Defining Acquired Hypothalamic Obesity: An Expert Call for Unified Diagnosis and Therapeutic Action

Acquired hypothalamic obesity (aHO) is a rare, complex, and often devastating disease resulting from loss of satiety signalling and reduced energy expenditure due to physical injury—often related to tumours or their treatment—affecting the mediobasal hypothalamus, in clear contrast with general obesity, which has a multifactorial or polygenic nature 1. Patients with aHO typically present with hyperphagia, accelerated and sustained weight gain, loss of initiative, and fatigue, which are often associated with hypothalamic syndrome and various neuroendocrine deficiencies 1, 2. A key factor in the development of aHO is the disruption of the leptin–proopiomelanocortin/agouti-related peptide–melanocortin-4 receptor (MC4R) pathway. Disruption of this pathway involves impaired leptin sensing, interrupted melanocortin signalling due to reduced production and reduced binding of alpha-melanocyte-stimulating hormone (α-MSH) to MC4Rs. These defects lead to reduced satiety and diminished resting energy expenditure because of altered autonomic output suppressing metabolism, as well as mild hyperinsulinism. Collectively, this combination results in hyperphagia, energy imbalance, and the excessive weight gain that is characteristic of aHO 1, 3-5. While the clinical manifestations of the broader hypothalamic syndrome can vary depending on the underlying aetiology and treatments, the characteristics of aHO are similar regardless of the underlying cause 6. Historically, aHO was described in the context of hypothalamic injury due to lesions, such as craniopharyngioma, low-grade glioma, and other sellar/suprasellar tumours, or surgery and/or radiation to treat those tumours. However, emerging evidence supports a broader aetiological spectrum, including traumatic brain injuries and other injuries to the hypothalamus, such as infectious or inflammatory diseases 1, 7-10. Recent evidence indicates that diverse causes of hypothalamic dysfunction lead to the development of consistent neuroendocrine effects, subsequent aHO, and similar therapeutic needs 8, 9, 11, suggesting a shared mechanism involving loss of hypothalamic regulatory control rather than distinct disease processes caused by the initiating injury or structural abnormality. Despite advances in understanding the neurobiological mechanisms underlying hypothalamic dysfunction, aHO remains under-recognised and inconsistently managed. While aHO may be a well-established disease as a consequence of craniopharyngioma and/or its treatment, in other aetiologies where aHO develops, it may not be readily recognised as such. This gap between growing mechanistic insights into aHO and real-world clinical practice reflects a central challenge in the field. Although patients with aHO share a common pathophysiology across diverse aetiologies, they are frequently evaluated and treated according to the underlying aetiology or managed as if they have general obesity. Given that patients across aetiologies exhibit similar neuroendocrine features, metabolic consequences, and clinical care needs, a unified mechanism-based framework is needed to improve diagnostic accuracy, promote earlier recognition, and harmonise management. As mechanism-driven therapies, including MC4R agonists that correct the loss of α-MSH and restore melanocortin signalling, become more widely available, consistent diagnostic criteria will be needed to ensure appropriate and equitable access to treatment. Therefore, our aim is to provide our expert clinical perspective on aHO as a distinct clinical entity, with the goal of advancing the mechanism-informed therapeutic framework. By collaborating as experts in this field, we seek to align on recommendations for a unified clinical definition, diagnostic criteria, and therapeutic goals for patients with aHO. Our objective is to offer clinicians a clear and practical framework that supports timely diagnosis and coordinated management, in addition to providing a foundation for future research and clinical trials. Under the umbrella of rare neuroendocrine diseases and rare hypothalamic MC4R pathway diseases, aHO shares common causes of physical injury to the hypothalamus that disrupt MC4R pathway signalling and other hypothalamic functions (Figure 1). The International Classification of Diseases, 10th Revision, Clinical Modification (ICD-10-CM) code E88.82 is currently used in some healthcare systems, particularly in North America, to classify obesity due to MC4R pathway diseases. In regions using ICD-10 base version or transitioning to ICD-11, equivalent classification may fall under endocrine/metabolic disorder categories. aHO is not only limited to patients with craniopharyngioma or other sellar/suprasellar tumours, such