TNIK is a conserved regulator of glucose and lipid metabolism in obesity

Tang Cam Phung Pham, Lucile Dollet, Mona Sadek Ali, Steffen Henning Raun, Lisbeth Liliendal Valbjørn Møller, Abbas Jafari, Nicholas Ditzel, Nicoline Resen Andersen, Andreas Mæchel Fritzen, Zachary Gerhart-Hines, Bente Kiens, Anu Suomalainen, Stephen J Simpson, Morten Salling Olsen, Arnd Kieser, Peter Schjerling, Anni I Nieminen, Erik A. Richter, Essi Havula*, Lykke Sylow*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

6 Citations (Scopus)
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Abstract

Obesity and type 2 diabetes (T2D) are growing health challenges with unmet treatment needs. Traf2- and NCK-interacting protein kinase (TNIK) is a recently identified obesity- and T2D-associated gene with unknown functions. We show that TNIK governs lipid and glucose homeostasis in Drosophila and mice. Loss of the Drosophila ortholog of TNIK, misshapen, altered the metabolite profiles and impaired de novo lipogenesis in high sugar-fed larvae. Tnik knockout mice exhibited hyperlocomotor activity and were protected against diet-induced fat expansion, insulin resistance, and hepatic steatosis. The improved lipid profile of Tnik knockout mice was accompanied by enhanced skeletal muscle and adipose tissue insulin-stimulated glucose uptake and glucose and lipid handling. Using the T2D Knowledge Portal and the UK Biobank, we observed associations of TNIK variants with blood glucose, HbA1c, body mass index, body fat percentage, and feeding behavior. These results define an untapped paradigm of TNIK-controlled glucose and lipid metabolism.

Original languageEnglish
Article numbereadf7119
JournalScience Advances
Volume9
Issue number32
Number of pages18
ISSN2375-2548
DOIs
Publication statusPublished - 2023

Keywords

  • Animals
  • Mice
  • Diabetes Mellitus, Type 2/genetics
  • Glucose/metabolism
  • Insulin Resistance
  • Lipid Metabolism
  • Lipids
  • Liver/metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity/genetics
  • Protein Serine-Threonine Kinases/metabolism

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