High-Fat Diet Induces Pre-Diabetes and Distinct Sex-Specific Metabolic Alterations in Negr1-Deficient Mice

Maria Kaare; Kaie Mikheim; Kersti Lilleväli; Kalle Kilk; Toomas Jagomäe; Este Leidmaa; Maria Piirsalu; Rando Porosk; Katyayani Singh; Riin Reimets; Egon Taalberg; Michael K E Schäfer; Mario Plaas; Eero Vasar; Mari-Anne Philips

doi:10.3390/biomedicines9091148

High-Fat Diet Induces Pre-Diabetes and Distinct Sex-Specific Metabolic Alterations in Negr1-Deficient Mice

Biomedicines. 2021 Sep 3;9(9):1148. doi: 10.3390/biomedicines9091148.

Authors

Maria Kaare^{1

2}, Kaie Mikheim^{1

2}, Kersti Lilleväli^{1

2}, Kalle Kilk^{2

3}, Toomas Jagomäe^{1

2

4}, Este Leidmaa⁵, Maria Piirsalu^{1

2}, Rando Porosk^{2

3}, Katyayani Singh^{1

2}, Riin Reimets⁴, Egon Taalberg^{2

3}, Michael K E Schäfer⁶, Mario Plaas⁴, Eero Vasar^{1

2}, Mari-Anne Philips^{1

2}

Affiliations

¹ Institute of Biomedicine and Translational Medicine, Department of Physiology, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia.
² Center of Excellence in Genomics and Translational Medicine, University of Tartu, 50411 Tartu, Estonia.
³ Institute of Biomedicine and Translational Medicine, Department of Biochemistry, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia.
⁴ Institute of Biomedicine and Translational Medicine, Laboratory Animal Center, University of Tartu, 14B Ravila Street, 50411 Tartu, Estonia.
⁵ Institute of Molecular Psychiatry, Medical Faculty, University of Bonn, 53129 Bonn, Germany.
⁶ Department of Anesthesiology, Focus Program Translational Neurosciences, Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.

Abstract

In the large GWAS studies, NEGR1 gene has been one of the most significant gene loci for body mass phenotype. The purpose of the current study was to clarify the role of NEGR1 in the maintenance of systemic metabolism, including glucose homeostasis, by using both male and female Negr1^-/- mice receiving a standard or high fat diet (HFD). We found that 6 weeks of HFD leads to higher levels of blood glucose in Negr1^-/- mice. In the glucose tolerance test, HFD induced phenotype difference only in male mice; Negr1^-/- male mice displayed altered glucose tolerance, accompanied with upregulation of circulatory branched-chain amino acids (BCAA). The general metabolomic profile indicates that Negr1^-/- mice are biased towards glyconeogenesis, fatty acid synthesis, and higher protein catabolism, all of which are amplified by HFD. Negr1 deficiency appears to induce alterations in the efficiency of energy storage; reduced food intake could be an attempt to compensate for the metabolic challenge present in the Negr1^-/- males, particularly during the HFD exposure. Our results suggest that the presence of functional Negr1 allows male mice to consume more HFD and prevents the development of glucose intolerance, liver steatosis, and excessive weight gain.

Keywords: Negr1; genetic models; glucose intolerance; metabolic disease; metabolomics; obesity.

Abstract

Grants and funding