as low-grade glioma, germ cell tumours and hypothalamic hamartoma; a wide range of injuries to the hypothalamus, including neurosurgery, radiation therapy, traumatic brain injury, and other (micro)injuries (e.g., infection and inflammation), can also result in hypothalamic dysfunction and subsequent aHO (Figure 1). Regardless of the initiating cause, these patient groups converge on similar clinical outcomes, including hyperphagia, reduced energy expenditure and accelerated and sustained weight gain driven by MC4R pathway dysfunction 3-5. Patients with aHO often have multiple hypothalamic and pituitary hormone deficiencies; however, the clinical presentation can vary significantly from one patient to another 12. Evidence from large, claims-based German cohorts demonstrated that patients with tumour/treatment-related aHO, traumatic brain injury-associated aHO, or microinjury-associated aHO demonstrated closely overlapping neuroendocrine profiles, including high rates of central adrenal insufficiency, central hypothyroidism, hypogonadism, growth hormone deficiency and arginine vasopressin deficiency, along with similarly intensive healthcare utilisation over multiple years 2, 8, 9. However, some forms of acquired hypothalamic dysfunction, such as aHO following low-grade glioma, may present initially with normal pituitary function that may later evolve into hypopituitarism 13. Despite different underlying aetiologies, the functional consequences of hypothalamic injury are similar, and there is a persistent need to identify any neuroendocrine dysfunction and for neuroendocrine replacement therapies to be implemented across all cohorts. Recognising this diversity in aetiology is essential for timely diagnosis and appropriate intervention 1. We therefore provide our initial recommendations and considerations for establishing unified diagnostic criteria for aHO (Figure 2). We propose distinguishing between core diagnostic features of aHO and supportive, non-mandatory features. Proposed core features of aHO include (1) documented acquired hypothalamic injury, supported by neuroimaging or neurosurgical history, or clinical hypothalamic dysfunction leading to (2) accelerated and sustained weight gain with hyperphagia or clear change in energy balance associated with the injury. The absence of documented hypothalamic injury, gradual weight gain without linkage, or clinical features consistent with general obesity should prompt reconsideration of the diagnosis. While impaired satiety signaling and reduced energy expenditure provide a biological explanation for the phenotype of aHO, these parameters are not routinely measurable in the clinic and should be considered mechanistic underpinnings rather than diagnostic requirements. Supportive features of aHO may include decreased physical activity, fatigue, loss of initiative, behavioral changes, temperature dysregulation, pituitary hormone deficiencies, and/or mild hyperinsulinemia. Although pituitary hormone deficiencies are common, they are not required for diagnosis, as some patients, such as those treated for low-grade glioma, may initially retain preserved pituitary function 12. Similarly, hyperinsulinaemia alone is not diagnostic of aHO and must be interpreted within the appropriate clinical context. The mild hyperinsulinemia observed in aHO is hypothesised to reflect altered autonomic signalling that affects pancreatic insulin secretion, rather than the peripheral insulin resistance typically responsible for hyperinsulinemia in general obesity 14. While these mechanisms may coexist, careful clinical evaluation is necessary to appropriately interpret hyperinsulinemia in the differential diagnosis. aHO represents a chronic clinical manifestation of hypothalamic dysfunction following physical injury and can be viewed more broadly as a disease of organ dysfunction rather than an aetiologically defined disease. This is analogous to how we conceptualise non-endocrine diseases such as chronic kidney disease or congestive heart failure: the organ dysfunction itself is the dominant clinical and therapeutic concern, and management is guided by the clinical consequences of dysfunction, even when the underlying cause varies (e.g., diabetes, hypertension, or autoimmune disease). Similar to central hypothyroidism, growth hormone deficiency, central hypogonadism, or central adrenal insufficiency, and like the non-endocrine examples described above, we propose that aHO should be recognised as a distinct clinical disease of hypothalamic disruption with consistent clinical features and therapeutic needs. Regardless of the initial cause or aetiology of aHO, we are in agreement that the goals of treatment are consistent: to mitigate hyperphagia and increase energy expenditure in order to achieve weight stabilisation or loss and