期刊
MOLECULAR METABOLISM
卷 6, 期 1, 页码 148-158出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.molmet.2016.10.005
关键词
Adipocyte; Complement 3a receptor; Ca2+; MAPK/ERK; beta-AR; Isoproterenol; VGF
资金
- NIH/NIDDK [R01 DK102496]
- Decade of Discovery in Diabetes Grant, Minnesota Partnership for Biotechnology and Medical Genomic
- NIH/NIDDK NORC Grant [P30 DK050456]
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, beta(1), beta(2), beta(3)-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 beta-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 beta-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. (C) 2016 The Author(s). Published by Elsevier GmbH.
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