hypothalamic obesity in humans

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2002 The International Association for the Study of Obesity. obesity reviews 3, 2734 27

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

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 space-

occupying lesions such as craniopharyngioma, other

tumours and aneurysms, inflammatory and infiltrative dis-

eases, and trauma (2) (Table 1). Affected individuals gain

weight as a result of either the underlying disease or its treat-

ment with surgery or radiotherapy, sometimes becoming

markedly obese. In children and young adults, cranio-

pharyngioma 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 cranio-

pharyngioma. In a report from Finland, six of 22 children

with craniopharyngioma were reported to be obese pre-

operatively, but this rose to 13 out of 21 children 1 year

post-operatively (4). Sklar also reported that obesity was

obesity reviews

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: [email protected]

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

SummaryObesity 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 hyperpha-

gia, a low metabolic rate, autonomic imbalance, growth hormone (GH) deficiency

and various other problems that contribute to weight gain. However, with the

exception of GH replacement, few clinical trials have evaluated significantnumbers of patients and so the roles of various behavioural, dietary, pharmaco-

logical and obesity surgery approaches are controversial. Sufficient 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.

obesity reviews (2002) 3, 2734

Introduction

Remarkable advances in basic science are unravelling the

neuroendocrine mechanisms through which the hypothala-

mus 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 difficulty

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 patho-

physiology of these forms of obesity in humans, and to eval-

uate the available options for clinical management.


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common after surgical treatment of craniopharyngioma (5).

In a study from the UK (6), 90% of 63 patients with cran-

iopharyngioma gained weight during follow-up, showing

that this is an expected part of the natural history following

surgical treatment. Villani and colleagues (7) reported long-

term follow-up of 27 children treated surgically for cranio-

pharyngioma; although the majority of patients were

reported to have achieved normal long-term social adjust-

ment, obesity was a common sequel. Although hypothala-

mic damage is a rare cause of obesity, these data demonstrate

that weight gain and obesity are common long-term prob-lems 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 deficiency,

hypogonadotrophic hypogonadism, complex behavioural

disorders and learning difficulties. 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, melanocortin-

4 receptors and proopiomelanocortin (POMC) (Table 1),

will not be discussed further in this article.

Mechanisms giving rise to hypothalamicobesity

The hypothalamus controls energy balance by integrating

neuroendocrine signals from other brain areas and the

periphery, controlling the endocrine milieu and the organ-

28 Hypothalamic obesity in humans J. Pinkneyet al. obesity reviews

2002 The International Association for the Study of Obesity. obesity reviews 3, 2734

isms behaviour through the anterior pituitary, descending

autonomic pathways and other brain regions. Experimen-

tally, lesions of the medial hypothalamus induce obesity,

whereas lateral hypothalamic lesions cause wasting (8).

These observations gave rise to the dual-centre hypothe-

sis 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 cran-

iopharyngioma 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 sufficient resolution

to identify at least some of those at high risk of post-

operative weight gain. A variety of specific neuroendocrine

mechanisms account for hypothalamic obesity, and the rela-tive 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 indi-

viduals with PWS (11). In its most extreme form, this behav-

iour can be highly anti-social and disruptive, with constant

foraging for food and even theft of food and money. Hyper-

phagia of this magnitude resembles that described with

deficiency 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 craniopharyn-

gioma, with the arcuate nucleus being situated in an ana-

tomically vulnerable position close to the midline in the

infundibular region. Consistent with this notion, in one

report 11 patients who had undergone excision of suprasel-

lar craniopharyngiomas were found to have elevated leptin

concentrations, as compared to three patients with intrasel-

lar tumours, suggesting that perhaps suprasellar cranio-

pharyngiomas disrupt the hypothalamic circuitry engagedby 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).

Autonomic dysfunction

Vagally mediated hyperinsulinaemia

Bray & Gallagher (2) observed increased fasting insulin

concentrations in four patients with hypothalamic obesity

Table 1 Causes of hypothalamic obesity in humans

Structural damage to the hypothalamus

Craniopharyngioma

Pituitary macroadenoma with suprasellar extension

Glioma

Meningioma

TeratomaGerm cell tumour

Metastasis

Aneurysm

Surgery

Radiotherapy

Genetic syndromes of obesity with hypothalamic dysfunction

PraderWilli syndrome (41)

Leptin deficiency (12)

Leptin receptor deficiency (13)

Proopiomelanocortin mutation (61)

Melanocortin-4 receptor mutations (62)

References are shown in parenthesis.


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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

significantly greater insulin response than that exhibited by

children with intrasellar tumours, although those children

also had a significantly 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 activ-

ity consequent to medial hypothalamic damage (and pre-

sumably mediated by increased insulin secretion) is essential

for the development of obesity, it was observed that subdi-

aphragmatic vagotomy prevented the onset of obesity after

bilateral parasagittal knife cuts in rats (19). A series of

experiments by Bray et al. (20) confirmed that lesions in the

obesity reviews Hypothalamic obesity in humans J. Pinkneyet al. 29


(a) (b)

(c) (d)

(e) (f)

(g) (h)

Pituitary

Hypothalamus

Hypothalamus

Pituitary

Optic chiasm

3rd ventricle

Glioma

Glioma

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.


