ESPE Yearbook of Paediatric Endocrinology

Lancet Diabetes Endocrinol. 2025 Jan;13(1):57-68. doi: 10.1016/S2213-8587(24)00283-3. https://pubmed.ncbi.nlm.nih.gov/39547253/Erratum in: Lancet Diabetes Endocrinol 2025 Jan;13(1):e1. doi: 10.1016/S2213-8587(24)00368-1. PMID: 39547253.

Brief Summary: This review covers the pathogenesis, diagnosis and treatment of hypothalamic obesity, and also presents the latest advances and new approaches for the management of these rare forms of obesity.

Perturbation of circuits in the hypothalamus, the primary regulator of body weight and energy homeostasis, can contribute to the development of obesity. Monogenic obesity syndromes, characterized by early onset and severe obesity, impair the function of these circuits. Most genetic variants known to cause monogenic obesity so far affect the leptin-melanocortin pathway [1] The authors describe the hypothalamic control of body weight through the fundamental nuclei and neuronal circuits, as well as other homeostatic systems and non-neuronal pathways. It was also shown that methylation in a variably methylated region in the POMC gene was associated with individual body weight [2]. Hypothalamic obesity mostly develops as a result of acquired causes, central nervous system tumors being the most common reason.

Patients with hypothalamic obesity demonstrate findings such as hyperphagia, diminished sympathetic activity, low metabolic rate and decreased voluntary physical activity. Management of these disorders should comprise multicomponent interventions, involving multidisciplinary teams. Weight reduction through lifestyle intervention is hardly possible. Findings suggest that setmelanotide and new GLP-1 receptor agonists may be effective for weight loss in these patients. Bariatric surgery was shown to be effective and relatively safe in the treatment of patients with obesity and craniopharyngioma [3]. Future research programmes using patient-derived stem cell-based model systems and single-cell methylome studies will elucidate in more detail the pathophysiology and treatment targets of hypothalamic obesity.

References: 1. Mainieri F, La Bella S, Rinaldi M, Chiarelli F. Rare genetic forms of obesity in childhood and adolescence: A narrative review of the main treatment options with a focus on innovative pharmacological therapies. Eur J Pediatr. 2024 Apr;183(4):1499-1508.2. Kühnen P, Handke D, Waterland RA, Hennig BJ, Silver M, Fulford AJ, Dominguez-Salas P, Moore SE, Prentice AM, Spranger J, Hinney A, Hebebrand J, Heppner FL, Walzer L, Grötzinger C, Gromoll J, Wiegand S, Grüters A, Krude H. Interindividual Variation in DNA Methylation at a Putative POMC Metastable Epiallele Is Associated with Obesity. Cell Metab. 2016 Sep 13;24(3):502-509.3. van Santen SS, Wolf P, Kremenevski N, Boguszewski CL, Beiglböck H, Fiocco M, Wijnen M, Wallenius VR, van den Heuvel-Eibrink MM, van der Lely AJ, Johannsson G, Luger A, Krebs M, Buchfelder M, Delhanty PJD, Neggers SJCMM, Olsson DS. Bariatric Surgery for Hypothalamic Obesity in Craniopharyngioma Patients: A Retrospective, Matched Case-Control Study. J Clin Endocrinol Metab. 2021 Oct 21;106(11):e4734-e4745.