ESPEYB15 15 Editor’s Choice New mechanisms: food aversion (1 abstracts)
15.8 Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15
Hsu JY , Crawley S , Chen M , Ayupova DA , Lindhout DA , Higbee J , Kutach A , Joo W , Gao Z , Fu D , To C , Mondal K , Li B , Kekatpure A , Wang M , Laird T , Horner G , Chan J , McEntee M , Lopez M , Lakshminarasimhan D , White A , Wang SP , Yao J , Yie J , Matern H , Solloway M , Haldankar R , Parsons T , Tang J , Shen WD , Alice Chen Y , Tian H & Allan BB
NGM Biopharmaceuticals, South San Francisco, California, USA
To read the full abstract: Nature 2017;550:255-259
Loss of appetite, and even aversion to food, is a common experience during periods of illness (e.g. infection and pyrexia) and/or treatment (e.g. chemotherapy). This responses is distinct from the body’s homeostatic mechanisms (the hypothalamic leptin receptor-AGRP-POMC-MC4R axis), which normally regulate appetite and weight gain in children, or weight maintenance in adults. Previous work identified the brainstem parabrachial nucleus as a mediator of the appetite suppression induced by the anorectic hormones, amylin and cholecystokinin. Here, the authors identify the receptor for GDF15 (also known as macrophage-induced cytokine 1, MIC-1), a member of the TGF-beta superfamily, which shows marked increases in circulatory concentrations during various conditions of stress, illness and inflammation, and which has long been known to suppress food intake in mice. They show that its receptor, GFRAL, is expressed exclusively in the brainstem, and is undetectable in all other regions, including the hypothalamus.
Several other papers high profile have been published in the last 12 months on GDF15 and its receptor. While its role in human body weight regulation remains to be shown, its general relevance in humans has been demonstrated during pregnancy. Hyperemesis gravidarum (HG) is the medical term for the nausea, vomiting and aversion to various foods during the early period of pregnancy when the fetus is most sensitive to chemical teratogens. Petry et al. (1) reported that higher maternal circulating GDF15 levels are associated with pregnancy-related vomiting in humans. Fezjo et al. (2) identified genetic variants at this locus that alter GDF15 expression as being robustly associated with HG. Steve O’Rahilly (3) provides a thoughtful overview of these recent developments, and proposes an evolutionary model for this system of protective food aversion, as an example of ‘allostasis’ (as opposed to ‘homeostasis’).
1. Petry CJ, Ong KK, Burling K, Barker P, Perry JRB, Acerini CL, Hughes IA, Dunger DB, O’Rahilly S. GDF15 Concentrations in Maternal Serum Associated with Vomiting in Pregnancy: the Cambridge Baby Growth Study. (2017). bioRxiv. https://doi.org/10.1101/221267.
2. Fejzo MS, Sazonova OV, Sathirapongsasuti JF, Hallgrimsdottir IB, Vacic V, MacGibbon KW, Schoenberg FP, Mancuso N, Slamon DJ, Mullin PM, 23andMe Research Team. Placenta and appetite genes GDF15 and IGFBP7. Nat Commun 2018;9:1178.
3. O’Rahilly S. GDF15-From Biomarker to Allostatic Hormone. Cell Metab. 2017; 26(6):807-808.
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ESPE Yearbook of Paediatric Endocrinology
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