Disruption of C5/C5a/C5aR1 Axis Promotes Obesity Accompanied by Hypothalamic Leptin Resistance and Subsequent Increased Food Intake

Background

Obesity is a significant risk factor for cardio-metabolic diseases. Hypothalamic inflammation e.g. through NF-κB signaling is known to contribute to obesity through dysregulated leptin signaling and subsequent hyperphagia. However, the role of the hypothalamic complement C5/C5a/C5a receptor 1 (C5aR1) axis in obesity and its effects on central appetite control have not been investigated yet. As C5aR1 inhibitors are clinically available, our study seeks to clarify the impact of hypothalamic complement C5 axis on metabolic syndrome. 

Methods

C5aR1-KO, C5-KO and C57BL/6J wildtype (WT) mice were fed a high-fat diet (HFD) for 16 weeks (n=24-32). Food intake, insulin resistance and glucose tolerance tests were evaluated in vivo. After the extraction of the hypothalamus at the end of the experiment, the evaluation of the leptin signaling cascade and inflammatory parameters was performed using qPCR.

Key Results

·      The C5aR1-KO and C5-KO result in significantly increased weight gain under HFD (A, B).

·      This is accompanied by increased gonadal and mesenteric fat mass (C, D).

·      Nonetheless, glucose tolerance in the GTT is better in C5aR1-KO and C5-KO mice than in WT. Additionally, in the ITT, C5aR1-KO mice exhibit improved insulin sensitivity (E-H).

·      At the central level, however, indicators of hypothalamic leptin resistance can be detected, such as increased expression of IL6, SOCS3, and NPY (I).

·      Correspondingly, food intake is increased in C5-KO animals (J).

Conclusion

Our findings demonstrate, for the first time, that the increased weight gain observed with the disruption of the C5/C5a/C5aR1 axis is associated with hypothalamic leptin resistance. This is evidenced by the elevated expression of IL6, SOCS3, and NPY in the hypothalamus. Conversely, at the peripheral level, we observed protective effects on insulin metabolism, as indicated by improved glucose tolerance and insulin sensitivity in C5aR1-KO and C5-KO mice.

These results have significant clinical implications. Therapeutic strategies targeting the complement system for the treatment of metabolic syndrome must consider the penetration of the blood-brain barrier. This is crucial because different effects are expected at central and peripheral levels. Effective treatment approaches should, therefore, aim to modulate the complement system in a manner that accounts for these distinct and potentially divergent outcomes.