When it comes to brain tumors, the three laws of New York real estate prevail: “Location, location, location.” Craniopharyngiomas are problematic less for what they are than for where they are. The hypothalamus, as is true for most hormonal systems, is the anatomic seat of peripheral energy regulation. When the hypothalamus is damaged, a syndrome of intractable weight gain ensues. This syndrome, termed “hypothalamic obesity,” originally described by Babinski (1900) and Frohlich (1901) at the turn of the twentieth century, documents the “organicity” of obesity. Hypothalamic obesity can occur due to the tumor itself, the surgery to extirpate it, or due to subsequent radiation therapy (Bray, 1984; Lustig, 2002). Although this co-morbidity usually manifests in children due to their increased incidence of tumors localized to the posterior fossa (Stahnke et al., 1984; Sorva, 1988; Pinto et al., 2000), adults can also exhibit similar weight gain after completion of therapy (Daousi et al., 2005). Craniopharyngioma accounts for half of the reported cases, with other posterior fossa tumors each contributing smaller numbers. However, the syndrome has also been reported in cases of pseudotumor cerebri, trauma, and infiltrative or inflammatory diseases of the hypothalamus (Bray, 1984).

Hypothalamic obesity can occur in response to any hypothalamic damage. Most studies have been performed in the acute lymphoblastic leukemia (ALL) survivor population (Lustig, 2002; Rogers et al., 2005), in which obesity may be due to several factors, including glucocorticoids and alterations in activity. Nonetheless, the majority of these studies document an abnormal increase in weight for height long after tumor therapy has been discontinued, and many of these studies demonstrate that cranial radiation is an important risk factor (Lustig, 2002).

An extremely high frequency of hypothalamic obesity of 30–77% has been documented after craniopharyngioma treatment (Stahnke et al., 1984; Sorva, 1988; Pinto et al., 2000; Muller, 2008; Vinchon et al., 2009). We analyzed the BMI curves of 148 children with brain tumors who survived longer than 5 years post-therapy, in order to determine risk factors for the development of obesity (Lustig et al., 2003a). We identified four parameters as being predictive. First, those with tumors localized to the hypothalamus or thalamus, along with those originating in the temporal lobe (due to stereoscopic position of the hypothalamus during radiation for this area) gained weight much more rapidly as did those with tumors in the posterior fossa or other hemispheric areas. Secondly, those with tumor histologies prominent in the diencephalon (craniopharyngioma, germinoma, optic glioma, prolactinoma, hypothalamic astrocytoma) also gained weight more rapidly. Third, those with quantitative direct radiation exposure of the hypothalamus of greater than 51 Gy gained excessive weight twice as rapidly after the completion of tumor therapy, even when those with hypothalamic or thalamic locations were removed from the analysis. Lastly, those with some other form of hypothalamic endocrinopathy (i.e., GH deficiency, hypothyroidism, precocious or delayed puberty, ACTH deficiency, diabetes insipidus) exhibited a BMI curve with a steeper upward slope. Thus, each significant risk factor was either linked to hypothalamic location, damage, or dysfunction. Factors not associated with obesity after tumor therapy included hydrocephalus, initial high-dose glucocorticoids, and peripheral or intrathecal chemotherapy.

More recently, Müller et al. (2011) respectively evaluated the long-term outcome data on the Kraniopharyngeom database in Germany. In this analysis, pre-operative hypothalamic involvement was specifically implicated in the development of post-operative hypothalamic obesity, suggesting again that tumor location is the most important risk factor for obesity.

Animal studies elaborating the negative feedback energy balance pathway have predicted the pathogenesis and symptomatology of hypothalamic obesity. This can best be described as “organic leptin resistance”; that is, a failure in leptin signaling in the afferent arm, due to hypothalamic damage; leading to autonomic dysfunction in the efferent arm, promoting inadequate energy expenditure, and excessive energy storage.

Rat models of hypothalamic damage, either due to bilateral electrolytic lesions or deafferentation of the VMH, lead to intractable weight gain (Berthoud and Jeanrenaud, 1979; Rohner-Jeanrenaud and Jeanrenaud, 1980; Bray et al., 1981; Jeanrenaud, 1985; Satoh et al., 1997), even upon food restriction (Bray and Nishizawa, 1978). Similarly, children with hypothalamic obesity exhibit weight gain, even in response to forced caloric restriction (Bray and Gallagher, 1975). This seems paradoxical, as one would expect that if hyperphagia were the reason for the obesity, then caloric restriction would be effective in preventing further weight gain. In fact, analysis of energy intake in children with hypothalamic obesity demonstrates no difference vs. control patients with simple obesity (Harz et al., 2003). Instead, both resting energy expenditure (Shaikh et al., 2008) and voluntary energy expenditure (Harz et al., 2003) is severely compromised in these patients. Indeed, the most prominent and concerning complaint in patients with hypothalamic obesity is the persistent fatigue, lack of energy, and lack of physical activity. This generalized malaise is not due to hypopituitarism, as it persists even after full hormonal replacement.

