obesity reviews

Hypothalamic obesity in humans: what do we know and what can be done?

J. Pinkney, J. Wilding, G. Williams and I. MacFarlane

University of Liverpool, Department of Medicine, Diabetes and Endocrinology Research Group, Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK Received 9 August 2001; revised 17 September 2001; accepted 26 September 2001 Address reprint requests to: Dr J Pinkney, University of Liverpool, Department of Medicine, Diabetes and Endocrinology Research Group, Clinical Sciences Centre, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, UK. E-mail: jpinkney@liverpool.ac.uk

Summary
Obesity is a common sequel to tumours of the hypothalamic region and their treatment with surgery and radiotherapy. The prevalence of hypothalamic obesity has been underestimated because it may take some years to develop, and the problem has been under-recognized by physicians. Weight gain results from damage to the ventromedial hypothalamus which leads, variously, to hyperphagia, a low metabolic rate, autonomic imbalance, growth hormone (GH) deciency and various other problems that contribute to weight gain. However, with the exception of GH replacement, few clinical trials have evaluated signicant numbers of patients and so the roles of various behavioural, dietary, pharmacological and obesity surgery approaches are controversial. Sufcient knowledge exists to identify those at high risk of hypothalamic obesity so that weight gain prevention approaches can be offered. In those who are already obese, we propose that the principal causal mechanisms in individual patients should be considered as a basis for guiding clinical management. Keywords: Craniopharyngioma, hypothalamus, obesity, pituitary.
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Introduction
Remarkable advances in basic science are unravelling the neuroendocrine mechanisms through which the hypothalamus controls energy balance. However, this knowledge has yet to be translated into therapeutic advances for patients with structural hypothalamic damage, for many of whom disordered eating and obesity are a nightmare. It has long been recognized that obesity complicates diseases of the hypothalamus and their treatment. Craniopharyngioma, and its treatment, is the commonest single structural cause of hypothalamic obesity, while PraderWilli syndrome has been considered the commonest genetic form of obesity to be associated with hypothalamic dysfunction. The difculty confronting the clinician is that, with the exception of trials of growth hormone (GH) therapy, most of the literature on treatment is anecdotal. The purpose of this article therefore is to examine what is currently known about the pathophysiology of these forms of obesity in humans, and to evaluate the available options for clinical management.

Occurrence of hypothalamic obesity

It has been recognized for over a century that structural lesions of the sellar region may give rise to obesity (1). The most common causes of hypothalamic damage are spaceoccupying lesions such as craniopharyngioma, other tumours and aneurysms, inammatory and inltrative diseases, and trauma (2) (Table 1). Affected individuals gain weight as a result of either the underlying disease or its treatment with surgery or radiotherapy, sometimes becoming markedly obese. In children and young adults, craniopharyngioma and/or its treatment is the single most common cause of acquired hypothalamic damage, although craniopharyngioma is still rare, with an estimated incidence in the USA of just 1.3 per million per year (3). Several reports provide data on the occurrence of obesity with craniopharyngioma. In a report from Finland, six of 22 children with craniopharyngioma were reported to be obese preoperatively, but this rose to 13 out of 21 children 1 year post-operatively (4). Sklar also reported that obesity was
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Table 1 Causes of hypothalamic obesity in humans Structural damage to the hypothalamus Craniopharyngioma Pituitary macroadenoma with suprasellar extension Glioma Meningioma Teratoma Germ cell tumour Metastasis Aneurysm Surgery Radiotherapy Genetic syndromes of obesity with hypothalamic dysfunction PraderWilli syndrome (41) Leptin deciency (12) Leptin receptor deciency (13) Proopiomelanocortin mutation (61) Melanocortin-4 receptor mutations (62) References are shown in parenthesis.

common after surgical treatment of craniopharyngioma (5). In a study from the UK (6), 90% of 63 patients with craniopharyngioma gained weight during follow-up, showing that this is an expected part of the natural history following surgical treatment. Villani and colleagues (7) reported longterm follow-up of 27 children treated surgically for craniopharyngioma; although the majority of patients were reported to have achieved normal long-term social adjustment, obesity was a common sequel. Although hypothalamic damage is a rare cause of obesity, these data demonstrate that weight gain and obesity are common long-term problems in patients with structural hypothalamic damage. In contrast to structural lesions, a series of genetic syndromes are associated with hypothalamic dysfunction (Table 1). PraderWilli Syndrome (PWS) was considered to be the commonest genetic form of obesity associated with overt hypothalamic dysfunction, although recent data suggest that melanocortin-4 receptor mutations, present in some 4% of morbidly obese patients, might be commoner. Features of PWS include short stature, GH deciency, hypogonadotrophic hypogonadism, complex behavioural disorders and learning difculties. PWS will be considered separately from acquired structural hypothalamic lesions. The recently described cases of human obesity caused by mutations in the genes for leptin, its receptor, melanocortin4 receptors and proopiomelanocortin (POMC) (Table 1), will not be discussed further in this article.

