Tankyrase inhibition ameliorates lipid disorder via suppression of PGC-1 alpha PARylation in db/db mice

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Wang , H , Kuusela , S , Rinnankoski-Tuikka , R , Dumont , V , Bouslama , R , Ramadan , U A , Waaler , J , Linden , A-M , Chi , N-W , Krauss , S , Pirinen , E & Lehtonen , S 2020 , ' Tankyrase inhibition ameliorates lipid disorder via suppression of PGC-1 alpha PARylation in db/db mice ' , International Journal of Obesity , vol. 44 , no. 8 , pp. 1691-1702 . https://doi.org/10.1038/s41366-020-0573-z

Title: Tankyrase inhibition ameliorates lipid disorder via suppression of PGC-1 alpha PARylation in db/db mice
Author: Wang, Hong; Kuusela, Sara; Rinnankoski-Tuikka, Rita; Dumont, Vincent; Bouslama, Rim; Ramadan, Usama Abo; Waaler, Jo; Linden, Anni-Maija; Chi, Nai-Wen; Krauss, Stefan; Pirinen, Eija; Lehtonen, Sanna
Contributor organization: Medicum
Department of Pathology
University of Helsinki
Sanna Lehtonen research group
CAMM - Research Program for Clinical and Molecular Metabolism
Faculty of Medicine
Research Programs Unit
Department of Anatomy
HUS Neurocenter
Helsinki University Hospital Area
Anni-Maija Linden / Principal Investigator
Esa Risto Korpi / Principal Investigator
Department of Pharmacology
Department of Biochemistry and Developmental Biology
Eija Pirinen / Principal Investigator
Date: 2020-08
Language: eng
Number of pages: 12
Belongs to series: International Journal of Obesity
ISSN: 0307-0565
DOI: https://doi.org/10.1038/s41366-020-0573-z
URI: http://hdl.handle.net/10138/318892
Abstract: 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-1 alpha and that TNKS inhibition attenuates PARylation of PGC-1 alpha, contributing to increased PGC-1 alpha level in WAT and muscle in db/db mice. PGC-1 alpha 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-1 alpha 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-1 alpha-driven transcriptional reprogramming in muscle and WAT, without affecting liver. This highlights inhibition of TNKS as a potential pharmacotherapy for obesity and T2DM.
Subject: FATTY-ACID OXIDATION
RECEPTOR COACTIVATOR PGC-1-ALPHA
BETA-CELL FUNCTION
SKELETAL-MUSCLE
GLUCOSE-METABOLISM
ADIPOSE-TISSUE
PHARMACOLOGICAL INHIBITION
HEPATIC GLUCONEOGENESIS
MITOCHONDRIAL-FUNCTION
PGC-1 COACTIVATORS
3121 General medicine, internal medicine and other clinical medicine
3143 Nutrition
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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