https://doi.org/10.1007/s00392-024-02526-y
1Universitätsklinikum Schleswig-Holstein Medizinische Klinik II / Kardiologie, Angiologie, Intensivmedizin Lübeck, Deutschland; 2Universitätsklinikum Mannheim GmbH I. Medizinische Klinik Mannheim, Deutschland; 3Universität zu Lübeck Institut für Pharmakologie und Toxikologie Lübeck, Deutschland; 4Universität zu Lübeck Institute for Systemic Inflammation Lübeck, Deutschland; 5Universität zu Lübeck Institute of Cardiogenetics Lübeck, Deutschland
Obesity represents a major risk factor for cardio-metabolic disease. While lipid-mediated hypothalamic inflammation has been implicated in the development of obesity, the role of hypothalamic complement system in dysregulated energy homeostasis is still unclear. As various complement inhibitors are currently being evaluated in preclinical and clinical approaches, we here aim to elucidate the impact of hypothalamic complement activation in metabolic syndrome, paving the way for translational approaches using complement receptor antagonists in cardio-metabolic patients.
Methods
C57BL/6J (WT) mice were treated with the complement receptor C3a (C3aR1) antagonist JR14a or vehicle and fed a high-fat diet (HFD) or a normal diet (chow) for at least 9 weeks (n=5-12). Leptin resistance, insulin resistance and glucose tolerance tests were performed in-vivo at different time points. Hypothalamic mHypoE-46 neuronal-cell line was used to assess the impact of C3a on leptin-mediated release of orexigenic Agouti-related Protein (AgRP) secretion in-vitro. To investigate the novel C3aR1 antagonist JR14a as a potential therapeutic against DIO, mice were fed a HFD over 18 weeks (n=4-5). Subsequently, administration of JR14a was started in one experimental group at week 19 (n=4). Functional tests, such as leptin resistance tests were performed in-vivo at various time points.
Key Results
• Diet-induced obesity (DIO) leads to impaired insulin sensitivity, central leptin resistance and to an increase of hypothalamic C3a and C3b expression (A-E)
• The novel C3aR1 antagonist JR14a protects against DIO and maintains glucose tolerance, insulin sensitivity and hypothalamic leptin sensitivity, as shown by reduced expression of SOCS3 and PTP1B, as well as decreased food intake (F-K)
• C3a diminishes leptin-mediated reduction of orexigenic AgRP secretion by mHypoE-46 cells, while inhibition of C3aR leads to a normalization of leptin signaling (L)
• Therapeutic use of JR14a leads to a significant reduction in body weight despite HFD and improves insulin sensitivity (M-O)
Conclusion and perspective
For the first time we show that DIO is accompanied by hypothalamic complement C3a/C3aR axis activation whereby complement receptor inhibition protects against the development of central leptin resistance and obesity. We are currently verifing these novel findings, by generating a hypothalamus-specific C3aR1 knock-out mice. Our work emphasizes the potential of hypothalamic complement inhibition as a novel therapeutic approach in metabolic syndrome.