Hypothalamic Obesity: The Sixth Cranial Endocrinopathy

The hypothalamus is “ground zero” for the neuroendocrine control of five hormonal systems, which are mediated through negative feedback regulation of pituitary hormone release. Energy balance is regulated by a more complex neuroendocrine feedback loop. The hypothalamus integrates peripheral neural and hormonal afferent signals of satiety and energy reserve and directs neuroendocrine efferent arms to effect energy storage versus expenditure; however, in this feedback loop, the pituitary is not integral. Damage to this hypothalamic control system results in a syndrome of intractable weight gain. This syndrome of hypothalamic obesity is usually caused by cranial insult, such as brain trauma, tumor, surgery, or radiation. In some cases, however, it may have a congenital cause. The cause and pathogenesis of obesity in such subjects is akin to an animal model of obesity in which the ventromedial hypothalamus (VMH) is destroyed or deafferented. The VMH-lesioned rat exhibits a vagally mediated potentiation of insulin secretion in response to glucose. Excess insulin secretion favors and promotes partitioning of energy substrate into fat, even with caloric restriction. Similarly, patients with hypothalamic obesity exhibit insulin hypersecretion. By suppressing insulin release at the β cell in a specific manner using the somatostatin agonist octreotide, the shunting of energy substrate to adipose is attenuated. Treated patients exhibit weight loss and improved quality of life, which correlate with insulin suppression. Thus, hypothalamic obesity is the sixth cranial endocrinopathy, with an identifiable cause, pathogenesis, diagnosis, and treatment.