. Even with the discrepancies explained, however, Reynolds' hypothesis (83) that hypothalamlc obesity results entirely from irritation of the adjacent lateral hypothalamlc "feeding center" was unsatisfactory. Not only had the concept of "centers" been abandoned, but it could not explain the weight gain in animals with nonimtatwe lesions. King and Frohman once again proposed an lrfitative hypothesis to explam hypothalamic obesity, but not in the original form proposed by Reynolds.

THE IRRITATIVE HYPOTHESIS RESTATED

King and Frohman (61,62) proposed that obesity produced by anodal electrolytic VMH lesions is the result of both tissue ablation and an irritative component resulting in basal hyperlnsuhnemia independent of hyperphagia. Accordmg to them, the irritatlve component contributes about 40% of the total weight gain after anodal electrolytic lesions. Thus, weight gain after nonimtatlve lesions is due exclusively to tissue ablation and animals with such lesions gain only about 60% of the weight gamed by animals with lmtatlve lesions. The key assumption in King and Frohman's hypothesis is that trrltatlve and nonlmtatlve VMH lesions produce equivalent amounts of tissue damage, but have different effects on plasma insulin levels. Imtatlve and nonlrritative VMH lesions had different effects on body weight and basal insulin levels in four replications (58, 59, 61, 62), but histological analysis revealed no apparent differences between the two groups with lesions other than one type left metalhc ion deposits and the other did not. If the basal hyperinsulinemia observed after VMH lesions was due solely to tissue ablation, then both types of lesions should have resulted m elevated insulin levels. In contrast to VMH lesions, they found that radio-frequency and electrolytic lesions of the paraventricular nucleus produced the same effects on weight gain and plasma insulin levels (65). Several other studies have also reported that obesity-reducing electrolytic lesions of the PVN have no effect on plasma insulin levels (100, 105, 106, 112), similar to the results found with parasagittal knife cuts (15, 92, 109). Rats wlth electrolytic PVN lesions also are not hyperreactive to handling (3). Thus, depositfree and deposit-inducing lesions of other nuclei generally produce slnular effects [also (81,84)], even for feeding behavior and msuhn responses. The fact that differences have been demonstrated numerous times with VMH lesions strongly suggests that deposits left by anodal electrolytic lesions do produce additional effects in the basomedlal hypothalamus. The use of cellular neurotoxins, which destroy neurons and not fibers of passage, offers a nonin-itative method of lesion production par excellence. Shimizu and colleagues (98) recently reported very moderate weight gains in male rats with bilateral

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lesions of the VMH produced w~th the neurotoxin ibotenic acid. Unfortunately, they &d not employ an electrolytic lesion control group nor measure plasma insulin levels. However, the ibotenic acid-induced weight gains were not characteristic of electrolytic VMH-lesioned animals and, in fact, were of the same small magnitude as those observed by King and Frohman (62) in male rats with radm-frequency lesions. Thus, the results with ibotenic acid are consistent with the hypothesis that nonirntatwe VMH lesions produce weight gain as a result of local tissue ablatmn and irntative lesions produce additional weight gain by stimulating fibers of passage. The hypothesis that metalhc ion deposits further enhance weight gain m VMH-lesioned animals by stimulatmg basal insulin responses ~s also consistent with the many studies c~ted earlier that have demonstrated VMH hyperphagia and/or obesity m absence of basal hyperinsulinemia. Of particular interest are those studies involving the vagus nerve. Stimulation of the vagus nerve increases insulin secretmn while vagotomy lowers serum insulin levels (33,55). Plasma insulin levels are elevated within minutes after electrolyuc VMH lesions (whale the ammals are still anestheuzed) and this too can be reversed by vagal transections (10). As discussed earlier, several studies have found that vagally transected or scopolamine-treated rats (at a dosage 80 umes greater than needed to block vagally medmted insulin secretmn) given VMH lesmns gain about 60% of the weight gamed by nontransected- or nontreated-VMH rats (19, 57, 90). Th~s ~s the same weight gain differential that is found between hypennsuhnermc, anodal electrolytic VMH-lesioned rats and normomsulinemic, nonimtatlve VMH-lesioned rats (59, 61, 62). The hypothesis proposed here differs considerably from prevmus hypotheses regarding the effects of VMH lesions on insuhn secreuon and body weight. Prevmus hypotheses have attributed much or all of the abnormal weight gain to a leslon-mduced disInhibition of vagally mediated msuhn responses (52-54, 68, 76, 77). The present hypothesis attributes 40% of the weight g~un to lesion-induced stimulation of vagally me&ated insulin responses. A dis~nh~bmon hypothesis cannot account for e~ther the absence of hyperinsuhnemia or the reduced weight gain in animals with nommtative VMH lesmns. The manner in which deposits in the basomedial hypothalamus stimulate vagally mediated insulin secretion has yet to be determined. Electrical st~mulatmn of the VMH for 3 minutes in anesthetized rats causes a rapid rise in plasma glucose levels, but no change in basal insulin levels until after stimulation ceases (32). However, the effects of VMH stimulatmn are of litfie relevance to the irritative hypothesis because this t~ssue ,s destroyed by lesions. It is the effects of stimulatmn of adjacent nuclei or fibers that are of importance. Furthermore, results of acute, short-term stimulation studies may have little similarity to what happens w~th chromc stimulation. Rats given electrolytic

