Hypothalamic Obesity

Learn about the prevalence, associated factors, mechanism of disease, and clinical manifestations below.

What is Hypothalamic Obesity?

Hypothalamic obesity is a severe acquired form of obesity associated with MC4R pathway impairment.1 It occurs most frequently following surgery or radiotherapy of craniopharyngioma and other suprasellar brain tumors.2,3

Causes of Hypothalamic Obesity (HO)

Estimated prevalence in the US5

aTo estimate the number of patients with incident and prevalent craniopharyngioma and astrocytoma with obesity, Rhythm analyzed the literature and used the number of new cases of each per year in the United States, overall survival rates after a diagnosis of each brain tumor type, and obesity rates among those patients at diagnosis or post-diagnosis.

Factors Associated With Hypothalamic Obesity

Multiple factors have been associated with an increased risk of developing hypothalamic obesity. Most risk factors for hypothalamic obesity that have been explored in studies are related to the impact of surgical approaches to tumor removal, characteristics of the tumor itself, or preoperative patient characteristics associated with weight gain.6,7

Mechanism of Disease

Neoplasms located centrally within the brain frequently impact the hypothalamus, pituitary gland, and optic nerve. Management strategies, including surgical resection of the tumor, can cause hypothalamic injury.7

The biology of hypothalamic obesity is tied to the MC4R pathway. MC4R-expressing hypothalamic neurons regulate appetite, energy expenditure, and glucose homeostasis, consequently affecting body weight.8-13

The damage to the hypothalamus can impair MC4R pathway signaling, leading to increased food intake, hyperphagia (pathological, insatiable hunger), decreased energy expenditure, and rapid-onset obesity.2,4,8-15

Clinical Manifestations

Typical clinical manifestation of hypothalamic obesity can be categorized into several domains with variability in their presentation.3

Only 11.5% of patients report having isolated hypothalamic obesity, while the vast majority experience a variety of comorbidities and other conditions, with pituitary dysfunction being the most common comorbidity (88.5% of respondents).2

Endocrine Dysfunction

Hypopituitarism is often present in patients with hypothalamic obesity as a result of damage to the hypothalamic-pituitary region2,6


Increased parasympathetic activity may lead to hyperinsulinemia. This can occur in response to glucose and lead to efficient, but undesirable, fat storage


Substantial feelings of hunger, which, in combination with impulse disorders, can result in food cravings and overeating

Sleep Disturbances

Decreased nighttime melatonin and increased cortisol concentrations are associated with decreased total sleep time, time of sleep, sleep efficiency, and daytime physical activity and increased frequency of awakening

Visual Impairment

As a result of the close proximity of the hypothalamus, pituitary and optic chiasm, visual disturbance can be present in more than 50% of patients with hypothalamic obesity due to craniopharyngioma

Psychosocial Disorders

Behavioral disturbances (aggressiveness, episodic rage, bursts of unpredictable anger); impaired social, emotional, and neurocognitive functioning; and overall reduced quality of life are often observed

Decreased Energy Expenditure

Decreased sympathetic activity (ie, heart rate, blood pressure, body temperature) can result in overall reduced metabolic activity and decreased physical activity

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  1. Children’s Hospital of Philadelphia. Accessed September 23, 2022. https://www.chop.edu/conditions-diseases/hypothalamic-obesity.
  2. Rose SR, et al. Obesity (Silver Spring). 2018;26(11):1727-1732.
  3. Van Iersel L, et al. Endocr Rev. 2019;40(1):193-235.
  4. Abuzzahab MJ, et al. Horm Res Paediatr. 2019;91(2):128-136.
  5. Rhythm Pharmaceuticals, Inc. Accessed September 23, 2022. https://ir.rhythmtx.com/static-files/86283e4f-3493-4c62-af27-a47ca6eab048.
  6. Bereket A. Horm Res Paediatr. 2020;93(9-10):497-509.
  7. Dimitri P. Front Endocrinol (Lausanne). 2022;13:846880.
  8. da Fonseca ACP, et al. J Diabetes Complications. 2017;31(10):1549-1561.
  9. Yazdi FT, et al. Peer J. 2015;3:e856.
  10. Farooqi IS, O’Rahilly S. Nat Clin Pract Endocrinol Metab. 2008;4(10):569-577.
  11. Baldini GB, Phelan KD. J Endocrinol. 2019;241(1):R1-R33.
  12. Sohn J-W, et al. Cell. 2013;152(3):612-619.
  13. Rossi J, et al. Cell Metab. 2011;13(2):195-204.
  14. Erfurth E-M. Neuroendocrinology. 2020;110(9-10):767-779.
  15. Roth CL. Front Endocrinol (Lausanne). 2011;2:49.
  16. Seo S, et al. Hum Mol Genet. 2009;18(7):1323-1331.

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