PMID- 24995977 OWN - NLM STAT- MEDLINE DCOM- 20140918 LR - 20220409 IS - 1097-4172 (Electronic) IS - 0092-8674 (Print) IS - 0092-8674 (Linking) VI - 158 IP - 1 DP - 2014 Jul 3 TI - Adipsin is an adipokine that improves beta cell function in diabetes. PG - 41-53 LID - S0092-8674(14)00726-0 [pii] LID - 10.1016/j.cell.2014.06.005 [doi] AB - A hallmark of type 2 diabetes mellitus (T2DM) is the development of pancreatic beta cell failure, which results in insulinopenia and hyperglycemia. We show that the adipokine adipsin has a beneficial role in maintaining beta cell function. Animals genetically lacking adipsin have glucose intolerance due to insulinopenia; isolated islets from these mice have reduced glucose-stimulated insulin secretion. Replenishment of adipsin to diabetic mice treated hyperglycemia by boosting insulin secretion. We identify C3a, a peptide generated by adipsin, as a potent insulin secretagogue and show that the C3a receptor is required for these beneficial effects of adipsin. C3a acts on islets by augmenting ATP levels, respiration, and cytosolic free Ca(2+). Finally, we demonstrate that T2DM patients with beta cell failure are deficient in adipsin. These findings indicate that the adipsin/C3a pathway connects adipocyte function to beta cell physiology, and manipulation of this molecular switch may serve as a therapy in T2DM. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Lo, James C AU - Lo JC AD - Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. FAU - Ljubicic, Sanda AU - Ljubicic S AD - Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. FAU - Leibiger, Barbara AU - Leibiger B AD - The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, 17176 Stockholm, Sweden. FAU - Kern, Matthias AU - Kern M AD - Department of Medicine, University of Leipzig, Leipzig 04103, Germany. FAU - Leibiger, Ingo B AU - Leibiger IB AD - The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, 17176 Stockholm, Sweden. FAU - Moede, Tilo AU - Moede T AD - The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, 17176 Stockholm, Sweden. FAU - Kelly, Molly E AU - Kelly ME AD - Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. FAU - Chatterjee Bhowmick, Diti AU - Chatterjee Bhowmick D AD - Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. FAU - Murano, Incoronata AU - Murano I AD - Department of Experimental and Clinical Medicine, University of Ancona, 60020 Ancona, Italy. FAU - Cohen, Paul AU - Cohen P AD - Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. FAU - Banks, Alexander S AU - Banks AS AD - Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. FAU - Khandekar, Melin J AU - Khandekar MJ AD - Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. FAU - Dietrich, Arne AU - Dietrich A AD - Department of Surgery, University of Leipzig, Leipzig 04103, Germany. FAU - Flier, Jeffrey S AU - Flier JS AD - Harvard Medical School, Boston, MA 02115, USA. FAU - Cinti, Saverio AU - Cinti S AD - Department of Experimental and Clinical Medicine, University of Ancona, 60020 Ancona, Italy. FAU - Bluher, Matthias AU - Bluher M AD - Department of Medicine, University of Leipzig, Leipzig 04103, Germany. FAU - Danial, Nika N AU - Danial NN AD - Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. FAU - Berggren, Per-Olof AU - Berggren PO AD - The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, 17176 Stockholm, Sweden. FAU - Spiegelman, Bruce M AU - Spiegelman BM AD - Dana-Farber Cancer Institute and the Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: bruce_spiegelman@dfci.harvard.edu. LA - eng GR - P30 DK043351/DK/NIDDK NIH HHS/United States GR - DK078081/DK/NIDDK NIH HHS/United States GR - R01 DK078081/DK/NIDDK NIH HHS/United States GR - K08 DK097303/DK/NIDDK NIH HHS/United States GR - R37 DK031405/DK/NIDDK NIH HHS/United States GR - DK097303/DK/NIDDK NIH HHS/United States GR - R01 DK031405/DK/NIDDK NIH HHS/United States GR - DK031405/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Cell JT - Cell JID - 0413066 RN - 0 (Insulin) RN - 80295-42-7 (Complement C3a) RN - EC 3.4.21.46 (CFD protein, human) RN - EC 3.4.21.46 (Complement Factor D) RN - EC 3.4.21.46 (complement factor D, mouse) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Adipose Tissue/metabolism MH - Animals MH - Complement C3a/metabolism MH - Complement Factor D/genetics/metabolism MH - Diabetes Mellitus, Type 2/*metabolism/physiopathology MH - Diet, High-Fat MH - Glucose/metabolism MH - Humans MH - Inflammation/metabolism MH - Insulin/metabolism MH - Insulin Secretion MH - Insulin-Secreting Cells/*metabolism MH - Mice PMC - PMC4128197 MID - NIHMS604256 EDAT- 2014/07/06 06:00 MHDA- 2014/09/19 06:00 PMCR- 2015/07/03 CRDT- 2014/07/05 06:00 PHST- 2013/12/12 00:00 [received] PHST- 2014/03/19 00:00 [revised] PHST- 2014/04/10 00:00 [accepted] PHST- 2014/07/05 06:00 [entrez] PHST- 2014/07/06 06:00 [pubmed] PHST- 2014/09/19 06:00 [medline] PHST- 2015/07/03 00:00 [pmc-release] AID - S0092-8674(14)00726-0 [pii] AID - 10.1016/j.cell.2014.06.005 [doi] PST - ppublish SO - Cell. 2014 Jul 3;158(1):41-53. doi: 10.1016/j.cell.2014.06.005.