Thyroid hormones regulate Zfp423 expression in regionally distinct adipose depots through direct and cell-autonomous action
Lisa Roth,
Kornelia Johann,
Georg Sebastian Hönes,
Rebecca Oelkrug,
Leonie Wagner,
Anne Hoffmann,
Knut Krohn,
Lars C. Moeller,
Juliane Weiner,
John T. Heiker,
Nora Klöting,
Anke Tönjes,
Michael Stumvoll,
Matthias Blüher,
Jens Mittag,
Kerstin Krause
Affiliations
Lisa Roth
Department of Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
Kornelia Johann
Institute for Endocrinology and Diabetes/Center of Brain, Behavior and Metabolism, University of Lübeck, 23562 Lübeck, Germany
Georg Sebastian Hönes
Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
Rebecca Oelkrug
Institute for Endocrinology and Diabetes/Center of Brain, Behavior and Metabolism, University of Lübeck, 23562 Lübeck, Germany
Leonie Wagner
Department of Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
Anne Hoffmann
Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, 04103 Leipzig, Germany
Knut Krohn
DNA Core Unit Leipzig, University of Leipzig, 04103 Leipzig, Germany
Lars C. Moeller
Department of Endocrinology, Diabetes and Metabolism, University Hospital Essen, University of Duisburg-Essen, 45122 Essen, Germany
Juliane Weiner
Department of Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
John T. Heiker
Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, 04103 Leipzig, Germany
Nora Klöting
Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, 04103 Leipzig, Germany
Anke Tönjes
Department of Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany
Michael Stumvoll
Department of Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, 04103 Leipzig, Germany
Matthias Blüher
Department of Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, 04103 Leipzig, Germany
Jens Mittag
Institute for Endocrinology and Diabetes/Center of Brain, Behavior and Metabolism, University of Lübeck, 23562 Lübeck, Germany
Kerstin Krause
Department of Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, 04103 Leipzig, Germany; Deutsches Zentrum für Diabetesforschung e.V., 85764 Neuherberg, Germany; Corresponding author
Summary: The hypothalamic pituitary thyroid axis is a major regulator of many differentiation processes, including adipose tissue. However, it remains unclear whether and how thyroid hormone (TH) signaling contributes to preadipocyte commitment and differentiation into mature adipocytes. Here, we show a cell-autonomous effect of TH on the transcriptional regulation of zinc finger protein 423 (Zfp423), an early adipogenic determination factor, in murine adipose depots. Mechanistically, binding of the unliganded TH receptor to a negative TH responsive element within the Zfp423 promoter activates transcriptional activity that is reversed upon TH binding. Zfp423 upregulation is associated with increased GFP+ preadipocyte recruitment in stromal vascular fraction isolated from white fat of hypothyroid Zfp423GFP reporter mice. RNA sequencing identified Zfp423-driven gene programs that are modulated in response to TH during adipogenic differentiation. Collectively, we identified Zfp423 as a key molecule that integrates TH signaling into the regulation of adipose tissue plasticity.
