Mechanisms of the pro-lipolytic and anti-obesity effects of the VGF-derived peptide TLQP-21

Abstract

Obesity is a major public health problem; in the U.S. nearly one third of the population is obese. The adipose tissue is innervated by the sympathetic nervous system (SNS), which regulates fat mass by playing a key role in initiating lipolysis and regulating lipid mobilization. TLQP-21, a 21 amino acid peptide encoded by the pre-pro-peptide VGF (non acronymic) expressed in the brain and sympathetic neurons innervating the adipose organ. Complement 3a receptor 1, C3aR1, is the target receptor for TLQP-21. Based on previous finding where peripheral TLQP-21 decreases adipocyte diameter and enhance β-adrenergic receptors (β-ARs) lipolysis in adipocytes the hypothesis tested in my thesis is that C3aR1 and β-ARs are required for TLQP-21 anti-obesity effects and the pro-lipolytic effects are mediated by increased mobilization of [Ca2+]i. Departing from the first experimental structural analysis of TLQP-21 in solution and receptor-bound state, we tested our hypothesis using a combined in vitro and in vivo approach. Using 3T3L1 cells and pre-adipocytes as our in vitro model, we determined that TLQP-21 enhances lipolysis via increased intracellular Ca2+ concentration [Ca2+]i, and activation of the MAPK/ERK pathway. The physiological effects of TLQP-21 were investigated in vivo using wild type, β-less (β1, β2, β3-AR KO) and C3aR1 KO mice. Chronic TLQP-21 treatment in obese wild type mice significantly decreased body weight and fat mass promoting an overall healthier metabolic phenotype. Conversely β-less and C3aR1 KO resulted fully resistant to the anti-obesity effects. Herein we identified the mechanism of TLQP-21 pro-lipolytic and anti-obesity effect and could thus be regarded as a novel target for pharmacotherapies of obesity.