Journal
AUTOPHAGY
Volume 15, Issue 1, Pages 131-150Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2018.1511263
Keywords
Autophagy; brown adipose tissue; mitochondria; mitophagy; thermogenesis; thyroid hormone
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Funding
- A*STAR [R-913-301-197-304]
- MOH \ National Medical Research Council (NMRC)
- Agency for Science, Technology and Research (A*STAR)
- [NMRC/CIRG/1457/2016]
- [NMRC/CSA/0054/2013]
- [NMRC/CIRG/1340/2012]
- [NMRC/OFYIRG/0002/2016]
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The thyroid hormone triiodothyronine (T-3) activates thermogenesis by uncoupling electron transport from ATP synthesis in brown adipose tissue (BAT) mitochondria. Although T-3 can induce thermogenesis by sympathetic innervation, little is known about its cell autonomous effects on BAT mitochondria. We thus examined effects of T-3 on mitochondrial activity, autophagy, and metabolism in primary brown adipocytes and BAT and found that T-3 increased fatty acid oxidation and mitochondrial respiration as well as autophagic flux, mitophagy, and mitochondrial biogenesis. Interestingly, there was no significant induction of intracellular reactive oxygen species (ROS) despite high mitochondrial respiration and UCP1 induction by T-3. However, when cells were treated with Atg5 siRNA to block autophagy, induction of mitochondrial respiration by T-3 decreased, and was accompanied by ROS accumulation, demonstrating a critical role for autophagic mitochondrial turnover. We next generated an Atg5 conditional knockout mouse model (Atg5 cKO) by injecting Ucp1 promoter-driven Cre-expressing adenovirus into Atg5(Flox/Flox) mice to examine effects of BAT-specific autophagy on thermogenesis in vivo. Hyperthyroid Atg5 cKO mice exhibited lower body temperature than hyperthyroid or euthyroid control mice. Metabolomic analysis showed that T-3 increased short and long chain acylcarnitines in BAT, consistent with increased beta-oxidation. T-3 also decreased amino acid levels, and in conjunction with SIRT1 activation, decreased MTOR activity to stimulate autophagy. In summary, T-3 has direct effects on mitochondrial autophagy, activity, and turnover in BAT that are essential for thermogenesis. Stimulation of BAT activity by thyroid hormone or its analogs may represent a potential therapeutic strategy for obesity and metabolic diseases.
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