Calcium Cycling as a Mediator of Thermogenic Metabolism in Adipose Tissue

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Abstract

Canonical nonshivering thermogenesis (NST) in brown and beige fat relies on uncoupling protein 1-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 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 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.

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Guarnieri, A. R., Benson, T. W., & Tranter, M. (2022, July 1). Calcium Cycling as a Mediator of Thermogenic Metabolism in Adipose Tissue. Molecular Pharmacology. American Society for Pharmacology and Experimental Therapy (ASPET). https://doi.org/10.1124/molpharm.121.000465

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