ExSec - Is secretin an exerkine? New DFG funding at the Exercise Biology

Exercise is a potent intervention for the prevention and treatment of over 25 chronic diseases, including metabolic, cardiovascular, neoplastic, and mental disorders. The health benefits of exercise are mediated by organ-specific adaptations and the systemic effects of exercise-induced signaling molecules, known as exerkines. Among these, the peptide hormone secretin—historically recognized for its role in pancreatic bicarbonate secretion—has re-emerged as a candidate exerkine with underexplored systemic functions.

Secretin, a 27-amino acid hormone originally discovered in 1902, is now known to be expressed by all enteroendocrine cell types in both mice and humans. Several studies from the 1980s, along with our recent data, demonstrate that circulating secretin levels increase during acute endurance exercise in both humans and mice. This response is absent in unfit individuals and patients with chronic heart failure, suggesting a link between fitness status and secretin responsiveness.

Recent findings from our group and collaborators reveal that secretin activates brown adipose tissue thermogenesis, enhances glucose uptake in skeletal muscle and heart, increases circulating non-esterified fatty acids, and suppresses appetite. These effects are consistent with a role for secretin in coordinating energy mobilization and utilization during states of increased demand, such as exercise. Furthermore, secretin infusion increases cardiac output and myocardial glucose uptake in humans, indicating positive inotropic and metabolic effects on the heart.

Genetic evidence supports the physiological relevance of secretin signaling: a missense variant (rs3731600, p.Ala122Pro) in the secretin receptor gene (SCTR) is associated with type 2 diabetes mellitus in East Asian populations. This suggests that impaired secretin signaling may contribute to metabolic disease susceptibility.

We propose that secretin functions as a catecholamine-like exerkine that supports exercise-induced metabolic and cardiovascular adaptations. Our central hypothesis is that secretin, released during endurance exercise, stimulates lipolysis in adipose tissue and glucose uptake in the heart, thereby enhancing fuel availability and cardiac performance. Understanding the role of secretin in exercise physiology may uncover novel therapeutic targets for metabolic and cardiovascular diseases.

To answer these questions, the research group led by Prof. Henning Wackerhage, in collaboration with Prof. Martin Klingenspor (Chair of Molecular Nutritional Medicine), has received a three-year research grant from the German Research Foundation (DFG).