isms behaviour through the anterior pituitary, descending autonomic pathways and other brain regions. Experimentally, lesions of the medial hypothalamus induce obesity, whereas lateral hypothalamic lesions cause wasting (8). These observations gave rise to the dual-centre hypothesis of weight regulation. The medial hypothalamus contains distinct nuclear groups that control the energy balance (9). Damage to these areas (Fig. 1), as a result of either the disease or its treatment, leads to hypothalamic obesity. In a follow-up study of 63 survivors of childhood craniopharyngioma treated surgically between 1973 and 1994, in which patients underwent magnetic resonance imaging (MRI) 1.919.2 years post-operatively, it was observed that more extensive hypothalamic damage was present in those who had experienced the most marked weight gain (6). It was suggested that MRI can give sufcient resolution to identify at least some of those at high risk of postoperative weight gain. A variety of specic neuroendocrine mechanisms account for hypothalamic obesity, and the relative contribution of different mechanisms seems to vary from one patient to another depending upon the distribution and extent of hypothalamic damage.

Hyperphagia
One pattern of behaviour described after surgical treatment of craniopharyngioma is severe hyperphagia and obsessive food-seeking behaviour (10). This is also observed in individuals with PWS (11). In its most extreme form, this behaviour can be highly anti-social and disruptive, with constant foraging for food and even theft of food and money. Hyperphagia of this magnitude resembles that described with deciency of leptin (12) or its receptor (13), and probably involves, at least in part, disruption of the arcuate nucleus function. Thus, damage to medial hypothalamic structures probably contributes to hyperphagia in craniopharyngioma, with the arcuate nucleus being situated in an anatomically vulnerable position close to the midline in the infundibular region. Consistent with this notion, in one report 11 patients who had undergone excision of suprasellar craniopharyngiomas were found to have elevated leptin concentrations, as compared to three patients with intrasellar tumours, suggesting that perhaps suprasellar craniopharyngiomas disrupt the hypothalamic circuitry engaged by leptin (14). However, overt hyperphagia is conspicuously absent in other patients with hypothalamic obesity, in keeping with the observation that hypothalamic obesity in animals can also occur in the absence of hyperphagia (15).

Mechanisms giving rise to hypothalamic obesity

The hypothalamus controls energy balance by integrating neuroendocrine signals from other brain areas and the periphery, controlling the endocrine milieu and the organ-

Autonomic dysfunction
Vagally mediated hyperinsulinaemia Bray & Gallagher (2) observed increased fasting insulin concentrations in four patients with hypothalamic obesity

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Figure 1 Magnetic resonance images. (a) Coronal brain section showing the normal human hypothalamus at the level of the optic chiasm and (b) line drawing of the principal structures. (c) Sagittal section through normal pituitary gland and hypothalamus and (d) line drawing of the principal structures. (e) Coronal section demonstrating suprasellar mass lesion (glioma) with invasion of the mediobasal hypothalamus and distortion of the 3rd ventricle and (f) line drawing of the principal structures. (g) Sagittal image showing upward expansion of glioma into medial hypothalamus and (h) line drawing of the principal structures.

Pituitary Hypothalamus

(a)

(b)

3rd ventricle

Hypothalamus Optic chiasm

Pituitary

(c)

(d)

Glioma

(e)

(f)

Glioma

(g)

(h)

compared with age- and weight-matched controls. While fasting led to a fall in plasma insulin levels in control obese patients, this was not seen in those with hypothalamic obesity. Oral glucose tolerance tests on children with suprasellar craniopharyngioma were found to result in a signicantly greater insulin response than that exhibited by children with intrasellar tumours, although those children also had a signicantly greater BMI (16). The hypothesis that autonomic imbalance contributes to hypothalamic obesity was formulated by Inoue & Bray (17). Subse-

quently, it has been interesting to note that autonomic imbalance is a consistent feature of most known forms of obesity, suggesting that it may play a pivotal role (18). In keeping with the hypothesis that increased autonomic activity consequent to medial hypothalamic damage (and presumably mediated by increased insulin secretion) is essential for the development of obesity, it was observed that subdiaphragmatic vagotomy prevented the onset of obesity after bilateral parasagittal knife cuts in rats (19). A series of experiments by Bray et al. (20) conrmed that lesions in the

