PMID- 32317752 OWN - NLM STAT- MEDLINE DCOM- 20211103 LR - 20211103 IS - 1476-5497 (Electronic) IS - 0307-0565 (Print) IS - 0307-0565 (Linking) VI - 44 IP - 8 DP - 2020 Aug TI - Tankyrase inhibition ameliorates lipid disorder via suppression of PGC-1alpha PARylation in db/db mice. PG - 1691-1702 LID - 10.1038/s41366-020-0573-z [doi] AB - OBJECTIVE: Human TNKS, encoding tankyrase 1 (TNKS1), localizes to a susceptibility locus for obesity and type 2 diabetes mellitus (T2DM). Here, we addressed the therapeutic potential of G007-LK, a TNKS-specific inhibitor, for obesity and T2DM. METHODS: We administered G007-LK to diabetic db/db mice and measured the impact on body weight, abdominal adiposity, and serum metabolites. Muscle, liver, and white adipose tissues were analyzed by quantitative RT-PCR and western blotting to determine TNKS inhibition, lipolysis, beiging, adiponectin level, mitochondrial oxidative metabolism and mass, and gluconeogenesis. Protein interaction and PARylation analyses were carried out by immunoprecipitation, pull-down and in situ proximity ligation assays. RESULTS: TNKS inhibition reduced body weight gain, abdominal fat content, serum cholesterol levels, steatosis, and proteins associated with lipolysis in diabetic db/db mice. We discovered that TNKS associates with PGC-1alpha and that TNKS inhibition attenuates PARylation of PGC-1alpha, contributing to increased PGC-1alpha level in WAT and muscle in db/db mice. PGC-1alpha upregulation apparently modulated transcriptional reprogramming to increase mitochondrial mass and fatty acid oxidative metabolism in muscle, beiging of WAT, and raised circulating adiponectin level in db/db mice. This was in sharp contrast to the liver, where TNKS inhibition in db/db mice had no effect on PGC-1alpha expression, lipid metabolism, or gluconeogenesis. CONCLUSION: Our study unravels a novel molecular mechanism whereby pharmacological inhibition of TNKS in obesity and diabetes enhances oxidative metabolism and ameliorates lipid disorder. This happens via tissue-specific PGC-1alpha-driven transcriptional reprogramming in muscle and WAT, without affecting liver. This highlights inhibition of TNKS as a potential pharmacotherapy for obesity and T2DM. FAU - Wang, Hong AU - Wang H AD - Department of Pathology, University of Helsinki, Helsinki, Finland. AD - Minerva Institute for Medical Research, Helsinki, Finland. FAU - Kuusela, Sara AU - Kuusela S AD - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland. FAU - Rinnankoski-Tuikka, Rita AU - Rinnankoski-Tuikka R AD - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland. FAU - Dumont, Vincent AU - Dumont V AUID- ORCID: 0000-0002-2893-5479 AD - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland. FAU - Bouslama, Rim AU - Bouslama R AD - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland. FAU - Ramadan, Usama Abo AU - Ramadan UA AD - Experimental MRI Laboratory, University of Helsinki and Helsinki University Hospital, Helsinki, Finland. FAU - Waaler, Jo AU - Waaler J AD - Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway. AD - Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. FAU - Linden, Anni-Maija AU - Linden AM AD - Department of Pharmacology, University of Helsinki, Helsinki, Finland. FAU - Chi, Nai-Wen AU - Chi NW AD - Endocrine Service, VA San Diego Healthcare System, San Diego, CA, USA. FAU - Krauss, Stefan AU - Krauss S AD - Department of Immunology and Transfusion Medicine, Oslo University Hospital, Oslo, Norway. AD - Hybrid Technology Hub-Centre of Excellence, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. FAU - Pirinen, Eija AU - Pirinen E AD - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland. FAU - Lehtonen, Sanna AU - Lehtonen S AUID- ORCID: 0000-0003-4189-2415 AD - Department of Pathology, University of Helsinki, Helsinki, Finland. sanna.h.lehtonen@helsinki.fi. AD - Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland. sanna.h.lehtonen@helsinki.fi. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20200421 PL - England TA - Int J Obes (Lond) JT - International journal of obesity (2005) JID - 101256108 RN - 0 (G007-LK) RN - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha) RN - 0 (Ppargc1a protein, mouse) RN - 0 (Sulfones) RN - 0 (Triazoles) RN - EC 2.4.2.30 (Tankyrases) RN - EC 2.4.2.30 (Tnks protein, mouse) SB - IM MH - Abdominal Fat MH - Adipose Tissue, White MH - Animals MH - Body Weight MH - Diabetes Mellitus, Type 2/*metabolism MH - Dyslipidemias/*drug therapy MH - Liver MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Inbred Strains MH - Obesity/*metabolism MH - Oxidation-Reduction MH - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/*metabolism MH - Poly ADP Ribosylation MH - Sulfones/therapeutic use MH - Tankyrases/*antagonists & inhibitors/metabolism MH - Triazoles/therapeutic use PMC - PMC7381423 COIS- The authors declare that they have no conflict of interest. EDAT- 2020/04/23 06:00 MHDA- 2021/11/04 06:00 PMCR- 2020/04/21 CRDT- 2020/04/23 06:00 PHST- 2019/09/06 00:00 [received] PHST- 2020/03/27 00:00 [accepted] PHST- 2020/03/06 00:00 [revised] PHST- 2020/04/23 06:00 [pubmed] PHST- 2021/11/04 06:00 [medline] PHST- 2020/04/23 06:00 [entrez] PHST- 2020/04/21 00:00 [pmc-release] AID - 10.1038/s41366-020-0573-z [pii] AID - 573 [pii] AID - 10.1038/s41366-020-0573-z [doi] PST - ppublish SO - Int J Obes (Lond). 2020 Aug;44(8):1691-1702. doi: 10.1038/s41366-020-0573-z. Epub 2020 Apr 21.