Editors' ChoiceMetabolism

Generating heat through Ca2+ cycling

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Sci. Signal.  12 Dec 2017:
Vol. 10, Issue 509, eaar7068
DOI: 10.1126/scisignal.aar7068

Beige fat regulates whole-body energy homeostasis by cycling Ca2+ through RyR2 and SERCA2b.

The protein UCP1 enables thermogenic tissues, such as brown fat and beige fat (which is white fat that has acquired some of the properties of brown fat), to uncouple mitochondrial respiration from ATP production and generate heat in response to cold or norepinephrine. Ikeda et al. investigated UCP1-independent thermogenic mechanisms in beige fat using Ucp1–/– mice with enhanced beige adipocyte biogenesis in white adipose tissue (WAT) because of overexpression of the transcriptional regulator Prdm16 under the control of the Fabp4 promoter (Prdm16 Tg × Ucp1–/– mice). Unlike Ucp1–/– mice, Prdm16 Tg × Ucp1–/– mice maintained their body temperature under cold conditions. In addition, the temperature of the inguinal WAT of Prdm16 Tg × Ucp1–/– mice increased to a greater extent in response to norepinephrine compared with that of control mice that did not overexpress Prdm16. Compared with Ucp1–/– mice, Prdm16 Tg × Ucp1–/– mice gained less weight on a high-fat diet, had better glucose tolerance, and showed enhanced glucose oxidation through glycolysis in beige fat. RNA-seq analysis of inguinal WAT from Prdm16 Tg × Ucp1–/– mice showed increased expression of Ryr2, which encodes a receptor that releases Ca2+ from the endoplasmic or sarcoplasmic reticulum (ER or SR), and Serca2b, which encodes an ATPase that refills Ca2+ stores in the ER or SR. These results suggested that Ca2+ cycling through RyR2 and SERCA2b (a process that is energetically expensive, as noted by Gamu and Tupling) mediated UCP1-independent thermogenesis in beige adipocytes. The expression of these genes was increased in primary beige adipocytes by norepinephrine, and the norepinephrine-induced increase in the oxygen consumption rate of Ucp1–/– beige adipocytes was reduced by pharmacological SERCA inhibition or genetic ablation of Atp2a2 (the gene that encodes SERCA2b). The norepinephrine-induced increase in temperature was decreased in the inguinal WAT of mice that did not express Atp2a2 in adipose tissue. Conversely, experimental manipulations that increased the abundance, stability, or activity of RyR2 enhanced the norepinephrine-induced increase in oxygen consumption in Ucp1–/– beige adipocytes or mice. Norepinephrine enhanced glycolysis in Ucp1–/– beige adipocytes or Prdm16-overexpressing pig adipocytes (which naturally lack UCP1), effects that were blocked by knockdown of Atp2a2. These results suggest that beige fat is an important regulator of whole-body energy homeostasis through both UCP1-dependent and -independent mechanisms.

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