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region of the ventromedial hypothalamic nucleus led to reduced sympathetic nervous system activity and enhanced glucose-stimulated insulin secretion, and furthermore showed that the latter was reduced by the administration of adrenaline and atropine. Dual-lesioning experiments suggested that these effects were independent of the lateral hypothalamus and presumably mediated by autonomic pathways descending from the hypothalamus into the spinal cord. In similar experiments, King & Frohman (21) suggested that vagally mediated hyperinsulinaemia may explain 40% of the observed increase in fat content, consistent with the concept that multiple mechanisms contribute to weight gain, both in different experimental paradigms and in different patients with hypothalamic damage. Autonomic imbalance probably develops in patients with damage to the vulnerably situated ventromedial hypothalamic nuclei, which give rise to descending autonomic projections. To our knowledge there are no data on this subject in patients with PWS. Impaired energy expenditure and thermoregulation Another aspect of autonomic dysfunction is impaired energy expenditure. Many factors impair energy expenditure in patients with hypothalamic disease and contribute to obesity. Several regions of the hypothalamus specically inuence energy expenditure and/or arousal mechanisms. An exhaustive review of these elds is beyond the scope of this article. However, the pre-optic anterior hypothalamus is an important site of thermoregulatory control (22), and the ventromedial nuclei are also important in giving rise to descending sympathetic pathways which, when activated, lead to increases in the metabolic rate (23). The medial hypothalamic pathways engaged by leptin also clearly play a role in the control of energy expenditure, because leptin administration to homozygous leptin-decient (lep-/lep-) obese mice increases oxygen consumption and peripheral uncoupling protein expression (24). All of these regions of the hypothalamus are vulnerably situated, being readily disrupted by midline lesions in the suprasellar region or in the course of surgery. Those patients who are somnolent may additionally be predisposed to gain weight through reduced voluntary energy expenditure, providing that adequate food intake is also maintained and/or insulin hypersecretion co-exists. The pathophysiology of hypothalamic somnolence and the role of hypothalamic regions in the control of arousal and sleep is not well characterized, and in the experimental setting lesions to both posterior and lateral hypothalamus implicate both areas in these phenomena. A full review of these elds is also beyond the scope of this article. However, reduced expression of orexins was demonstrated recently in the brains of patients with narcolepsy (25), which may represent one mechanism through which lateral hypothalamic damage might contribute to somnolence. Also conrming the role of the

Table 2 Factors contributing to weight gain and/or increased body fat mass in patients with hypothalamic damage Increased energy intake Decreased energy expenditure Hyperphagia

Low resting metabolic rate (autonomic imbalance) Somnolence Reduced mobility Visual failure Hyperinsulinaemia (autonomic imbalance) Growth hormone deciency Thyrotrophin deciency Gonadotrophin deciency

Enhanced fuel storage Hormone deciencies

hypothalamus in the control of arousal and thermoregulation in humans are case reports of transient cataplexy following surgical removal of a craniopharyngioma (26), and reports of hypothermia secondary to structural hypothalamic lesions (2731). Finally, it is probable that reduced physical activity associated with prolonged periods of medical treatment and its sequelae will have an impact on body weight. Patients with damage to the optic chiasma may suffer visual impairment and nd that this reduces their opportunities for exercise. Table 2 summarizes the principal mechanisms that contribute to obesity in patients with hypothalamic disease.

Obesity in the PraderWilli syndrome

In the case of PWS, the proposal that hypothalamic and pituitary dysfunction is the cause of the obesity is supported by pituitary hypoplasia on MRI scan (32), the presence of GH and insulin-like growth factor-1 deciency (33,34), hypogonadotrophic hypogonadism (34) and reduced volumes of the hypothalamic paraventricular nuclei (35). Reduced lean body mass also contributes to a decreased metabolic rate (36). Severe hyperphagia, with foraging for food and food theft, is a well-recognized part of the syndrome (11,37) and is probably the main cause of the obesity. Feeding studies demonstrate markedly impaired satiety in PWS patients compared to control subjects (38,39), with a preference for sweet food (40). Against this backdrop, hypogonadism and GH deciency further aggravate an unfavourable body composition. Severe obesity is often the result. Despite recent advances in understanding the genetics of PWS (41), however, the cause of the neuroendocrine abnormalities is currently unresolved. In conclusion, a variety of mechanisms probably contribute to weight gain, particularly in the post-operative setting, in patients with hypothalamic damage. The contribution of individual mechanisms presumably varies from

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one patient to another depending upon the distribution and extent of hypothalamic damage. This suggests, in theory, that identication of a predominant defect might guide medical therapy. Similarly, obesity in PWS is likely to be multifactorial. Besides hyperphagia, GH deciency and a low metabolic rate are probably contributing factors. Can this information be used to assist clinical practice?

