FGF21-FGFR4 signaling in cardiac remodeling

• Applicant: Dr. Dominik Kentrup
• Subject Area: Cardiology, Angiology ; Endocrinology, Diabetology, Metabolism
• Term: from 2016 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 325760137

Patients with diabetes are considerably more likely to suffer from cardiovascular disease (CVD), and left ventricular hypertrophy (LVH) is an important mechanism of CVD and death in diabetes. The clinical syndrome of progressive cardiac dysfunction caused by the risk-multiplying connections with diabetes has been termed diabetic cardiomyopathy. To date the molecular mechanisms underlying this pathological interrelationship are largely unknown. Fibroblast growth factor (FGF) 21 is an adipokine that is mainly produced by hepatocytes. FGF21 regulates important aspects of nutrient sensing and energy homeostasis primarily in adipose tissue. Under physiological conditions, hepatic and circulating FGF21 levels rise in response to starvation causing an increase in insulin sensitivity and elevated glucose uptake and fatty acid storage in adipocytes. FGF21 lowers circulating and hepatic triglyceride and cholesterol concentrations, reduces blood glucose levels, causes weight loss and increases life span. FGF21 effects are mediated by FGF receptors (FGFR) that in mammals exist in four isoforms (FGFR1-4). In complex with its co-receptor beta-klotho, FGF21 binds FGFR1, 2 and 3, but not FGFR4, and thereby induces Ras/mitogen-activated protein kinase (MAPK) signaling and downstream effects in adipocytes. Serum FGF21 levels are elevated in animal models and in patients with type 2 diabetes. However, as beat-klotho expression is reduced in diabetes, FGF21 cannot fulfill its metabolic functions and diabetic patients are assumed to be resistant to the physiologic effects of FGF21.In our recent studies of cardiac injury in chronic kidney disease (CKD), we found that FGF23, a bone-derived, phosphate-regulating hormone, can induce cardiac hypertrophy in vitro and in vivo. We could show that this effect is mediated by FGFR4 but does not require alpha-klotho, which is the FGF23 co-receptor in the kidney that is not expressed in the heart. Since the heart does not express beta-klotho, it has been assumed that FGF21 cannot directly affect cardiac function and induce cardiac injury. However, we propose that like FGF23, FGF21 can directly target cardiac myocytes in a klotho-independent manner and regulate cardiac remodeling.We hypothesize that FGF21-mediated activation of FGFR4 in cardiac myocytes induces LVH in diabetes. Therefore, in diabetic patients elevated FGF21 might not only have beneficial and compensatory effects, but may also be causatively linked to the development of diabetic cardiomyopathy.Our specific aims for this project are:Aim 1: Identify the cardiac FGF21 receptor and downstream signaling events in vitro.Aim 2: Determine if FGF21 induces LVH via FGFR4 in vivo.Aim 3: Study if FGFR4 blockade attenuates cardiac injury in diabetic mice.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Christian Faul