The decrease in energy expenditure is mediated through suppression of SNS activity by the hypothalamic damage. Recent reports demonstrate an impaired ability of such patients to mount an epinephrine response to insulin-induced hypoglycemia (Schofl et al., 2002; Coutant et al., 2003), and document decreased 24-h epinephrine excretion (Coutant et al., 2003), along with decreased urinary homovanillic acid and vanillylmandelic acid (Roth et al., 2007); all pointing to decreased sympathetic tone. It is thought that this malaise and decrease in sympathetic tone may account for decreased rates of lipolysis through the adipocyte β₃-adrenergic receptor (al-Adsani et al., 1997), which results in decreased resting and voluntary energy expenditure.

In addition to “organic leptin resistance,” it is possible that such patients also manifest “organic ghrelin resistance,” in that ghrelin’s suppression of hunger may be attenuated in children with hypothalamic obesity (O’Gorman et al., 2911). This may increase total food intake; although alterations in total food intake in these patients is not different from otherwise healthy obese controls (Harz et al., 2003).

A retrospective analysis of growth records of children with craniopharyngioma (Muller et al., 2004) indicates that increased weight and BMI gain is evident even before the diagnosis of the tumor. However, after surgery or radiotherapy, the weight gain is immediate, rapid, and highly exaggerated. Evidence of aberrant energy deposition is obvious within the first month. Physicians sometimes confuse this weight gain with glucocorticoid effect, and reduce the dose of maintenance hydrocortisone, which does not impact the obesity, and renders the patient with even more fatigue and malaise.

Children with hypothalamic obesity frequently have normal fasting insulin levels, especially during the rapid weight gain phase. It is important that such metabolic testing be dynamic, as the phenomenon that distinguishes hypothalamic obesity is insulin hypersecretion, not insulin resistance, and so may not be obvious with a fasting insulin level. In addition, stimulation of the alimentary tract so as to activate the vagal efferent component of insulin secretion is required to document the effect. Two sets of studies on insulin dynamics demonstrate insulin hypersecretion (as measured by an increased Corrected Insulin Response, or CIR; Sluiter et al., 1976) on oral glucose tolerance testing (OGTT); and surprisingly these patients also have insulin sensitivity (as measured by an increased Composite Insulin Sensitivity Index (Matsuda and DeFronzo, 1999) within the normal range, and certainly better than BMI-matched healthy obese children (Preeyasombat et al., 2005; Simoneau-Roy et al., 2010; Figure 3). However, other studies suggest that some hypothalamic obesity patients may also manifest signs of metabolic syndrome (Tiosano et al., 2003; Srinivasan et al., 2004). These patients may also have an increased incidence of obstructive sleep apnea, which may predispose them to the co-morbidities of the metabolic syndrome (O’Gorman et al., 2010). It is not clear whether those patients with both hypothalamic obesity and metabolic syndrome represent a subgroup, or a different pathogenetic phenomenon entirely, or just the late evolution of their morbid obesity. A retrospective evaluation suggests that the degree of hypothalamic involvement of the tumor at its presentation predicts the degree of metabolic disturbance (Müller et al., 2011), though mechanisms for the metabolic alteration are still unclear.

The best treatment is prevention. The hypothalamus is extremely sensitive to both surgical intervention and/or external beam radiation (Lustig et al., 2003a). Rather than employing gross total or subtotal resection as a primary therapy for some posterior fossa tumors, newer strategies have been developed which treat them more conservatively, using stereotactic biopsy and conformal irradiation (Karavitaki et al., 2006; Spoudeas et al., 2006). A retrospective single-institutional followup of craniopharyngioma subjected either to gross total resection or stereotactic surgery and conformal radiation demonstrates equal survival and residual rates of hypopituitarism; however those treated with gross total resection exhibit higher incidences of obesity and neurological complications (Merchant et al., 2002).

Bray demonstrated the futility of lifestyle intervention by noting weight gain even with severe caloric restriction (Bray and Gallagher, 1975). Thus, treatment needs to be early and intensive to have any chance at success. A recent report suggests that intensive lifestyle can reduce the rate of BMI gain by half (from 8.4 kg/m²/year to 4.5 kg/m²/day), but the rate of increase is still quite unacceptable to rely on (Rakhshani et al., 2010).

The hypothalamus interprets afferent signals for energy balance, and transduces them into autonomic efferent signals to either expend or store energy. When this negative feedback system breaks down, as after craniopharyngioma therapy, the phenomenon of hypothalamic obesity ensues. While this disorder is a defect in the afferent pathway, treatment focuses on the efferent pathway, as it is modulable with drugs and surgical techniques that are currently available. Physicians need to explain the risks of this disorder to patients prior to tumor therapy, and must be willing to act quickly and decisively once the intractable weight gain begins, in order to provide intensive management so that the obesity will not get worse.

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.