Path4HCPs

The hypothalamic MC4R pathway

The hypothalamus

The hypothalamus is an important region of the brain that controls diverse neuroendocrine functions, including regulation of energy balance, appetite, and body weight.^1,2

It is a collection of interconnected nuclei located in the suprasellar region of the brain above the pituitary gland that controls:^3,4

Sleep, arousal, and circadian rhythms
Fatigue
Thermoregulation
Thirst, salt, and water balance
Energy balance through the melanocortin-4 receptor pathway

What is the melanocortin-4
receptor pathway?

The melanocortin-4 receptor (MC4R) pathway in the hypothalamus is a key signalling pathway responsible for regulating hunger, food [caloric] intake, and energy expenditure, which consequently affects body weight.^5–7

Proper regulation of appetite requires sufficient levels of α-melanocyte-stimulating hormone (α-MSH) that activate MC4R neurons, triggering a reduction in hunger and concomitant increase in energy expenditure.^8,9,10

1
The MC4R pathway plays a key role in regulating satiety signalling, which involves neural activation within the hypothalamic region of the brain in response to leptin release from adipose tissue.
2
Proper regulation of satiety signalling requires sufficient levels of the neuropeptide alpha-melanocyte stimulating hormone (α-MSH), which binds to the MC4R.
3
MC4R activation by α-MSH controls satiety, food intake, and energy expenditure, all of which contribute to the regulation of body weight/composition.

Disruption of the
MC4R pathway

Rare hypothalamic MC4R pathway diseases can arise following physical injury or structural abnormality of the hypothalamus with MC4R pathway disruption and other functional impairment, or due to rare genetic variants directly disrupting the MC4R pathway.¹¹

Disruption of the MC4R pathway may lead to decreased α-MSH production, impairing MC4R signalling and resulting in hyperphagia (pathological, insatiable hunger), decreased energy expenditure and significantly increased body weight, the key clinical features observed in patients with these diseases.^11-13

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Acquired hypothalamic obesity

Acquired hypothalamic obesity (aHO) is an accelerated and sustained weight gain resulting from physical injury or structural abnormality of the hypothalamus with MC4R pathway disruption and other hypothalamic functional impairment.¹⁴

This disruption of the MC4R pathway decreases the production of alpha melanocyte-stimulating hormone (α-MSH) and can potentially lead to aHO, which is associated with hyperphagia and decreased energy expenditure.^11-14

Causes of aHO

Craniopharyngioma’s (CP) are rare, benign brain tumours of the sellar/parasellar area that start from epithelial cells of the Rathke’s pouch and craniopharyngeal duct. Given their proximity to the hypothalamic-pituitary axis, CP’s, although benign, can affect the hypothalamus leading to direct damage and causing aHO.^15,16

CP treatment includes surgery and/or radiotherapy, both of which are risk factors for hypothalamic functional damage that could lead to aHO.^15,17-19

Inflammation
Prolonged activation of inflammatory processes in the hypothalamus can lead to apoptosis of pro-opiomelanocortin (POMC) neurons and may lead to a dysregulation in energy homeostasis and resulting in aHO.²⁵

Infection
Intercranial viral infection has been shown to cause degeneration of hypothalamic neurons which may lead to continuous weight gain over 3 to 4 months, suggesting aHO.²⁶

Stroke
Vascular insults, such as stroke, can lead to hyperphagia and aHO through hypothalamic injury.^20,27

Rare genetic variants directly disrupting the MC4R pathway: Syndromic and monogenic diseases

In syndromic and monogenic diseases, MC4R pathway signalling can be disrupted due to genetic variants upstream of the MC4R, leading to hyperphagia and early-onset obesity.^7,12,30

Genetic causes

In complex syndromic diseases, such as Bardet-Biedl syndrome (BBS), MC4R pathway signalling is disrupted by genetic variants, where hyperphagia and early-onset obesity are often accompanied by neurodevelopmental delay or dysmorphic features, and organ-specific developmental abnormalities.^12,30

Variants in at least 26 BBS genes and 4 modifier genes have been identified to disrupt LEPR signalling and subsequent activation of downstream MC4R-expressing neurons, potentially leading to hyperphagia and early-onset obesity.³¹

Learn more about:

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BBS and rod-cone dystrophy

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References:

1.
Farooqi IS. Biol Psychiatry. 2022;91(10):856–59
2.
Yeo GSH, et al. Mol Metab. 2021;48:101206
3.
Van Santen HM, et al. Eur J Endocrinol. 2023;188:10.1093/ejendo/lvad009
4.
Waterson MJ, and Horvath TL. Cell Metab. 2015;22:962–970
5.
Krashes MJ, et al. Nat Neurosci. 2016;19(2):206–19
6.
Cone RD. Endocr Rev. 2006;27(7):736–49
7.
Loos RJF and Yeo GSH. Nat Rev Gens. 2022;23(2):120–133
8.
Van Santen HM. Horm Res Paediatr. 2025:10.1159/000543544
9.
Dimitri P, et al. Front Endocinol. 2022; 13:8468803
10.
Garnett MR, et al. Orphanet J Rare Dis. 2007;2:10.1186/1750-1172-2-18
11.
Roth CL, et al. Obesity (Silver Spring). 2015;23(6):1226–1233
12.
Hochberg I, et al. Obes Rev. 2010;11:709–721
13.
Roth CL, et al. Diabetes Obes Metab. 2024;26:34–45
14.
Madsen PJ, et al. J Neurosurg Pediatr. 2019;24(3):236–245
15.
Van Santen HM and Muller HL. Endocr Rev. 2025:10.1210/endrev/bnaf025
16.
Ruiz S et al. Eur J Endocrinol. 2022;186(6):R79–R92
17.
Maas AI, et al. Lancet Neurol. 2008;7(8):728–741
18.
Crenn P, et al. Clin Nutr. 2014;33(2):348–353
19.
Mele C, et al. Int J Mol Sci. 2021;22:10.3390/ijms22052686
20.
Jais A and Bruning JC. J Clin Invest. 2017;127:24–32
21.
Goszyonyi G, et al. Brain Structure and Function. 2020;225:1459–1482
22.
Etemadifar M, et al. Care Rep Med. 2012:10.1155/2012/768580
23.
Cerbone M, et al. E Clinical Medicine. 2020;19:100224
24.
Hietamäki J, et al. E Clinical Medicine. 2022;51:101556
25.
Beales PL, et al. Obes Rev. 2025;26:10.1111/obr.13915
26.
Baldini G and Phelan KD. J Endocrinol. 2019;241:R1–R33
27.
Roth et al. Obesity. 2011;19:36-42
28. Fonseca ACP, et al. J Diabetes Complications. 2017;31:1549–1561.
29.
Huvenne H, et al. Obes Facts. 2016;9:158–173
30. Hampl SE, et al. Pediatrics. 2023;151(2).
31. Malhotra S, et al. J Pediatr Genet. 2021;10;194–203
32. Sivasubramanian R. and Malhotra S. Gastroenterol Clin N Am. 2023;52:323–332.
33. Argente J, et al. Lancet Diabetes Endocrinol. 2024;13(1):29–37.
34. Poitou C, et al. Eur J Endocrinol. 2020;183;R149–R166