Special Section on Cardiometabolic Diseases: At the Crossroads of Adipose Tissue and the Heart-Minireview Calcium Cycling as a Mediator of Thermogenic Metabolism in Adipose Tissue

Canonical nonshivering thermogenesis (NST) in brown and beige fat relies on uncoupling protein 1???mediated heat genera-tion, although alternative mechanisms of NST have been identi-fied, including sarcoplasmic reticulum (SR)???calcium cycling. Intracellular calcium is a crucial cell signaling molecule for which compartmentalization is tightly regulated, and the sarco/ endoplasmic reticulum 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 ac-tivity of SERCA, resulting in the energy of ATP catalysis being expended as heat in the absence of calcium transport. Regu-lins, a class of SR membrane proteins, act to decrease the cal-cium 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 cal-cium influx is equally offset by SR calcium efflux, resulting in ATP consumption without a net change in calcium compart-mentalization. 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 brown adipose tissue???medi-ated 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 signifi-cance of these pathways remain largely unexplored. Thus, this minireview discusses the state of the field regarding calcium cy-cling as a thermogenic mediator in adipose tissue.

Automated summary

This review discusses the role of SERCA-mediated calcium cycling as a significant mediator of thermogenesis in both brown and beige adipocytes, proposing two primary mechanisms: direct uncoupling of ATPase and calcium pump activity, and futile cycling of SR calcium.