Summary
A bioRxiv preprint reports that C3a receptor signalling in leptin-receptor neurons contributes to leptin resistance and obesity-related cardiac changes in mice. Human measurements of complement markers offer an associated finding, not evidence that targeting the pathway treats obesity in people.
A bioRxiv preprint reports that complement signalling in the hypothalamus contributes to leptin resistance and obesity-associated heart changes in mice. The researchers identify the C3a receptor, or C3aR, on neurons expressing ObRb, the long form of the leptin receptor, as a link between diet-induced obesity and weakened leptin signalling. The preprint also reports elevated circulating complement-activation markers in people with obesity that declined after bariatric surgery.
How the pathway affected leptin signalling
Leptin is a hormone involved in signalling the body’s energy stores to the brain. In the hypothalamus, leptin-receptor neurons help regulate processes including food intake. Leptin resistance describes a reduced response to the hormone’s signals.
In the mouse experiments, diet-induced obesity was accompanied by local activation of the complement system in the hypothalamus and production of C3a, a complement-derived signalling molecule. The authors report that C3a signalling through C3aR on ObRb-expressing neurons blunted leptin signalling.
Removing C3aR from those neurons preserved leptin responsiveness during dietary challenge. The mice also ate less, gained less weight and had better glucose homeostasis. In a separate intervention, systemic pharmacological targeting of C3aR in mice with established obesity induced weight loss and improved leptin responsiveness. These are experimental results in mice, not evidence of treatment efficacy in people.
Links to cardiac changes and human findings
The preprint reports that genetic or pharmacological targeting of C3aR also reduced obesity-associated diastolic dysfunction and myocardial fibrosis in mice. Diastolic dysfunction concerns the heart’s ability to relax and fill between contractions; myocardial fibrosis is the accumulation of scar-like connective tissue in heart muscle.
Pair-feeding experiments indicated that the cardiac protection included a component beyond the effect of reduced weight gain. It was associated with lower cardiac sympathetic innervation, referring to the presence of nerve fibres linked to the sympathetic nervous system. The reported association suggests a possible connection between brain signalling and cardiac remodelling, while the abstract does not establish that the change in innervation caused the heart effects.
In humans, the researchers report higher circulating complement-activation markers in obesity and a decline in those markers after bariatric surgery. This human finding is about biomarkers; the pathway-targeting interventions described in the preprint were conducted in mice. The work is a bioRxiv preprint, so its findings should be read as preliminary research.