The role of CaSR signalling in adipocytes and its regulation by ADMA

Higgins, Erin Dawn (2023) The role of CaSR signalling in adipocytes and its regulation by ADMA. PhD thesis, University of Glasgow.

Abstract

The amino acid sensitive calcium-sensing receptor (CaSR) plays a critical role in regulating extracellular calcium ([Ca2+]o) levels. In addition to maintaining [Ca2+] homeostasis, the CaSR is involved in a variety of non-calciotropic functions, among which it has emerged as a mediator of adipocyte (patho)physiology.

Recent work in our lab has revealed that adipocyte hypertrophy is stimulated by the amino acid asymmetric dimethylarginine (ADMA) via a nitric oxideindependent, CaSR pathway. However, the underpinning mechanisms and relevance in adipocytes was not clearly identified. This thesis aimed to delineate CaSR signalling pathways in vitro, and subsequently test the effect of ADMA on CaSR downstream signalling and functions. CaSR was investigated first in HEK293 cells overexpressing CaSR, which showed CaSR-dependent ERK1/2 signalling in response to pharmacological CaSR stimulation and exogenous ADMA. Next, CaSR/ADMA signalling pathways were examined using 3T3-L1 cells modelling mature adipocytes. Agonist-induced CaSR signalling caused adipocyte hypertrophy, leptin secretion and lipogenic gene expression. ADMA enlarged adipocytes, and ADMA-induced lipogenic gene expression was perturbed by CaSR blockade indicating ADMA/CaSR crosstalk in adipocytes. However, ADMA was unable to fully replicate the effects of CaSR acting in adipocytes highlighting the complexity of CaSR signalling pathways requiring further investigation.

Adipose tissue (AT) dysfunction is a key mechanism linking metabolic disorders and cardiovascular disease (CVD). The CaSR is associated with CVD, but the relevance of adipocyte CaSR in cardiovascular health has not been directly examined. Therefore, this thesis also aimed to investigate the function of adipocyte CaSR, and determine its significance in AT and cardiovascular biology. To investigate the role of adipocyte CaSR in vivo, this thesis generated a murine model of adipocyte-specific CaSR deficiency. In female mice specifically, body weight, adipocyte size and AT-induced vascular contractility was reduced. This thesis establishes ADMA as a potentially novel ligand of CaSR, and demonstrates that adipocyte CaSR can impact on AT biology as well as cardiometabolic health in the intact animal.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Supported by funding from the British Heart Foundation.
• Subjects: Q Science > QR Microbiology
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Supervisor's Name: Leiper, Professor James and Milligan, Professor Graeme
• Date of Award: 2023
• Depositing User: Theses Team
• Unique ID: glathesis:2023-83784
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 28 Aug 2023 13:28
• Last Modified: 28 Aug 2023 13:31
• Thesis DOI: 10.5525/gla.thesis.83784
• URI: https://theses.gla.ac.uk/id/eprint/83784

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