Calcium cycling as a mediator of thermogenic metabolism in adipose tissue

Abstract

Canonical non-shivering thermogenesis (NST) in brown and beige fat relies on uncoupling protein 1 (UCP1)-mediated heat generation, although alternative mechanisms of NST have been identified, including sarcoplasmic reticulum (SR)-calcium cycling. Intracellular calcium is a crucial cell signaling molecule for which compartmentalization is tightly regulated, and the sarco-endoplasmic calcium ATPase (SERCA) actively pumps calcium from the cytosol into the SR. In this review, we discuss the capacity of SERCA-mediated calcium cycling as a significant mediator of thermogenesis in both brown and beige adipocytes. Here, we suggest two primary mechanisms of SR calcium mediated thermogenesis. The first mechanism is through direct uncoupling of the ATPase and calcium pump activity of SERCA, resulting in the energy of ATP catalysis being expended as heat in the absence of calcium transport. Regulins, a class of SR membrane proteins, act to decrease the calcium affinity of SERCA and uncouple the calcium transport function from ATPase activity, but remain largely unexplored in adipose tissue thermogenesis. A second mechanism is through futile cycling of SR calcium whereby SERCA-mediated SR calcium influx is equally offset by SR calcium efflux, resulting in ATP consumption without a net change in calcium compartmentalization. A fuller understanding of the functional and mechanistic role of calcium cycling as a mediator of adipose tissue thermogenesis and how manipulation of these pathways can be harnessed for therapeutic gain remains unexplored. Significance Statement Enhancing thermogenic metabolism in brown or beige adipose tissue may be of broad therapeutic utility to reduce obesity and metabolic syndrome. Canonical BAT-mediated thermogenesis occurs via uncoupling protein 1 (UCP1). However, UCP1-independent pathways of thermogenesis, such as sarcoplasmic (SR) calcium cycling, have also been identified, but the regulatory mechanisms and functional significance of these pathways remain largely unexplored. Thus, this mini-review discusses the state of the field with regard to calcium cycling as a thermogenic mediator in adipose tissue.

Keywords: Adipose tissue; calcium signaling.

Fig. 1.

Expression profile of SERCA regulins in muscle and adipose tissue. Expression of the regulins in skeletal muscle, cardiac muscle (atrium and ventricle), and adipose tissue (visceral and subcutaneous WAT) is represented in transcripts per million (TPM) as obtained and compiled from the Genotype-Tissue Expression Project (BAT expression data were not available at the time these data were compiled). ALN expression is enriched in subcutaneous and visceral adipose tissue depots. PLN is readily expressed in adipose tissue as well, although to a lesser extent than what is observed in cardiac and skeletal muscle, while SLN expression is present but limited.

Fig. 2.

Thermogenesis through uncoupling of SR calcium transport. Under normal physiological conditions of SR calcium cycling, SERCA utilizes the energy of ATP hydrolysis to transport calcium against its concentration gradient into the SR (Left). The uncoupling of calcium transport from ATP hydrolysis occurs through structural changes to the calcium binding domains of SERCA induced by binding of unphosphorylated regulins (PLN, SLN, MLN, ELN, and ALN) (Right), and renders SERCA less efficient at calcium transport without affecting ATP hydrolysis activity. In this regulin- bound state, the ATPase-mediated calcium pump efficiency of SERCA is reduced and the excess free energy of ATP hydrolysis is released as heat. Under both conditions, release of calcium from the SER is primarily mediated by RyRs, as well as IP3 receptors. β-adrenergic activation of these pathways potentiates calcium cycling via phosphorylation of RyRs and regulins, which reduces their interaction with SERCA through a PKA/cAMP-dependent mechanism. α-adrenergic signaling can also induce SER calcium release through a PLC/IP3-dependent activation of IP3 receptors. As the SERCA-mediated calcium pump is inherently inefficient, a second potential thermogenic mechanism is futile SR calcium transport by SERCA that is offset by equal RyR- or IP3-mediated SR calcium efflux.