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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 sug-

gested 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 ventrome-

dial 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 expendi-

ture in patients with hypothalamic disease and contribute

to obesity. Several regions of the hypothalamus specifically

influence energy expenditure and/or arousal mechanisms.

An exhaustive review of these fields 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-deficient (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 ade-

quate food intake is also maintained and/or insulin hyper-

secretion 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 phe-

nomena. A full review of these fields 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 con-

tribute to somnolence. Also confirming the role of the



hypothalamus in the control of arousal and thermoregula-

tion in humans are case reports of transient cataplexy fol-

lowing surgical removal of a craniopharyngioma (26), andreports of hypothermia secondary to structural hypothala-

mic 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 find 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 sup-

ported by pituitary hypoplasia on MRI scan (32), the pres-

ence of GH and insulin-like growth factor-1 deficiency

(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 deficiency

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 con-

tribute to weight gain, particularly in the post-operative

setting, in patients with hypothalamic damage. The contri-

bution of individual mechanisms presumably varies from

Table 2 Factors contributing to weight gain and/or increased body fat

mass in patients with hypothalamic damage

Increased energy Hyperphagia

intake

Decreased energy Low resting metabolic rate (autonomic imbalance)

expenditure Somnolence

Reduced mobility

Visual failure

Enhanced fuel storage Hyperinsulinaemia (autonomic imbalance)

Hormone deficiencies Growth hormone deficiency

Thyrotrophin deficiency

Gonadotrophin deficiency


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one patient to another depending upon the distribution and

extent of hypothalamic damage. This suggests, in theory,

that identification of a predominant defect might guide

medical therapy. Similarly, obesity in PWS is likely to be

multifactorial. Besides hyperphagia, GH deficiency 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 mecha-

nisms. 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 cri-

teria would be difficult to establish given the considerable

interindividual variation in these parameters. Notwith-standing these difficulties, several suggestions can be made

regarding possible approaches to treatment.

The mild-to-moderately obese hypothalamicpatient

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 first to

approach the question of overweight by expert review of

diet and lifestyle, as this is the usual cornerstone of effec-tive 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 environ-

ments more conducive to weight loss. However, there are

relatively few data on the efficacy of this approach. The

possibility of drug treatment is discussed below.

The management of hyperphagia

Obesity of greater severity, resulting from frank hyperpha-

gia, is typically refractory to simple advice on diet and exer-

cise, 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 modifications 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 difficulties. In this

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 nora-

drenergic transmission) may work mainly through hypo-

thalamic 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 supervi-

sion. Further research will be needed to determine whether

melanocortin-4 receptor (MC4R) agonists, neuropeptide-Y

(NPY) or galanin antagonists, and perhaps cytokine ago-nists, 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 hypo-

thalamic 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, fenfluramine has been used with

partial success (49), although this drug is not now avail-

able. This might, however, provide a rationale for using

other drugs which enhance serotonergic transmission. Flu-

oxetine was reported to assist weight loss in one patient

with PWS (50). Thus, the available data for drug therapyare 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 sig-

nificant weight loss in children with intractable hypothala-

mic 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 deter-

mine the patients who would benefit and to ascertain




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whether this expensive treatment has long-term benefits

together with an acceptable side-effect profile. 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 con-

tributes to weight gain, this should be addressed. Volun-

tary 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 spon-

taneous motor activity may be augmented in humans bysympathomimetic 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. b3-adrenergic ago-

nists 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.

GH replacement

The role played by deficiencies of anterior pituitary hor-

mones in the development of weight gain after hypothala-

mic 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 deficiency significantly

increases body fat and diminishes muscle mass. Patients

with hypothalamic and pituitary disorders and GH defi-

ciency have an 5% higher BMI and more central fat dis-

tribution than control subjects (52). When GH-deficient

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 comput-

erized tomography (CT) scanning, increased by as much as

48% after 12 months of GH withdrawal (57). GH replace-

ment in children with GH deficiency or with PWS also

improves lean body and muscle mass by similar degrees

(5860). Although it is doubtful whether GH deficiency is



a major factor contributing to frank obesity in those with

primary hypothalamic lesions, it seems to make some con-

tribution to weight gain and an unfavourable reduction in

lean body mass, at least in patients in whom GH deficiency

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 under-

lines the importance of screening for, and treating, GH

deficiency.

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 aftersurgery the majority of patients experience some degree

of weight gain. For a significant 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 distribu-

tion 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, includingPWS, personal and family behavioural management may

be the best approach.

The identification and treatment of GH deficiency is an

important aspect of management. Currently available anti-

obesity drugs and surgical procedures look to have rela-

tively little role for most hypothalamic obesity sufferers,

although the literature is scant and more research is cer-

tainly 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 hypo-

thalamic obesity is worthwhile, and could identify poten-

tially treatable factors. Many patients continue to seek help

and support for this problem and a neglected area of

endocrinology calls for greater attention.

Acknowledgements

We wish to acknowledge Dr T. Nixon, Walton Centre for

Neurology and Neurosurgery, Liverpool, for kindly allow-

ing reproduction of the MRI images.


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