Characterization of growth differentiation factor 15 (GDF15) as a neurotropic adipokine permeable to the brain

Abstract

Abstract GDF15 (growth/differentiation factor-15) belongs to the superfamily of transforming growth factor-beta. Little is known about adipocytic regulation of GDF15, its concentrations in serum and cerebrospinal fluid (CSF), its permeability to the brain, and its correlation with neurological diseases. This knowledge is important for a potential and clinical role of GDF15 as a mediator of the fat-brain axis in metabolic and neurological diseases. GDF15 mRNA expression in 3T3-L1 adipocytes was measured by qPCR and GDF15 protein levels in supernatants, serum and CSF were determined by ELISA. In vitro, GDF15 expression is nearly absent in pre-adipocytes and strongly upregulated during adipocyte differentiation. Insulin upregulates GDF15 secretion in adipocytes under normo- and hyperglycemic conditions. In vivo, we quantified GDF15 protein concentrations in paired samples of serum and CSF in a large and well-characterized clinical cohort of n = 390 patients undergoing neurological investigation and spinal puncture. This broad data set could serve as a basis for the development of GDF15 reference values in serum and CSF. GDF15 is highly permeable to the brain according to a specific CSF / serum ratio of 306 × 10–3. GDF15 is significantly increased in overweight and type 2 diabetic patients and correlates positively with serum glucose and HbA1c. GDF15 in CSF is elevated in patients with increased CSF cell count and impaired blood–brain-barrier function. Among five subsets of neurological diagnoses, GDF15 is exclusively increased in CSF and serum of patients with infectious diseases. GDF15 represents a promising adipokine and mediator of the fat-brain-axis that is co-regulated with metabolic factors and elevated in neurological patients with infectious diseases.