The neuropeptide TLQP-21 opposes obesity via C3aR1-mediated enhancement of adrenergic-induced lipolysis

Abstract

ObjectivesObesity is characterized by excessive fat mass and is associated with serious diseases such as type 2 diabetes. Targeting excess fat mass by sustained lipolysis has been a major challenge for anti-obesity therapies due to unwanted side effects. TLQP-21, a neuropeptide encoded by the pro-peptide VGF (non-acronymic), 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-associated diseases. The molecular mechanism is still largely uncharacterized.MethodsWe used a combination of pharmacological and genetic gain and loss of function approaches. 3T3-L1 and mature murine adipocytes were used for in vitro experiments. Chronic in vivo experiments were conducted on diet-induced obese wild type, β1, β2, β3-adrenergic receptor (AR) deficient and C3aR1 knockout mice. Acute in vivo lipolysis experiments were conducted on Sprague Dawley rats.ResultsWe demonstrated that TLQP-21 does not possess lipolytic properties per se. Rather, it enhances β-AR activation-induced lipolysis by a mechanism requiring Ca2+ mobilization and ERK activation of Hormone Sensitive Lipase (HSL). TLQP-21 acutely potentiated isoproterenol-induced lipolysis in vivo. Finally, chronic peripheral TLQP-21 treatment decreases body weight and fat mass in diet induced obese mice by a mechanism involving β-adrenergic and C3a receptor activation without associated adverse metabolic effects.ConclusionsIn conclusion, our data identify an alternative pathway modulating lipolysis that could be targeted to diminish fat mass in obesity without the side effects typically observed when using potent pro-lipolytic molecules.

Leptin and brain–adipose crosstalks

“…Overall, these observations indicate that SNS activity decreases leptin expression independently of adiposity, and most likely through activation of β 3 -AR 25–29 , although other receptors may also regulate leptin. Notably, the VGF-derived neuropeptide TLQP21, which is involved in energy balance regulation 60 , might potentiate β 3 -AR-dependent lipolysis through an adipocyte complement 3a receptor 1 (C3aR1)-dependent mechanism 61 ; however, whether TLQP21 also affects leptin production requires further investigation.…”

Multiscale causal network models of Alzheimer’s disease identify VGF as a key regulator of disease

“…In the present study, we extended this approach by taking advantage of three layers of information, integrating genomic, transcriptomic and proteomic data to characterize the molecular association to AD and build predictive network models in order to causally infer relationships among these molecular traits and AD. The The VGF gene we identified and validated is a nerve growth factor and brain-derived neurotrophic factor (BDNF) inducible gene (99) that is expressed in neurons in many different brain regions, and encodes a 615 amino-acid (617 in mouse) long precursor polypeptide (100) that is processed into several bioactive peptides that regulate neuronal activity and survival, neurogenesis, energy balance and lipolysis, and behavior (35,36,(100)(101)(102)(103)(104)(105). Moreover, induction of adult hippocampal neurogenesis in combination with elevation of BDNF levels, which occurs following exercise in rodents, has recently been shown to rescue cognitive deficits in 5xFAD mice (106).…”

Embryonic ablation of neuronal VGF increases energy expenditure and reduces body weight

“…TLQP-21 activates two receptors, the G protein-coupled complement 3a receptor (C3aR1) (Cero et al, 2014; Hannedouche et al, 2013) and the gC1q complement receptor (Chen et al, 2013), and recent data indicate that TLQP-21/C3aR1 is the predominant pathway by which peripheral actions of this peptide on lipolysis are transduced (Cero et al., 2016). Other VGF-derived peptides including TLQP-62, NERP-1, and NERP-2, are likely to act on distinct receptors that remain to be identified.…”

“…VGF signals, at least in part, through the binding of the VGF-derived peptide TLQP-21 to two recently identified receptors, the G-protein coupled C3a complement receptor (Cero et al, 2014; Hannedouche et al, 2013) and/or the gC1q complement receptor (Chen et al, 2013). Recent studies demonstrate that C3aR1 is likely to be the critical TLQP-21 receptor for central and peripheral metabolic regulation, working in concert with beta-adrenergic receptors to regulate lipolysis, body weight and adiposity (Cero et al, 2016). Data further indicate that VGF and the VGF-derived peptide TLQP-21 regulate energy balance by modulating sympathetic outflow to peripheral metabolic tissues (Bartolomucci et al, 2006; Possenti et al., 2012; Watson et al, 2009) through mechanisms that may be mediated by VGF-derived peptides or by the ‘granulogenic’ function of VGF in large dense core vesicles (LDCVs) and the secretory pathway (Fargali et al, 2014).…”