4.5 Article

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

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INTERNATIONAL JOURNAL OF OBESITY
卷 44, 期 8, 页码 1691-1702

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SPRINGERNATURE
DOI: 10.1038/s41366-020-0573-z

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资金

  1. European Research Council [242820]
  2. Academy of Finland [277485, 286359]
  3. Sigrid Juselius Foundation
  4. Faculty of Medicine and HiLife, University of Helsinki
  5. Finnish Cultural Foundation
  6. Diabetes Research Foundation
  7. Department of Veterans Affairs [5I01BX000702]
  8. Doctoral Programme in Biomedicine
  9. European Research Council (ERC) [242820] Funding Source: European Research Council (ERC)
  10. Academy of Finland (AKA) [277485, 277485, 286359, 286359] Funding Source: Academy of Finland (AKA)

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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.

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