The calcium-sensing-receptor (CaSR) in adipocytes contributes to sex-differences in the susceptibility to high fat diet induced obesity and atherosclerosis

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-alpha alpha (ER alpha) alpha ) is affected by the calcium-sensing-receptor (CaSR). Therefore, we investigated sex-differences upon diet-induced obesity and the role of adipocyte-specific fi c CaSR herein. Methods Adipocyte-specific fi c Casr deficient fi cient mice ( AdipoqCre + Casr fl ox ) and control mice ( Casr fl ox ) 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 fi c Casr deficiency. fi ciency. Furthermore, while females showed elevated levels of inflammatory fl ammatory cytokines and CD3+CD8+ + CD8 + T cell accumulation in vWAT, compared to males, adipocyte-specific fi c Casr deficiency fi ciency abrogated this sex-phenotype and demonstrated an inhibition of inflammatory fl ammatory signalling pathways. The expression of Er alpha , as well as associated genes involved in adipocyte differentiation, was increased in female mice in a mostly adipocyte-specific fi c 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 fi c Casr deficiency. fi ciency. Interpretation Our fi ndings indicate that female mice show a more pronounced vWAT dysfunction compared to males upon obesity. This sex effect is abolished upon adipocyte-specific fi c Casr deficiency. fi ciency. In contrast, females show diminished atherosclerotic plaque formation compared to males, an effect that was abrogated by adipocyte-specific fi c Casr deficiency. fi ciency. 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. Copyright (c) 2024 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).