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

T C Phung Pham1,2, Lucile Dollet3, Mona S Ali1,2

  • 1Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.

Science Advances
|August 9, 2023
PubMed

Insights

Traf2- and NCK-interacting protein kinase (TNIK) regulates fat and sugar metabolism. TNIK gene variants are linked to obesity and type 2 diabetes, suggesting it as a potential therapeutic target.

Area of Science:

  • Metabolic research
  • Genetics of metabolic disorders
  • Molecular biology

Background:

  • Obesity and type 2 diabetes (T2D) represent significant global health challenges with limited effective treatments.
  • Traf2- and NCK-interacting protein kinase (TNIK) is a gene recently associated with obesity and T2D, but its functional role remains unclear.

Purpose of the Study:

  • To investigate the function of TNIK in regulating lipid and glucose homeostasis.
  • To explore the potential of TNIK as a therapeutic target for metabolic diseases.

Main Methods:

  • Utilized Drosophila melanogaster (fruit fly) models to study the ortholog gene 'misshapen' in larvae fed a high-sugar diet.
  • Generated and analyzed Tnik knockout mice to assess metabolic phenotypes, including activity, body composition, and insulin sensitivity.
  • Examined human genetic data from the T2D Knowledge Portal and UK Biobank to correlate TNIK variants with metabolic traits and feeding behavior.

Main Results:

  • Loss of the Drosophila TNIK ortholog impaired de novo lipogenesis and altered metabolite profiles in larvae.
  • Tnik knockout mice displayed increased activity and protection against diet-induced obesity, insulin resistance, and fatty liver disease.
  • Tnik knockout mice showed improved glucose and lipid metabolism, with enhanced insulin-stimulated glucose uptake in muscle and adipose tissue.
  • Human genetic data revealed associations between TNIK variants and key metabolic indicators like blood glucose, HbA1c, BMI, and body fat percentage.

Conclusions:

  • TNIK plays a crucial role in governing both lipid and glucose metabolism in preclinical models.
  • Genetic variations in TNIK are linked to human obesity and type 2 diabetes risk factors.
  • These findings establish TNIK as a novel and significant regulator of metabolic homeostasis, presenting a potential new avenue for therapeutic intervention.

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