Hyperleptinaemia rather than fasting hyperinsulinaemia is associated with obesity following hypothalamic damage in children.

BACKGROUND: Obesity following hypothalamic damage is often severe and resistant to lifestyle changes. Disruption of hypothalamic feedback mechanisms that maintain energy homeostasis may be responsible for this intractable obesity. Adipocytokines including insulin and leptin are also known to be important regulators of appetite and weight. OBJECTIVE: To investigate the role of insulin, leptin, adiponectin and resistin in the aetiology of hypothalamic obesity (HO). DESIGN: This was a cross-sectional study of three groups of children, those with HO, congenital hypopituitarism (CH) and simple obesity (SO). RESULTS: A total of 69 children (HO=28, CH=18, SO=23) had leptin, resistin, adiponectin and insulin measured. Although fasting hyperinsulinaemia and insulin resistance were demonstrated, no differences in insulin or insulin resistance were seen between the groups. The HO group, however, had higher levels of leptin, adiponectin and resistin, which persisted even after adjusting for fat mass, compared with the other groups (P<0.05). CONCLUSION: No differences in fasting hyperinsulinaemia or insulin resistance were seen between the groups; however, leptin levels are elevated, even after adjusting for fat mass, suggesting that an element of leptin resistance is associated with HO. This is consistent with the inability of leptin to act on the hypothalamus, either due to transport across the blood-brain barrier or dysfunctional receptors. The lack of response to leptin may be more important in the development of obesity in these individuals, and the fasting hyperinsulinaemia is a result of the increased adipose tissue rather than the cause of the weight gain.

Reductions in basal metabolic rate and physical activity contribute to hypothalamic obesity.

CONTEXT: Obesity after hypothalamic damage is often severe and resistant to lifestyle changes. It is postulated that differences in basal metabolic rate (BMR) and physical activity may contribute to hypothalamic obesity (HO). OBJECTIVE: Our objective was to investigate the role of energy expenditure, BMR, and physical activity in the etiology of hypothalamic obesity. DESIGN: This was a cross-sectional study of three groups of children: those with HO, congenital hypopituitarism (CH), and simple obesity (SO). RESULTS: A total of 47 children (HO = 18, CH = 13, and SO = 16) had BMR measured, using indirect calorimetry (Deltatrac II). A lower BMR was seen in the HO group, which remained even after adjusting for lean mass. Physical activity, assessed using triaxial accelerometry, demonstrated longer activity periods in the HO group, although the degree of activity was reduced. No significant differences were seen in calorie intake. CONCLUSION: Energy expenditure, rather than energy intake, has a greater role in the development of obesity after cranial tumor therapy. Reductions in BMR and physical activity, leading to a positive energy balance and weight gain despite an age-appropriate calorie intake, may contribute to hypothalamic obesity.

Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans.

The transcription factor SOX2 is expressed most notably in the developing CNS and placodes, where it plays critical roles in embryogenesis. Heterozygous de novo mutations in SOX2 have previously been associated with bilateral anophthalmia/microphthalmia, developmental delay, short stature, and male genital tract abnormalities. Here we investigated the role of Sox2 in murine pituitary development. Mice heterozygous for a targeted disruption of Sox2 did not manifest eye defects, but showed abnormal anterior pituitary development with reduced levels of growth hormone, luteinizing hormone, and thyroid-stimulating hormone. Consequently, we identified 8 individuals (from a cohort of 235 patients) with heterozygous sequence variations in SOX2. Six of these were de novo mutations, predicted to result in truncated protein products, that exhibited partial or complete loss of function (DNA binding, nuclear translocation, or transactivation). Clinical evaluation revealed that, in addition to bilateral eye defects, SOX2 mutations were associated with anterior pituitary hypoplasia and hypogonadotropic hypogonadism, variable defects affecting the corpus callosum and mesial temporal structures, hypothalamic hamartoma, sensorineural hearing loss, and esophageal atresia. Our data show that SOX2 is necessary for the normal development and function of the hypothalamo-pituitary and reproductive axes in both humans and mice.