The calcium-sensing-receptor (CaSR) in adipocytes contributes to sex-differences in the susceptibility to high fat diet induced obesity and atherosclerosisResearch in context
Svenja Adam,
Sanne L. Maas,
Rosanna Huchzermeier,
Leonida Rakateli,
Kathrin Abschlag,
Mathias Hohl,
Liangliang Liao,
Matthias Bartneck,
Margee Teunissen,
Kristiaan Wouters,
Donato Santovito,
Joachim Jankowski,
Erik A.L. Biessen,
Emiel P.C. van der Vorst
Affiliations
Svenja Adam
Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen 52074, Germany; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Aachen 52074, Germany
Sanne L. Maas
Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen 52074, Germany; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Aachen 52074, Germany
Rosanna Huchzermeier
Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen 52074, Germany; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Aachen 52074, Germany
Leonida Rakateli
Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen 52074, Germany; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Aachen 52074, Germany
Kathrin Abschlag
Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen 52074, Germany; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Aachen 52074, Germany
Mathias Hohl
Klinik für Innere Medizin III, Universität des Saarlandes, Homburg, Germany
Liangliang Liao
Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany; Japan Union Hospital of Jilin University, Changchun, China
Matthias Bartneck
Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany; DWI-Leibniz Institute for Interactive Materials, Aachen, Germany; Institute of Technical and Macromolecular Chemistry, RWTH Aachen University, Aachen, Germany
Margee Teunissen
Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht 6229 ER, the Netherlands
Kristiaan Wouters
Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht 6229 ER, the Netherlands
Donato Santovito
Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich 80336, Germany; German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich 80336, Germany
Joachim Jankowski
Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen 52074, Germany; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Aachen 52074, Germany
Erik A.L. Biessen
Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen 52074, Germany; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Aachen 52074, Germany; Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht 6229 ER, the Netherlands
Emiel P.C. van der Vorst
Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen 52074, Germany; Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Aachen 52074, Germany; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich 80336, Germany; Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen 52074, Germany; Corresponding author. Pauwelsstrasse 17, Aachen 52074, Germany.
Summary: Background: Female mice are more resistant to obesogenic effects of a high-fat diet (HFD), compared to male mice. Although the underlying mechanisms are poorly understood, sex hormones seem to play an important role. Interestingly, the activity of the oestrogen receptor-α (ERα) is affected by the calcium-sensing-receptor (CaSR). Therefore, we investigated sex-differences upon diet-induced obesity and the role of adipocyte-specific CaSR herein. Methods: Adipocyte-specific Casr deficient mice (AdipoqCre+Casrflox) and control mice (Casrflox) were injected with AAV8-PCSK9 to make them prone to develop atherosclerosis and fed an obesity-inducing diet for 12 weeks. Findings: Female mice have lower visceral white adipose tissue (vWAT) mass compared to male mice, while this sex-difference is abolished upon adipocyte-specific Casr deficiency. Furthermore, while females showed elevated levels of inflammatory cytokines and CD3+CD8+ T cell accumulation in vWAT, compared to males, adipocyte-specific Casr deficiency abrogated this sex-phenotype and demonstrated an inhibition of inflammatory signalling pathways. The expression of Erα, as well as associated genes involved in adipocyte differentiation, was increased in female mice in a mostly adipocyte-specific Casr dependent manner. Interestingly, circulating lipid levels were reduced in female compared to male mice, which correlated with decreased atherosclerotic plaque formation. These systemic effects were abrogated upon adipocyte-specific Casr deficiency. Interpretation: Our findings indicate that female mice show a more pronounced vWAT dysfunction compared to males upon obesity. This sex effect is abolished upon adipocyte-specific Casr deficiency. In contrast, females show diminished atherosclerotic plaque formation compared to males, an effect that was abrogated by adipocyte-specific Casr deficiency. Funding: This work was supported by a grant from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University, by the Corona Foundation, by the Deutsche Forschungsgemeinschaft (DFG), the BMBF and Free State of Bavaria and the DZHK.
