Biology subjects

Koehl, J.

Publications and source records attributed to Koehl, J..

3 recordsLinked to original sources

bioRxiv2026

C3a receptor signalling in ObRb-expressing neurons promotes leptin resistance and obesity-associated cardiac remodelling

Obesity is associated with hypothalamic inflammation, leptin resistance and increased cardiometabolic risk, but the neuroimmune signals linking nutrient excess to these outcomes remain incompletely defined. Here we show that diet-induced obesity is accompanied by local complement activation in the mouse hypothalamus, leading to C3a generation that signals through C3a receptor (C3aR) on leptin receptor (ObRb)-expressing neurons and blunts leptin signaling. Deletion of C3aR in ObRb-expressing neurons preserves leptin responsiveness, reduces food intake and weight gain, and improves glucose homeostasis during dietary challenge. Systemic pharmacological C3aR targeting induces weight loss and improves leptin responsiveness in established obesity. Genetic or pharmacological C3aR targeting also attenuates obesity-associated diastolic dysfunction and myocardial fibrosis; pair-feeding experiments reveal an additional component of cardiac protection beyond reduced weight gain, associated with lower cardiac sympathetic innervation. In humans, circulating complement activation markers are elevated in obesity and decline after bariatric surgery. Together, our findings identify C3aR signaling in ObRb-expressing neurons as a neuroimmune pathway contributing to hypothalamic leptin resistance and obesity-associated cardiac remodeling, highlighting complement signaling as a potential therapeutic target in cardiometabolic disease.

immunology↗

bioRxiv2026

Complement 3a Receptor mediates high fat diet induced hypothalamic accumulation of lipid associated microglia to regulate neuroinflammation and obesity

Microglia, the resident macrophages of the central nervous system, are recognized for their heterogeneity and integral role in brain function and diseases. In the context of high fat diet (HFD) feeding and obesity, microglia become overactive, acquiring a prevailing lipid associated microglial phenotype (also known as LAM). Yet, how microgliosis is induced and regulated remains unclear. Here we report a key role for the Complement 3a Receptor (C3aR), on HFD-induced hypothalamic gliosis and weight gain in mice. HFD consumption leads to elevated microglial expression of C3aR, which parallels widespread accumulation of reactive microglia, selectively in the hypothalamus. Conditional microglial C3aR deletion protects mice from HFD-induced hypothalamic reactive microgliosis. C3aR deletion or pharmacological antagonism opposes HFD-induced weight gain in male but not female mice. Mechanistically, we demonstrated that C3aR is essential for lipid-induced lipid droplet formation, and acquisition of a LAM molecular signature. In summary, we uncovered a previously unknown role for C3aR in the acquisition of a LAM signature driving diet-induced gliosis, identifying this receptor as a new viable therapeutic candidate for conditions associated with hypothalamic neuroinflammation.

immunology↗

bioRxiv2022

Complement receptor C5aR1 signaling in sensory neuron-associated macrophages drives neuropathic pain

Neuroimmune interactions across the pain pathway play a predominant role in the development of neuropathic pain. Previous reports demonstrated that complement driven effector systems including the C5a/C5aR1 axis contribute to these neuro-immune mechanisms. However, the cellular and molecular mechanisms underlying C5a/C5aR1 signaling-mediated neuropathic pain development remain ill-identified. Here we show that neuropathic pain following peripheral nerve injury was attenuated in C5aR1-deficient male and female mice as well as in wild type mice treated with a selective allosteric C5aR1 antagonist. Using two complementary cell-specific C5aR1 knockout mouse strains, we identified C5a/C5aR1 driven-activation of sensory neuron-associated macrophages (sNAMs) located in the sensory ganglia as the key site of peripheral nerve injury-induced neuropathic pain, whereas activation of macrophages of the local of peripheral nerve injury was not involved. Mechanistically, we uncovered IL-1b the main mediator of pain hypersensitivity in response to C5aR1 signaling in sNAMs. Our findings highlight a crucial role of C5a/C5aR1 axis activation in sNAMs for the development of neuropathic pain and identify this pathway as a promising novel target for neuropathic pain therapy.

pharmacology and toxicology↗