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The TLQP‐21 neuropeptide and the complement 3a receptor (C3aR1) regulate a novel prolipolytic pathway

Obesity results in fat mass accumulation and is associated with serious comorbidities such as type 2 diabetes and cardiovascular disease. Targeting excess fat by lipolysis has been a major challenge due to side effects. TLQP‐21, a neuropeptide encoded by the pro‐peptide VGF (nonacronymic), that binds the complement 3a receptor 1 (C3aR1) on the adipocyte membrane, is emerging as a novel modulator of adipocyte functions and a potential target for obesity. However, the molecular mechanism is still largely uncharacterized. In current study, we aim to understand the role of C3aR1 in murine, human adipocytes and in vivo in diet‐induced obese mice. In vitro experiments using loss and gain of function approaches in 3T3‐L1 adipocytes demonstrate that C3aR1 knockdown prevents TLQP‐21‐induced prolipolytic response. Likewise, TLQP‐21 treatment decreases body weight and fat mass in diet induced obese mice by a mechanism requiring C3aR1 activation. Finally, we demonstrate that this lipolytic pathway is conserved in human adipocytes and can be activated by the rodent but not the human TLQP‐21 peptide, a finding in line with our previous demonstration of a low potency of the human compared to the rodent TLQP‐21 at the human C3aR1 (Cero et al., Structure 2014). In summary, our results identified a novel lipolytic pathway involving TLQP‐21 and C3aR1, a receptor classically studied for its role in innate immunity thus offering a novel target to develop new effective pharmacotherapies for obesity and associated diseases.