Schwartz Group – University of Copenhagen

Schwartz Group

Metabolite Receptology

The research focus has gradually over the last five years changed from Enteroendocrinology to Metabolite Receptology, although control of gut hormone secretion by nutrient metabolites and their receptors and the signaling of gut hormones through in particular afferent vagal mechanisms still is an important part of our research.

Metabolite Receptology - In addition to their bioenergetic intracellular function, a number of classical metabolites act also as extracellular signaling molecules activating cell surface G-protein coupled receptors (GPCRs), similar to hormones and neurotransmitters.

‘Signaling metabolites’ generated from nutrients and by gut microbiota in large numbers and amounts are absorbed from the gut lumen, and target primarily enteroendocrine, neuronal and immune cells in the lamina propria of the gut mucosa, and by way of the portal vein also the liver. Obesity is associated with decreased intestinal barrier function and accordingly increased exposure of cells in the gut mucosa and the rest of the body to gut microbiota-derived signaling metabolites as well as LPS and other bacterial components.

Endogenous circulating metabolites such as beta-hydroxy-butyrate function not only as exchangeable energy sources between tissues but also as signaling molecules controlling for example immune cell function through specific GPCRs.

Importantly a number of intracellular intermediary metabolism metabolites, such as acetate and succinate, act as metabolic stress-induced signals. An important theme of our research is that such intermediary metabolism derived metabolites act mainly locally in both autocrine feedback mechanisms -controlling the function of the metabolic or endocrine cells themselves – and paracrine mechanisms controlling the function of neighboring cells, such as stellate cells in the liver.

Importantly, these signaling metabolites also target GPCRs on tissue-resident innate and adaptive immune cells and a favorite notion is that stress-induced signaling metabolites may function as important paracrine regulators or drivers of the low grade inflammation associated with obesity and insulin resistance. 

Based on our background in molecular pharmacology and extensive collaborations and research alliances with biotech and pharmaceutical companies as well as academic medicinal chemistry groups, pharmacological tool compounds and drug candidates constitute key elements of our research which covers from basic in vitro signal transduction over a large number of ex vivo models to in vivo models including a large number of genetic models.

We believe that metabolite GPCRs constitute a highly interesting almost untapped pharmacotherapeutic potential through which novel means to control metabolic and endocrine cell function, and importantly to address metabolic inflammation to treat obesity and type 2 diabetes, can be developed.