Diabetologie und Stoffwechsel 2022; 17(S 01): S54-S55
DOI: 10.1055/s-0042-1746359
Abstracts | DDG
02. Poster

A metabolically-healthy lean phenotype is sustained in GPR146-deficient mice during diet-induced obesity

Sebastian Brachs
1   Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin, Germany, Department of Endocrinology and Metabolism, Berlin, Germany
,
Knut Mai
1   Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin, Germany, Department of Endocrinology and Metabolism, Berlin, Germany
,
Julia Sbierski-Kind
1   Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin, Germany, Department of Endocrinology and Metabolism, Berlin, Germany
,
Jule Klockgeter
1   Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin, Germany, Department of Endocrinology and Metabolism, Berlin, Germany
,
Aida Harutyunyan
1   Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin, Germany, Department of Endocrinology and Metabolism, Berlin, Germany
,
Aoxue Liu
1   Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin, Germany, Department of Endocrinology and Metabolism, Berlin, Germany
,
Maria Brachs
1   Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin, Germany, Department of Endocrinology and Metabolism, Berlin, Germany
,
Leonard Spranger
1   Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin, Germany, Department of Endocrinology and Metabolism, Berlin, Germany
,
Séverine Kunz
2   Max-Delbrück-Centrum für Molekulare Medizin (MDC), Berlin, Germany, CF Electron Microscopy, Berlin, Germany
,
Sanghee Ki
3   Institute for Cellular and Molecular Biology, The University of Texas at Austin, Department of Molecular Biosciences, Austin, United States
,
Lauren Ehrlich
3   Institute for Cellular and Molecular Biology, The University of Texas at Austin, Department of Molecular Biosciences, Austin, United States
,
Kaihui Hu He
4   Sanofi-Aventis Deutschland GmbH, Research and Development, Frankfurt, Germany
,
Maximilian Bielohuby
4   Sanofi-Aventis Deutschland GmbH, Research and Development, Frankfurt, Germany
,
Paulus Wohlfart
4   Sanofi-Aventis Deutschland GmbH, Research and Development, Frankfurt, Germany
,
Joachim Spranger
1   Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt- Universität zu Berlin, Berlin, Germany, Department of Endocrinology and Metabolism, Berlin, Germany
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    The G protein-coupled orphan receptor 146 (GPR146) was found to be highly expressed in murine and human adipose tissue. We revealed an adipose GPR146 increase during a 3-month weight reduction in our human MAINTAIN study. Therefore, we analyzed GPR146 correlations in MAINTAIN and metabolically characterized Gpr146-deficient mice (GPR146-/-).

    GPR146-/- males were extensively phenotyped under diet-induced obesity (DIO) feeding a standard-control (STD), high-fat (HFD) and western diet (WD) for 3 month. We investigated basal metabolic parameters, body composition, and glucose and insulin sensitivity. Moreover, adipocyte differentiation, lipid metabolism, activity and energy expenditure was examined. For it, glucose challenges, hyperinsulinemic-euglycemic clamps, indirect calorimetry, lipid tolerance and other in vitro and ex vivo experiments were performed focusing on liver and adipose tissue parameters in cells and GPR146-/- mice.

    We observed decreased weight together with reduced fat content during DIO, while lean mass increased under HFD and even more under WD. Generally, GPR146-/- exhibited lower plasma concentrations of cholesterol, triglycerides and free fatty acids regardless of diet. While activity was comparable under STD, GPR146-/- mice exhibited low activity from beginning of WD, at which fatty diet intake is significantly reduced. Energy expenditure seemed to be elevated and glucose handling and insulin sensitivity improved in GPR146-/- during DIO. RNA sequencing primarily revealed adipose inflammatory pathways regulated under HFD and lean-phenotype-associated immune cells were observed in GPR146-/- feeding WD.

    In summary, Gpr146-null mice preserve an anti-inflammatory immune cell profile, and show beneficial changes in body weight progression and lipid metabolism against obesity-inducing diets.


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    Conflict of Interest

    This work was supported by a joint Charité-Sanofi Diabetes-Lab until 2018.

    Publication History

    Article published online:
    26 May 2022

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