Clinical management
Different strategies might best ameliorate hypothalamic obesity, depending upon the major contributing mechanisms. Frank hyperphagia and physical inactivity are often immediately apparent from the individuals history. There are, however, no established criteria for the diagnosis of hyperphagia, autonomic dysfunction, hyperinsulinaemia or impaired energy expenditure in this situation, and such criteria would be difcult to establish given the considerable interindividual variation in these parameters. Notwithstanding these difculties, several suggestions can be made regarding possible approaches to treatment.

The mild-to-moderately obese hypothalamic patient

In the absence of overt hyperphagia and food-seeking, in the case of the mild-to-moderately overweight patient (BMI < 35) whose weight is stable and whose pituitary function is intact or fully replaced, it makes sense rst to approach the question of overweight by expert review of diet and lifestyle, as this is the usual cornerstone of effective obesity treatment. Whilst these measures may not achieve ideal body weight, they will probably at least limit weight gain. For children with hypothalamic damage or PWS, this approach will require full participation by family members in order to make the home and school environments more conducive to weight loss. However, there are relatively few data on the efcacy of this approach. The possibility of drug treatment is discussed below.

situation dietary advice alone may not be fully effective. However, behavioural approaches have been helpful in treating hyperphagia in PWS (4244). Obesity surgery has also occasionally been employed in patients with PWS. Case reports of biliopancreatic diversion in PWS report both successes (45,46) and failures (47). In another report, vertical band gastroplasty was ineffective in a patient with PWS (48). However, such data are fragmentary. Anorectic drugs (which enhance serotonergic and noradrenergic transmission) may work mainly through hypothalamic actions, as does recombinant leptin, and so it is possible that these drugs would not act to full effect in the presence of hypothalamic damage. Lipase inhibitors require dietary adherence and are therefore unlikely to have a useful role in the presence of hyperphagia or behavioural disturbance, unless the patient is under constant supervision. Further research will be needed to determine whether melanocortin-4 receptor (MC4R) agonists, neuropeptide-Y (NPY) or galanin antagonists, and perhaps cytokine agonists, are effective. It is possible, however, that anorectic agents targeted at other brain areas might offer more hope of blocking hyperphagia in the presence of medial hypothalamic damage. One such set of targets could include the systems involved in reward, including the dopaminergic system of the nucleus accumbens and the endogenous opioid system. In PWS, fenuramine has been used with partial success (49), although this drug is not now available. This might, however, provide a rationale for using other drugs which enhance serotonergic transmission. Fluoxetine was reported to assist weight loss in one patient with PWS (50). Thus, the available data for drug therapy are fragmentary, short-term and provide little help with clinical management. Finally, although lesioning other feeding centres (such as the lateral hypothalamus) could be another approach in the management of hyperphagia, this may risk additional complications such as somnolence.

The management of autonomic dysfunction

The combination of sympathomimetic and anti-cholinergic agents, or any other drugs that similarly reduce pancreatic nerve activity, may offset the putative vagally mediated hyperinsulinaemia that contributes to obesity in a subset of patients. Lustig and colleagues investigated the use of octreotide for this purpose. In a small uncontrolled study of six months duration, octreotide was found to result in signicant weight loss in children with intractable hypothalamic obesity, and this was accompanied with a decreased insulin response to oral glucose and decreased recalled calorie intake (51). These observations support the concept that autonomically mediated hyperinsulinaemia contributes to weight gain in some patients with hypothalamic damage. However, it is clear that further research is required to determine the patients who would benet and to ascertain

The management of hyperphagia

Obesity of greater severity, resulting from frank hyperphagia, is typically refractory to simple advice on diet and exercise, current anorectic drugs and gastric surgery (although there are few data on gastric surgery and this option holds little appeal in children and may be abortive or even dangerous in the face of determined hyperphagia). Close behavioural supervision is usually necessary to minimize consumption of unsuitable foods and restrict food-seeking behaviour, including modications of both personal and family behaviour as well as the home environment. In PWS, hyperphagia usually presents an even greater challenge because of concurrent learning difculties. In this

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whether this expensive treatment has long-term benets together with an acceptable side-effect prole. Additional possible means to the same end, yet to be explored, could include the use of low-carbohydrate diets to reduce insulin secretion, as well as selective pancreatic vagotomy.

