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

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): IZKF Female mice are more resistant to the 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 estrogen receptor-α (ERα) is affected by the calcium-sensing-receptor (CaSR). Therefore, we investigated sex-differences upon HFD feeding and the role of adipocyte-specific CaSR herein. Adipocyte-specific Casr deficient mice (AdipoqCre+Casrflox) and control mice (Casrflox) were injected with AAV8-PCSK9 and fed a HFD for 12 weeks. Female mice have a lower visceral white adipose tissue (vWAT) mass then male mice, while this sex-difference is abolished upon adipocyte-specific Casr deficiency. Furthermore, while females showed an increase of IL-6, TNF-α and CCL2 in vWAT, compared to males, adipocyte-specific Casr deficiency rescued this sex-phenotype and demonstrated an inhibition of inflammatory signaling 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 coincided and correlated with decreased atherosclerotic plaque formation. These systemic effects were abrogated upon adipocyte-specific Casr deficiency. Our findings indicate that female mice show a more pronounced obesity associated vWAT dysfunction compared to males. This sex effect is abolished in mice with an adipocyte-specific Casr deficiency. In contrast, females show a diminished hyperlipidemic response to HFD feeding and less atherosclerotic plaque formation compared to males, an effect that was rescued by adipocyte-specific Casr deficiency.