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

Mol Metab. 2016 Oct 31;6(1):148-158. doi: 10.1016/j.molmet.2016.10.005. eCollection 2017 Jan.


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.

Keywords: Adipocyte; Ca2+; Complement 3a receptor; Isoproterenol; MAPK/ERK; VGF; β-AR.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / drug effects*
  • Adipocytes / metabolism
  • Adrenergic Agents / metabolism
  • Animals
  • Diabetes Mellitus, Type 2 / metabolism
  • Extracellular Signal-Regulated MAP Kinases
  • Lipolysis / drug effects
  • Lipolysis / physiology
  • MAP Kinase Signaling System / physiology
  • Male
  • Mice
  • Mice, Obese
  • Mitogen-Activated Protein Kinase Kinases
  • Neuropeptides / metabolism
  • Obesity / chemically induced
  • Obesity / metabolism
  • Peptide Fragments / metabolism*
  • Peptide Fragments / physiology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Complement / drug effects*
  • Receptors, Complement / metabolism
  • Signal Transduction
  • Sterol Esterase / adverse effects


  • Adrenergic Agents
  • Neuropeptides
  • Peptide Fragments
  • Receptors, Complement
  • TLQP-21 peptide
  • complement C3a receptor
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase Kinases
  • Sterol Esterase