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

Cheryl Cero, Maria Razzoli, Ruijun Han, Bhavani Shankar Sahu, Jessica Patricelli, Zeng Kui Guo, Nathan A. Zaidman, John M. Miles, Scott M. O'Grady, Alessandro Bartolomucci

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)148-158
Number of pages11
JournalMolecular Metabolism
Volume6
Issue number1
DOIs
StatePublished - Jan 1 2017

Keywords

  • Adipocyte
  • Ca
  • Complement 3a receptor
  • Isoproterenol
  • MAPK/ERK
  • VGF
  • β-AR

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Cero, C., Razzoli, M., Han, R., Sahu, B. S., Patricelli, J., Guo, Z. K., Zaidman, N. A., Miles, J. M., O'Grady, S. M., & Bartolomucci, A. (2017). The neuropeptide TLQP-21 opposes obesity via C3aR1-mediated enhancement of adrenergic-induced lipolysis. Molecular Metabolism, 6(1), 148-158. https://doi.org/10.1016/j.molmet.2016.10.005