Abstract
Autophagy is upregulated in adipose tissue (AT) from people with obesity. We showed that activation of the calcium-sensing receptor (CaSR) elevates proinflammatory cytokines through autophagy in preadipocytes. Our aim is to understand the role of CaSR on autophagy in AT from humans with obesity. We determined mRNA and protein levels of CaSR and markers of autophagy by qPCR and western blot in human visceral AT explants or isolated primary preadipocytes (60 donors: 72% female, 23–56% body fat). We also investigated their association with donors’ anthropometric variables. Donors’ % body fat and CaSR mRNA expression in AT were correlated (r = 0.44, p < 0.01). CaSR expression was associated with mRNA levels of the autophagy markers atg5 (r = 0.37, p < 0.01), atg7 (r = 0.29, p < 0.05) and lc3b (r = 0.40, p < 0.01). CaSR activation increased becn and atg7 mRNA expression in AT. CaSR activation also upregulated LC3II by ~50%, an effect abolished by the CaSR inhibitor. Spermine (CaSR agonist) regulates LC3II through the ERK1/2 pathway. Structural equation model analysis suggests a link between donors’ AT CaSR expression, AT autophagy and expression of Tumor Necrosis Factor alpha TNF-α. CaSR expression in visceral AT is directly associated with % body fat, and CaSR activation may contribute to obesity-related disruption in AT autophagy.
Highlights
Autophagy is a conserved intracellular catabolic mechanism that delivers damaged organelles and macromolecules to lysosomes for degradation, which is critical for energy supply and cellular homeostasis
We found that greater calcium-sensing receptor (CaSR) mRNA correlates with higher autophagy marker transcripts, and that CaSR activation induces LC3II accumulation in human adipose tissue (AT) explants
Previous studies have reported that CaSR modulates autophagy in THP-1 macrophages [20], cardiac fibroblasts [21] and kidney cells [22]
Summary
Autophagy is a conserved intracellular catabolic mechanism that delivers damaged organelles and macromolecules to lysosomes for degradation, which is critical for energy supply and cellular homeostasis. In vivo and in vitro studies have proposed that autophagy is dysregulated in obesity in a tissue/cell-dependent manner [1,2,3,4], contributing to development of cardiometabolic comorbidities. Adipose tissue (AT) from patients with obesity and T2D shows enhanced autophagy [1,2,7]. A study in AT from patients with obesity showed greater mRNA expression of the autophagy-related genes Atg, lc3a and lc3b than their lean counterparts, as well as in visceral versus subcutaneous depot [2]. Atg, lc3a and lc3b mRNA levels were higher in visceral AT of patients with obesity and insulin resistance as compared with those with obesity but who are insulin-sensitive [2], suggesting an association between increased AT autophagy markers and the presence of obesity-related metabolic derangements
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