Adipogenic effect of calcium sensing receptor activation

Abstract

We established that human adipose cells and the human adipose cell line LS14 express the calcium-sensing receptor (CaSR) and that its activation induces inflammatory cytokine production. Also, its expression is enhanced upon exposure to obesity-associated proinflammatory cytokines. We have thus proposed that CaSR activation may be associated with adipose dysfunction. Here, we evaluated a possible effect on adipogenesis. We induced adipose differentiation of primary and LS14 human preadipocytes with or without the simultaneous activation of CaSR, by the exposure to the calcimimetic cinacalcet. Activation of the receptor for 24 h decreased by 40 % the early differentiation marker CCAAT/enhancer-binding protein β. However, upon longer-term (10 day) exposure to the adipogenic cocktail, cinacalcet exerted the opposite effect, causing a dose-response increase in the expression of the mature adipose markers adipocyte protein 2, adiponectin, peroxisome proliferator-activated receptor γ, fatty acid synthase, and glycerol-3-phosphate dehydrogenase. To assess whether there was a time-sensitive effect of CaSR activation on adipogenesis, we evaluated the 10 day effect of cinacalcet exposure for the first 6, 24, 48 h, 6, and 10 days. Our observations suggest that regardless of the period of exposure, 10 day adipogenesis is elevated by cinacalcet. CaSR activation may interfere with the initial stages of adipocyte differentiation; however, these events do not seem to preclude adipogenesis from continuing. Even though adipogenesis (particularly in subcutaneous depots) is associated with insulin sensitivity and adequate adipose function, the implications of our findings in visceral adipocytes, especially in the context of inflamed AT and overnutrition, remain to be established.

Preadipocyte proliferation is elevated by calcium sensing receptor activation

“…5) proposes that CaSR activation in preadipose cells elicits both a proliferative effect and an elevation in proinflammatory cytokines and chemokines. According to continued CaSR stimulation and other metabolic cues present, part of the preadipocytes will proceed to differentiation (Villarroel et al, 2013) and others may continue to proliferate and contribute to perpetuate the proinflammatory environment. Newly differentiated Fig.…”

Tissue specific role of calcium sensing receptor

“…CaSR activation may interfere with the initial stages of adipocyte differentiation; however, these events do not seem to preclude adipogenesis from continuing. Even though adipogenesis (particularly in subcutaneous depots) is associated with insulin sensitivity and adequate adipose function, the implications of our findings in visceral adipocytes, especially in the context of inflamed AT and over nutrition, remain to be established (Villarroel et al, 2013). Adipocyte differentiation and adipogenesis are closely related to obesity and obesity-induced metabolic disorders.…”

Calcium Sensing Receptor as a Novel Mediator of Adipose Tissue Dysfunction: Mechanisms and Potential Clinical Implications

“…In addition, CaSR activation stimulates the proliferation, and proinflammatory cytokine expression in preadipocytes (Rocha et al, 2015). Moreover, CaSR activation elevates adipogenesis in visceral preadipose cells (Villarroel et al, 2013). …”

“…Studies in both SW872 and LS14 human adipose cell lines have revealed an adipogenic effect of CaSR (He et al, 2012; Villarroel et al, 2013). Exposure to CaSR activators increases the mRNA levels of peroxisome proliferator-activated receptor γ (PPARγ), a master regulator of the adipogenic genetic program, thereby upregulating its downstream genes, such as adipose fatty acid-binding protein (aP2), lipoprotein lipase (LPL), CCAAT element binding protein α (C/EBPα), glycerol-3-phosphate dehydrogenase (GPD), and adiponectin.…”