VMH lesions, for example, do not begin to display elevations ,n plasma insulin levels until 20 minutes afterwards (10). Based on the ventral placement of some of their smallest electrolytic VMH lesions and also on the fact that dorsomedlal hypothalamlc lesions do not elevate body fat or insulin levels (8), King and Frohman (61) concluded that the critical area must be m the ventral hypothalamus. The most likely adjacent area where deposits might mfluence parasympathetic responses is the lateral hypothalamus (LH) because of its relation with the dorsal motor nucleus of the vagus m the medulla (6, 94, 97). Electrical stimulation of the LH promotes glycogenesls in the liver (95) and enhances gastric secretmn (73), but short-term stimulatmn does not increase insulin secretion (96). (The effects of chronic stimulation have not been explored.) However, adrenergic and noradrenerglc stimulatmn of the LH do reduce elevated insulin levels (25,96). The major difference between Reynolds' hypothesis (83) and that presently proposed is that the latter attributes only part of the weight gmn produced by electrolytic lesmns to lrritative deposits. All of the obesity produced by nonirritative lesions and 60% of that produced by irritatlve lesions is attributed to t~ssue ablation. Thus, although they differ with respect to basal insulin levels, the two obesity syndromes should also have many similarities. Both types of lesmns result in elevated corticosterone levels (59) and secondary hyperinsuhnemm when food is given ad lib (59,61). Stimulation of the VMH activates sympathetic nervous system responses [see (95)] and thus either type of les,on might promote obesity by inhtbitmg sympathetic responses (14,53). Electrolytic VMH lesions and (nontrritatlve) parasag,ttal knife cuts result m similar reducuons m sympathet,c nervous system activity (107,108). The hypothesis also does not preclude the possibility that VMH lesions damage neural systems mediating satiety (104). In summary, only anodal electrolytic VMH lesions have consistently been found to result in both hyperphagta/obesity and elevations m plasma insulin levels. Hyperphagm and/or obesity in absence of hyperinsuhnemia have been observed m a m m a l s with procaine anesthetization of the VMH (I 1), parasaglttal knife cuts lateral to the VMH (15, 92, 109), paraventricular nucleus lesions (65, 100, 105, 106, 112), and more recently, lesmns of the VMH that do not leave metallic ion deposits (21, 58, 59, 61, 62). Previous hypotheses that attribute VMH hyperphagia/ obesity to destruction of sat,ety mechanisms (104) or disinhibited parasympathetic responses (76) [and/or decreased sympathetic activity (53)] cannot account for the differences in weight gmn and plasma insuhn levels observed between rats with irritatlve and nomrritative lesions. The presently proposed hypothesis explains this difference by attributing VMH lesmn obesity not only to tissue ablation, but in the case of irritat,ve, anodal electrolytic lesions, to metallic ion deposits stimulating vagally mediated insulin responses as well.

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REEXAMINATION OF THE IRRITATIVE HYPOTHESIS

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