In a study published yesterday in the Proceedings of the National Academy of Sciences (PNAS), researchers described a new way that the body senses damage and activates hormones in response to stressful situations – involving the protein GDF15. The research was led by investigators from the University of Cambridge and Pfizer, in collaboration with a diverse international team, including scientists from Novo Nordisk A/S in Denmark and the Instituto Gulbenkian Ciência (IGC) in Portugal.
In stressful situations, the body engages in the hormonal stress response – a condition essential for survival. The hormonal stress response is commonly associated with the idea of “fight or flight,” but it also influences how the body fights illness. Knowing that circulating levels of GDF15 rise as part of the stress response and that the protein plays a role in the reduction in appetite that occurs when people are ill, the researchers set out to discover more about how GDF15 influences the production of hormones during stressful states, including illness.
To better understand the relationship between GDF15 and hormone production during stressful situations, the researchers, who included Stephen O’Rahilly, Tony Coll, Debra Rimmington and joint first author Irene Cimino, all based at the Wellcome-MRC Institute of Metabolic Science, exposed mice to various external stimuli to instigate physical stress in the animals. The experiments showed that GDF15 strongly activates the area of the brain that controls how much corticosterone (the mouse equivalent of cortisol, a “stress steroid”) is circulating in the body. Previous studies have shown that increased levels of corticosterone in the blood are essential for surviving severe acute illnesses – and GDF15 appears to be particularly important for communicating the effects of cellular damage and inducing the steroid stress response.
Exposure to stress-inducing stimuli was likely to be a frequent occurrence throughout evolution, so it is not surprising that animals have evolved mechanisms to sense the damage from such stimuli and activate hormonal defence mechanisms in response. Although our work was predominantly undertaken in rodents, there is every reason to believe this system is also operating in humans.
Senior author Stephen O’Rahilly, Director the MRC Metabolic Diseases Unit at the University of Cambridge
The authors suggest that these results are potentially relevant to a range of conditions in which levels of GDF15 are high – including disease states like cancer cachexia, a condition involving loss of appetite, unintentional weight loss, weakness and fatigue that commonly affects people with advanced cancer – and suggest a mechanism for the reported anti-inflammatory properties of GDF15. Because it suppresses food intake, GDF15 is under study by several companies as a possible therapy for obesity. The fact that it turns out to have additional potent actions on the brain’s control of the endocrine system will need to be factored into any plans for its development as a therapy for this indication.
This research study involved scientists from the Universities of Cambridge (with funding from MRC and Wellcome Trust), Newcastle and Lisbon; the Instituto Gulbenkian de Ciência in Oeiras, Portugal; Sunderland Royal Hospital; and biopharmaceutical industry collaborators Pfizer Inc. (Cambridge, Mass., U.S.), Novo Nordisk A/S (Maaloev, Denmark) and Kymab Ltd (Cambridge, U.K.).