Management of decreased energy expenditure

Where the history suggests that a sedentary lifestyle contributes to weight gain, this should be addressed. Voluntary energy expenditure is the component of energy expenditure that can be increased most, and with greatest ease. In contrast, the smaller thermic effect of food (TEF) may be optimized by the consumption of regular meals, and is highest with high-protein meals and lowest with high-fat meals. Therefore, meal patterns and content are important factors to consider in dietary management. Although resting metabolic rate (RMR) and perhaps spontaneous motor activity may be augmented in humans by sympathomimetic agents, currently available drugs to date remain untested in patients with hypothalamic obesity. Sibutramine is one possibility, but we are not aware of any data on its use in hypothalamic obesity. b -adrenergic agonists are another possibility, having lipolytic, anorectic and thermogenic effects. In the presence of hypothalamic damage, agents that promote energy expenditure through actions at other sites might offer the best hope for drug treatment.
3

a major factor contributing to frank obesity in those with primary hypothalamic lesions, it seems to make some contribution to weight gain and an unfavourable reduction in lean body mass, at least in patients in whom GH deciency has been demonstrated. A sense of full well-being, adequate muscle mass and strength are essential to optimize both resting and exercise-induced thermogenesis, and this underlines the importance of screening for, and treating, GH deciency.

Conclusions
Patients and parents of children with hypothalamic obesity secondary to diseases such as craniopharyngioma, or its treatment, are unprepared for the development of obesity. Frequently, little education or support are available. However, several conclusions can be drawn regarding the nature of hypothalamic obesity. First, weight gain is common with structural hypothalamic disease, and after surgery the majority of patients experience some degree of weight gain. For a signicant minority of patients the problem is severe and disabling. The neuroanatomical and neuroendocrine basis for hypothalamic obesity is emerging, but multiple mechanisms are involved, varying from one patient to another depending on the extent and distribution of hypothalamic damage. The extent of damage as assessed by MRI scan may correlate with the chances of long-term weight problems, and this may forewarn patients and families. To be alert to the possibility of hyperphagia may allow active management to start before severe obesity has developed. Where frank hyperphagia exists, including PWS, personal and family behavioural management may be the best approach. The identication and treatment of GH deciency is an important aspect of management. Currently available antiobesity drugs and surgical procedures look to have relatively little role for most hypothalamic obesity sufferers, although the literature is scant and more research is certainly required, particularly with regard to drugs that alleviate autonomic defects such as low metabolic rate and hyperinsulinaemia. In time, anti-obesity drugs that are currently in development may offer new hope. Meanwhile, we propose that a careful analysis of the causes and factors contributing to weight gain in hypothalamic obesity is worthwhile, and could identify potentially treatable factors. Many patients continue to seek help and support for this problem and a neglected area of endocrinology calls for greater attention.

GH replacement
The role played by deciencies of anterior pituitary hormones in the development of weight gain after hypothalamic damage is open to debate. Although relative increases in body fat may occur in secondary hypothyroidism and hypogonadotrophic hypogonadism, pure pituitary lesions (excluding chronic untreated panhypopituirarism) are not characteristically associated with the same degree of weight gain as with hypothalamic damage. However, a substantial body of data now suggests that GH deciency signicantly increases body fat and diminishes muscle mass. Patients with hypothalamic and pituitary disorders and GH deciency have an 5% higher BMI and more central fat distribution than control subjects (52). When GH-decient adults received GH replacement for different lengths of time, fat mass decreased by 1012% and lean body mass concomitantly rose by 510% (5355). Withdrawal of GH replacement leads to the reversal of these changes (56). In one report, intra-abdominal fat, as assessed by computerized tomography (CT) scanning, increased by as much as 48% after 12 months of GH withdrawal (57). GH replacement in children with GH deciency or with PWS also improves lean body and muscle mass by similar degrees (5860). Although it is doubtful whether GH deciency is

Acknowledgements
We wish to acknowledge Dr T. Nixon, Walton Centre for Neurology and Neurosurgery, Liverpool, for kindly allowing reproduction of the MRI images.

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