title: The neuropeptide TLQP-21 opposes obesity via C3aR1-mediated enhancement of adrenergic-induced lipolysis.
abstract: 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.
  
  
  
  We used a combination of pharmacological and genetic gain and loss of function approaches. 3T3-L1 and mature murine adipocytes were used forin vitroexperiments. Chronicin vivoexperiments were conducted on diet-induced obese wild type, β1, β2, β3-adrenergic receptor (AR) deficient and C3aR1 knockout mice. Acutein vivolipolysis experiments were conducted on Sprague Dawley rats.
  
  
  
  We demonstrated that TLQP-21 does not possess lipolytic propertiesper 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 lipolysisin 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.
  
  
  
  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.
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th St. SE, Minneapolis, MN 55455, USA.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Cero
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th St. SE, Minneapolis, MN 55455, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Razzoli
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th St. SE, Minneapolis, MN 55455, USA.
authors.forename: Ruijun
authors.initials: R
authors.lastname: Han
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th St. SE, Minneapolis, MN 55455, USA.
authors.forename: Bhavani Shankar
authors.initials: BS
authors.lastname: Sahu
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th St. SE, Minneapolis, MN 55455, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Patricelli
authors.affiliation: Endocrine Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Internal Medicine, Mayo Foundation, 5-194 Joseph, Rochester, MN 55905, USA.
authors.forename: ZengKui
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th St. SE, Minneapolis, MN 55455, USA.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Zaidman
authors.affiliation: Endocrine Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Internal Medicine, Mayo Foundation, 5-194 Joseph, Rochester, MN 55905, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Miles
authors.affiliation: Department of Animal Science, Integrative Biology and Physiology, University of Minnesota, 480 Haecker Hall, 1364 Eckles Avenue, St Paul, MN 55108, USA.
authors.forename: Scott M
authors.initials: SM
authors.lastname: O'Grady
authors.affiliation: Department of Integrative Biology and Physiology, University of Minnesota, 2231 6th St. SE, Minneapolis, MN 55455, USA. Electronic address: abartolo@umn.edu.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bartolomucci
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D018663:Adrenergic Agents / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases; D008066:Lipolysis / Q000187:drug effects / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D020929:Mitogen-Activated Protein Kinase Kinases; D009479:Neuropeptides / Q000378:metabolism; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011951:Receptors, Complement / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction; D002787:Sterol Esterase / Q000009:adverse effects
chemical_list: D018663:Adrenergic Agents; D009479:Neuropeptides; D010446:Peptide Fragments; D011951:Receptors, Complement; C522412:TLQP-21 peptide; C085567:complement C3a receptor; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D002787:Sterol Esterase
keywords: Adipocyte; Ca2+; Complement 3a receptor; Isoproterenol; MAPK/ERK; VGF; β-AR