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Biology subjects

Leiper, J. M.

Publications and source records attributed to Leiper, J. M..

2 recordsLinked to original sources

The Calcium-sensing receptor is an important regulator of female visceral and perivascular adipocyte function.

The Calcium-sensing receptor (CaSR) is a G protein-coupled receptor activated by fluctuations in extracellular calcium concentrations. Its importance in calcium homeostasis has long been established, though its role in other tissues is not well understood. Obesity is a major epidemic with both clinical and social consequences, therefore, understanding the full function and regulation of adipocytes is of critical importance. Adipocyte CaSR has previously been linked to lipolysis and inflammation in vitro. In this study, we set out to further our understanding of adipocyte CaSR in vivo via the generation of an adipocyte specific CaSR knockout mouse (CaSRAd-/-). We found female CaSRAd-/- mice weighed less than wildtype littermates with a significant reduction in visceral adipocyte size potentially due to increased expression of brown fat markers UCP-1 and Cidea. We also established that CaSR is expressed in perivascular adipose tissue (PVAT) and that its deletion protects female mice from PVAT driven hypercontractility. In contrast CaSR deletion had no effect on male body mass, adipocyte size or vascular reactivity. In conclusion, CaSR seems to be of importance in female but not male visceral and perivascular adipose tissue.

physiology↗

Asymmetric dimethylarginine positively modulates Calcium-Sensing Receptor signalling to promote lipid accumulation and adiposity

Irreversible methylation of arginine residues generates asymmetric dimethylarginine (ADMA). ADMA is a competitive inhibitor of nitric oxide (NO) synthase and an independent risk factor for cardiovascular disease. Plasma ADMA concentrations increase with obesity and fall following weight loss. Here, we demonstrate that ADMA drives lipid accumulation through a newly identified NO-independent pathway via the amino-acid sensitive calcium-sensing receptor (CaSR). ADMA treatment of 3T3-L1 and HepG2 cells activates mTOR signalling and upregulates a suite of lipogenic genes with an associated increase in triglyceride content. Pharmacological blockade of CaSR inhibits ADMA driven lipid accumulation and ADMA treatment potentiates CaSR signalling via both Gq and Gi/o pathways. Impairment of ADMA metabolism in adipocytes in vivo, by dimethylamine dimethylaminohydrolase-1 (DDAH1) deletion, increases visceral adiposity and adipocyte hypertrophy. This study identifies a signalling mechanism for ADMA as an endogenous ligand of the G protein-coupled receptor CaSR that potentially contributes to the impact of ADMA in cardiometabolic disease.

physiology↗