Function of the antimicrobial peptide cathelicidin (CAMP) in context of obesity and biology of adipocytes

• Applicant: Dr. Alexandra Höpfinger
• Subject Area: Endocrinology, Diabetology, Metabolism ; Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 497565841

The aim of this research project is to elucidate the physiology and pathophysiology of the adipokine cathelicidin in endocrine, autocrine, and paracrine contexts. In basic scientific approaches we apply cell culture techniques and a transgenic mouse model. Human samples (adipose tissue specimens and blood serum) will be applied for clinical issues with translational perspectives.Cathelicidin plays an important role in the innate immune system because it has both antibacterial and antiviral properties and exerts chemotactic and immunomodulatory effects. Its regulation is linked to TLR-mediated processes. According to the latest findings, cathelicidin is secreted by adipocytes and is therefore a newly identified adipokine. As shown in our preliminary work, there is a connection between TLR activation and cathelicidin expression in adipocytes. The underlying signaling pathways are in the focus of the present research project in order to characterize function and mechanisms of cathelicidin action in adipose tissue inflammation.In vitro, the effects of metabolic and inflammatory stimuli (with a focus on TLRs) on the expression and secretion of cathelicidin are investigated on murine and human adipocytes. The aim is to gain knowledge about the regulation of cathelicidin expression and secretion. By stimulation of adipocytes with cathelicidin, its paracrine and autocrine mode of action in adipose tissue inflammation as well as mechanistic knowledge about the signaling pathways involved will be revealed. Transgenic TLR9 knockout mice will be applied due to previous data on detection of DAMPs (DNA fragments and nuclear proteins as damage-associated molecular patterns) derived from necrotic adipocytes and vascular cells. Moreover, a specific regulatory and inflammatory role of intracellular TLR9 in adipocytes has recently been published in our study group.An intense crosstalk between adipocytes and macrophages exists in adipose tissue, with cathelicidin putatively playing an essential role within these complex interactions. As an adipokine and peptide of the innate immune system, it is affected by both metabolic and inflammatory signals.Primary human adipocytes are being obtained from adipose tissue of severely obese patients (BMI > 40 kg/m2). By comparing gene expression and protein secretion patterns of primary adipocytes derived from obese and normal-weight individuals, metabolically induced chronic changes in adipocytes in obesity – especially regarding immuno-regulatory processes and cathelicidin functions – can be characterized in detail.With the mechanisms of metaflammation providing a significant translational potential for the treatment of obesity, T2D, and insulin resistance, elucidation of cathelicidin’s role in this context opens an innovative and highly relevant field of research.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Andreas Schmid