improve body composition; to reduce cardiovascular risk; to optimise neuroendocrine replacement therapies (recognising that the impaired signalling through the MC4R pathway represents a neuroendocrine deficiency requiring targeted replacement therapy); to address disturbances of circadian rhythm (i.e., sleep); and to enhance psychosocial function, including the drive to engage in daily activities. Management of aHO requires a multidisciplinary approach that includes nutritional and behavioural interventions, psychosocial support, and targeted pharmacologic therapy where appropriate. Together, these interventions are projected to culminate in improved quality of life. aHO is a debilitating disease with profound metabolic and psychosocial consequences. Recognising aHO as a distinct clinical entity, defined by functional hypothalamic disruption rather than solely by aetiology, is essential for advancing research, improving diagnosis and care, and expanding access to emerging therapies. We advocate for a patient-first approach that prioritises clinical presentation and functional impairment over aetiological classification to further advance the therapeutic framework by collaborating and aligning on disease definition, diagnostic criteria, and therapeutic goals for patients with aHO. Such a unified framework may facilitate standardised diagnostic criteria, enable broader inclusion in clinical trials, support equitable access to emerging therapies, and ultimately lead to better outcomes for patients living with aHO 2, 6, 15, 16. Importantly, clinical development programmes should reflect the unified nature of aHO, encompassing patients across different aetiologies to ensure generalisability of results and access to treatment. All authors contributed to the conceptualisation, interpretation, drafting of this manuscript and critical review for important intellectual content. All authors approved the submission. Medical writing and editorial assistance were provided by Maggie Tarrio Watson, Ph.D., funded by Rhythm Pharmaceuticals Inc. according to the Good Publication Policy guidelines. The work was supported by Rhythm Pharmaceuticals is a pharmaceutical company. The authors have nothing to report. Hanneke M. van Santen is a local primary investigator of clinical trials funded by Rhythm Pharmaceuticals Inc.; has received funding from Novo Nordisk, Pfizer, and Rhythm Pharmaceuticals Inc. for the organisation of the ESPE Science Symposium and 6th Craniopharyngioma Post-graduate Course; has received reimbursement for travel expenses for scientific meetings from Rhythm Pharmaceuticals Inc.; and has received funding for research projects from Pfizer and Rhythm Pharmaceuticals Inc. Ashley H. Shoemaker has received institutional funding for clinical trials sponsored by Aardvark Therapeutics, Eli Lilly, Novo Nordisk, Rhythm Pharmaceuticals Inc., and Soleno Therapeutics; and has received consulting honoraria from Rhythm Pharmaceuticals Inc. and Soleno Therapeutics. Mehul T. Dattani is a local primary investigator of clinical trials funded by Rhythm Pharmaceuticals Inc.; has received lecture fees from Neurocrine and Novo Nordisk; and has received consulting fees from Besins Healthcare, Pfizer, and Sandoz. Christian L. Roth is supported by grants from the National Institutes of Health (award numbers R21HD115119, R01DK135125, R01DK098466, and R01DK135211); has received clinical trial funding from, and serves on the advisory board of Rhythm Pharmaceuticals Inc. Mohamad Maghnie has received grant support from Merck Serono, Novo Nordisk, Pfizer, and Rhythm Pharmaceuticals Inc.; has received consulting fees and payment or honoraria for lectures, presentations, speaker's bureaus, manuscript writing or educational events from BioMarin, Merck Serono, Novo Nordisk, Pfizer, Rhythm Pharmaceuticals Inc., and Sandoz; and has participated on a data safety monitoring board or advisory board for Pfizer. Kevin C. J. Yuen has received institutional funding for clinical trials sponsored by Ascendis Pharma, Corcept Therapeutics, Novo Nordisk, and Sparrow; and has received consulting honoraria from Ascendis, Camurus, Chiesi, Crinetics, Neurocrine, Novo Nordisk, Corcept, Recordati, and Rhythm Pharmaceuticals Inc. Christine Poitou received compensation for participation in advisory boards and conferences organised by Rhythm Pharmaceuticals Inc. Hermann L. Müller has received reimbursement for scientific meetings (participation and travel expenses) and honoraria from Rhythm Pharmaceuticals Inc.; and is supported for the KRANIOPHARYNGEOM studies by a grant from the German Childhood Cancer Foundation, Bonn, Germany (H.L.M., DKS2014.13). Data sharing not applicable to this article as no datasets were generated or analysed for this publication. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.70725.