Elsevier

Molecular Metabolism

Volume 6, Issue 1, January 2017, Pages 148-158
Molecular Metabolism

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

https://doi.org/10.1016/j.molmet.2016.10.005Get rights and content
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Highlights

  • TLQP-21/C3aR1 does not possess lipolytic properties per se.

  • TLQP-21 enhances β-AR-induced lipolysis by a mechanism requiring Ca2+ mobilization and ERK activation of HSL.

  • TLQP-21 acutely potentiated isoproterenol-induced lipolysis in vivo.

  • TLQP-21 treatment decreases body weight and fat mass in DIO mice by a mechanism involving β-AR and C3aR activation.

  • TLQP-21 anti-obesity effect is not associated with adverse metabolic effects.

Abstract

Objectives

Obesity 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.

Methods

We 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.

Results

We 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.

Conclusions

In 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.

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Keywords

Adipocyte
Complement 3a receptor
Ca2+
MAPK/ERK
β-AR
Isoproterenol
VGF

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