Progress in drug therapy for hypothalamic obesity

doi:10.16352/j.issn.1001-6325.2024.05.0729

Abstract

Abstract: Hypothalamic obesity (HO) is a complicated and uncommon disease affecting multiple regulatory pathways of energy intake and metabolism in the brain, regulation of the autonomic nervous system and peripheral hormonal signaling. Currently, drug treatment mainly involves stimulating sympathetic nerve excitation and fat tissue thermogenesis, thereby inhibiting rapid weight gain by increasing fat breakdown and energy consumption. In addition, some drugs can also act on the reward center of the brain to inhibit excessive food intake in HO patients. This article systematically introduces the clinical benefit data, adverse reactions, and application prospects of newly developed drugs such as oxytocin (OXT), phentermine and topiramate(Ph/T), tesofensine, setmelanotide, etc.

Key words: obesity, brain tumor, hypothalamic injury, energy homeostasis, drug intervention

CLC Number:

R589.2

ZHANG Liyuan, DU Hanze, PAN Hui. Progress in drug therapy for hypothalamic obesity[J]. Basic & Clinical Medicine, 2024, 44(5): 729-732.

References

[1] Lee M, Park MJ, Lee KH, et al. Obesity mechanism after hypothalamic damage: cohort analysis of neuroimaging, psychological, cognitive, and clinical phenotyping data[J]. Front Endocrinol (Lausanne), 2023, 14: 1114409. doi:10.3389/fendo.2023.1114409.
[2] Miao Y, Fan K, Peng X, et al. Postoperative hypothalamic-pituitary dysfunction and long-term hormone replacement in patients with childhood-onset craniopharyngioma[J]. Front Endocrinol (Lausanne), 2023, 14:1241145. doi:10.3389/fendo.2023.1241145.
[3] van Schaik J, Welling MS, de Groot CJ, et al. Dextroamphetamine treatment in children with hypothalamic obesity[J]. Front Endocrinol (Lausanne), 2022, 13:845937. doi:10.3389/fendo.2022.845937.
[4] Rydin AA, Severn C, Pyle L, et al. Novel clinical algorithm for hypothalamic obesity in youth with brain tumours and factors associated with excess weight gain[J]. Pediatr Obes, 2022, 17: e12903. doi:10.1111/ijpo.12903.
[5] Kerem L, Lawson EA. The effects of oxytocin on appetite regulation, food intake and metabolism in humans[J]. Int J Mol Sci, 2021, 22: 7737. doi:10.3390/ijms22147737.
[6] Hsu EA, Miller JL, Perez FA, et al. Oxytocin and naltrexone successfully treat hypothalamic obesity in a boy post-craniopharyngioma resection[J]. J Clin Endocrinol Metab, 2017, 103: 370-375. doi:10.1210/jc.2017-02080.
[7] McCormack SE, Wang Z, Wade KL, et al. A pilot randomized clinical trial of intranasal oxytocin to promote weight loss in individuals with hypothalamic obesity[J]. J Endocr Soc, 2023, 7: 1-16. doi:10.1210/jendso/bvad037.
[8] Hsia DS, Gosselin NH, Williams J, et al. A randomized, double-blind, placebo-controlled, pharmacokinetic and pharmacodynamic study of a fixed-dose combination of phentermine/topiramate in adolescents with obesity[J]. Diabetes Obes Metab, 2020, 22: 480-491. doi:10.1111/dom.13910.
[9] Son JW, Kim S. Comprehensive review of current and upcoming anti-obesity drugs[J]. Diabetes Metab J, 2020, 44: 802-818. doi:10.4093/dmj.2020.0258.
[10] Danielsson P, Janson A, Norgren S, et al. Impact sibutramine therapy in children with hypothalamic obesity or obesity with aggravating syndromes[J]. J Clin Endocrinol Metab, 2007, 92: 4101-4106. doi:10.1210/jc.2007-0826.
[11] Hansen HH, Hansen G, Tang-Christensen M, et al. The novel triple monoamine reuptake inhibitor tesofensine induces sustained weight loss and improves glycemic control in the diet-induced obese rat: comparison to sibutramine and rimonabant[J]. Eur J Pharmacol, 2010, 636: 88-95. doi:10.1016/j.ejphar.2010.03.026.
[12] Huynh K, Klose M, Krogsgaard K, et al. Randomized controlled trial of Tesomet for weight loss in hypothalamic obesity[J]. Eur J Endocrinol, 2022, 186: 687-700. doi:10.1530/EJE-21-0972.
[13] Quarta C, Claret M, Zeltser LM, et al. POMC neuronal heterogeneity in energy balance and beyond: an integrated view[J]. Nat Metab, 2021, 3: 299-308. doi:10.1038/s42255-021-00345-3.
[14] Heyder NA, Kleinau G, Speck D, et al. Structures of active melanocortin-4 receptor Gs-protein complexes with NDP-α-MSH and setmelanotide[J]. Cell Res, 2021, 31: 1176-1189. doi:10.1038/s41422-021-00569-8.
[15] Wei R, Li D, Jia S, et al. MC4R in central and peripheral systems[J]. Adv Biol (Weinh), 2023, 7: e2300035. doi:10.1002/adbi.202300035.
[16] Rossi J, Balthasar N, Olson D, et al. Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis[J]. Cell Metab, 2011, 13:195-204. doi:10.1016/j.cmet.2011.01.010.
[17] Wang Y, Bernard A, Comblain F, et al. Melanocortin 4 receptor signals at the neuronal primary cilium to control food intake and body weight[J]. J Clin Invest, 2021, 131: e142064. doi:10.1172/JCI142064.
[18] Yeo GSH, Chao DHM, Siegert AM, et al. The melanocortin pathway and energy homeostasis: from discovery to obesity therapy[J]. Mol Metab, 2021, 48: 101206. doi:10.1016/j.molmet.2021.101206.
[19] Emet DC, Ozon A, Alikasifoglu A, et al. Alpha-melanocyte-stimulating hormone is elevated in hypothalamic obesity associated with childhood craniopharyngioma[J]. Obesity (Silver Spring), 2021, 29: 402-408. doi:10.1002/oby.23087.
[20] Clement K, van den Akker E, Argente J, et al. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials[J]. Lancet Diabetes Endocrinol, 2020, 8: 960-970. doi:10.1016/S2213-8587(20)30364-8.
[21] Haws R, Brady S, Davis E, et al. Effect of setmelano-tide, a melanocortin-4 receptor agonist, on obesity in Bardet-Biedl syndrome[J]. Diabetes Obes Metab, 2020, 22: 2133-2140. doi:10.1111/dom.14133.
[22] van Santen HM, Denzer C, Müller HL. Could setmelanotide be the game-changer for acquired hypothalamic obesity?[J]. Front Endocrinol (Lausanne), 2024, 14: 1307889. doi:10.3389/fendo.2023.1307889.
[23] Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity[J]. N Engl J Med. 2022, 387: 205-216. doi:10.1056/NEJMoa2206038.
[24] Jastreboff AM, Kaplan LM, Frias JP, et al. Triple hormone-receptor agonist retatrutide for obesity-a phase 2 trial[J]. N Engl J Med. 2023, 389: 514-526. doi:10.1056/NEJMoa2301972.