https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Schleswig-Holstein Medizinische Klinik II / Kardiologie, Angiologie, Intensivmedizin Lübeck, Deutschland; 2Universitätsklinikum Schleswig-Holstein Institut für Kardiogenetik Lübeck, Deutschland; 3Institute for Systemic Inflammation Research (ISEF) Lübeck, Deutschland
Background
Obesity is a major risk factor for cardiometabolic diseases. Hypothalamic inflammation, such as that mediated by NF-κB signaling, is known to contribute to obesity by disrupting leptin signaling and promoting increased food intake (hyperphagia). However, the role of the hypothalamic complement system, specifically the C5/C5a/C5a receptor 1 (C5aR1) axis, in the development of obesity and its impact on central appetite regulation has not been thoroughly investigated.
Methods
C57BL/6J wild-type (WT), C5 knock-out (C5-KO), and C5aR1 knock-out (C5aR1-KO) mice were fed either a high-fat diet (HFD) or a standard chow diet over a 16-week period (n=11–14 per group). Functional assessments of glucose tolerance, insulin sensitivity, and food intake were conducted at multiple time points, and hypothalamic leptin signaling and inflammatory markers were evaluated using quantitative PCR (qPCR).
Key Results
- The C5aR1-KO and C5-KO result in significantly increased weight gain under HFD. (A)
- This is accompanied by increased gonadal and mesenteric fat mass. (B-C)
- Nonetheless, glucose tolerance in the GTT is better in C5aR1-KO and C5-KO mice than in WT. (D-E) Additionally, in the ITT, C5aR1-KO mice exhibit improved insulin sensitivity. (F)
- At the central level, however, indicators of hypothalamic leptin resistance can be detected, such as increased expression of SOCS3, NPY, C3, and IL-6. (G-J)
- Correspondingly, food intake is increased in C5-KO animals. (K)
Conclusion and perspective
Our findings reveal for the first time that the increased weight gain resulting from disruption of the C5/C5a/C5aR1 axis is linked to hypothalamic leptin resistance, as evidenced by elevated hypothalamic expression of IL6, SOCS3, and NPY. In contrast, at the peripheral level, we observed beneficial effects on insulin metabolism, reflected by improved glucose tolerance and heightened insulin sensitivity in C5aR1-KO and C5-KO mice.
These results underscore the need for therapeutic strategies targeting the complement system in metabolic syndrome to consider blood-brain barrier penetration. Effective approaches should seek to modulate the complement system in a way that balances these distinct and potentially opposing central and peripheral effects. Our future studies employing conditional, hypothalamic- and adipocyte-specific knockouts will be essential to further validate and refine these findings.
Figure 1: Increased weight gain of HFD-fed C5-KO and C5aR1-KO mice (A-C, n=11-14), however, accompanied by improved glucose metabolism (D-E) and insulin sensitivity (F). Hypothalamic (HT) expression of SOCS3 and NPY are increased, indicating central leptin resistance which may be mediated by upregulation of C3 axis (G-J), causing hyperphagia (K).