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other·endocrinology, biomedical research, preclinical research, internal medicine, epidemiology·PMC10411879

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

Science Advances · 20 authors, 17 centres

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TL;DR

This preclinical study used Drosophila and Tnik knockout mice to show that TNIK loss protects against diet-induced obesity, insulin resistance, and hepatic steatosis. Human genetic data from the UK Biobank and T2D Knowledge Portal linked TNIK variants to metabolic traits.

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The study investigated the metabolic function of TNIK, an obesity- and type 2 diabetes-associated gene, using Drosophila, Tnik knockout mice, and human genetic association data. In Drosophila, loss of the TNIK ortholog misshapen altered metabolite profiles and impaired lipogenesis in sugar-fed larvae. In mice, Tnik knockout conferred protection against diet-induced fat expansion, insulin resistance, and hepatic steatosis, accompanied by enhanced insulin-stimulated glucose uptake and handling in skeletal muscle and adipose tissue. These systemic effects were not direct, cell-autonomous effects in skeletal muscle. Human genetic analyses using the T2D Knowledge Portal and UK Biobank revealed associations of TNIK variants with blood glucose, HbA1c, body mass index, body fat percentage, and feeding behavior. Limitations include the inability to measure TNIK activity directly, potential confounders from experimental conditions affecting glucose tolerance tests, and the focus on obesity and prediabetes rather than established type 2 diabetes.

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other

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endocrinology

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ORIGINAL PAPER

PMC10411879

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

Science Advances

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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.

CITATION EXPORT

T. C. Phung Pham, Lucile Dollet, Mona S. Ali et al.. TNIK is a conserved regulator of glucose and lipid metabolism in obesity. Science Advances. (2023). https://doi.org/10.1126/sciadv.adf7119

AUTHORS

20 · 17 CENTRES

T. C. Phung Pham, Lucile Dollet, Mona S. Ali, Steffen H. Raun, Lisbeth L. V. Møller, Abbas Jafari, Nicholas Ditzel, Nicoline R. Andersen, Andreas M. 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

1Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
2Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
3Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
4Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
5Molecular Endocrinology and Stem Cell Research Unit (KMEB), Department of Endocrinology and Metabolism, Odense University Hospital and University of Southern Denmark, Odense, Denmark.
6Biomedical Laboratory, The Faculty of Health Sciences, University of Southern Denmark, Denmark.
7Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Finland.
8Helsinki University Hospital, HUS Diagnostic Center, Helsinki 00290, Finland.
9Charles Perkins Centre, The University of Sydney, Camperdown 2006, Australia.
10School of Life and Environmental Sciences, The University of Sydney, Camperdown, 2006, Australia.
11Laboratory for Molecular Cardiology, Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Building 9312, Henrik Harpestrengs Vej 4C, Copenhagen 2100, Denmark.
12Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.
13Helmholtz Centre Munich–German Research Centre for Environmental Health, Research Unit Signaling and Translation, Ingolstaedter Landstr. 1, Neuherberg 85764, Germany.
14German Center for Infection Research (DZIF), Partner Site Munich, Munich, Germany.
15Institute of Sports Medicine, Department of Orthopaedic Surgery M, Bispebjerg Hospital, Copenhagen, Denmark.
16Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
17FIMM Metabolomics Unit, Institute for Molecular Medicine Finland, University of Helsinki, Finland.