title: The PARsylation activity of tankyrase in adipose tissue modulates systemic glucose metabolism in mice.
abstract: OBJECTIVE
  Tankyrase (TNKS) is a ubiquitously expressed molecular scaffold that is implicated in diverse processes. The catalytic activity of TNKS modifies substrate proteins through poly-ADP-ribosylation (PARsylation) and is responsive to cellular energetic state. Global deficiency of the TNKS protein in mice accelerates glucose utilisation and raises plasma adiponectin levels. The aim of this study was to investigate whether the PARsylation activity of TNKS in adipocytes plays a role in systemic glucose homeostasis.
  
  
  METHODS
  To inhibit TNKS-mediated PARsylation, we fed mice with a diet containing the TNKS-specific inhibitor G007-LK. To genetically inactivate TNKS catalysis in adipocytes while preserving its function as a molecular scaffold, we used an adipocyte-selective Cre transgene to delete TNKS exons that encoded the catalytic domain at the C-terminus. Tissue-specific insulin sensitivity in mice was investigated using hyperinsulinaemic-euglycaemic clamps. To model adipose-liver crosstalk ex vivo, we applied adipocyte-conditioned media to hepatocytes and assessed the effect on gluconeogenesis.
  
  
  RESULTS
  The TNKS inhibitor G007-LK improved glucose tolerance and insulin sensitivity and promptly increased plasma adiponectin levels. In female mice, but not in male mice, adipocyte-selective genetic inactivation of TNKS catalysis improved hepatic insulin sensitivity and post-transcriptionally increased plasma adiponectin levels. Both pharmacological and genetic TNKS inhibition in female mouse-derived adipocytes induced a change in secreted factors to decrease gluconeogenesis in primary hepatocytes.
  
  
  CONCLUSIONS
  Systemic glucose homeostasis is regulated by the PARsylation activity of TNKS in adipocytes. This regulation is mediated in part by adipocyte-secreted factors that modulate hepatic glucose production. Pharmacological TNKS inhibition could potentially be used to improve glucose tolerance.
authors.affiliation: VA San Diego Healthcare System, San Diego, CA, USA.|Department of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0673, USA.
authors.forename: Linlin
authors.initials: L
authors.lastname: Zhong
authors.affiliation: VA San Diego Healthcare System, San Diego, CA, USA.|Department of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0673, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0673, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Bandyopadhyay
authors.affiliation: Oslo University Hospital, Oslo, Norway.
authors.forename: Jo
authors.initials: J
authors.lastname: Waaler
authors.affiliation: Department of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0673, USA.
authors.forename: Emma
authors.initials: E
authors.lastname: Börgeson
authors.affiliation: New York University School of Medicine, New York, NY, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Smith
authors.affiliation: Department of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0673, USA.|First Affiliated Hospital of Xinjiang Medical University, Xinjiang, People's Republic of China.
authors.forename: Mingchen
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, University of California, San Diego, CA, USA.
authors.forename: Susan A
authors.initials: SA
authors.lastname: Phillips
authors.affiliation: Department of Pathology, University of California, San Diego, CA, USA.
authors.forename: Sepi
authors.initials: S
authors.lastname: Mahooti
authors.affiliation: VA San Diego Healthcare System, San Diego, CA, USA.|Department of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0673, USA.
authors.forename: Sushil K
authors.initials: SK
authors.lastname: Mahata
authors.affiliation: Department of Pediatrics, University of California, San Diego, CA, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shao
authors.affiliation: Oslo University Hospital, Oslo, Norway.
authors.forename: Stefan
authors.initials: S
authors.lastname: Krauss
authors.affiliation: VA San Diego Healthcare System, San Diego, CA, USA. nwchi@ucsd.edu.|Department of Medicine, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA, 92093-0673, USA. nwchi@ucsd.edu.
authors.forename: Nai-Wen
authors.initials: NW
authors.lastname: Chi
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects* / Q000201:enzymology*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D050260:Carbohydrate Metabolism / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000378:metabolism*; D008297:Male; D051379:Mice; D013450:Sulfones / Q000494:pharmacology; D038501:Tankyrases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014230:Triazoles / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; C582305:G007-LK; D013450:Sulfones; D014230:Triazoles; D038501:Tankyrases; D005947:Glucose
keywords: Adipokines; Adiponectin; Glucose homeostasis; Hepatic glucose production; Insulin sensitivity; Mouse genetic model; Poly-ADP-ribosylation (PARsylation); Tankyrase (TNKS); Tissue-specific knockout