Thermogenic activation represses autophagy in brown adipose tissue

Cairó, Montserrat; Villarroya, Joan; Cereijo, Rubén; Campderrós, Laura; Giralt, Marta; Villarroya, Francesc

doi:10.1038/ijo.2016.115

Cited by 44 publications

(35 citation statements)

References 46 publications

(45 reference statements)

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“…Cold exposure is the primary stimulus for adaptive thermogenesis, but the involvement of autophagy during BAT activation remains unclear. A recent study shows that one day of cold exposure leads to inhibition of autophagy in BAT accompanied by accumulation of mitochondria and UCP1 proteins [52]. However, Martinez-Lopez et al show that activation of lipophagy in BAT after 1 h of acute cold exposure [25].…”

Section: Both Cold Exposure and Thyroid Hormone Increase Autophagy Anmentioning

confidence: 98%

Thyroid hormone (T₃) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy

et al. 2018

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The thyroid hormone triiodothyronine (T) activates thermogenesis by uncoupling electron transport from ATP synthesis in brown adipose tissue (BAT) mitochondria. Although T can induce thermogenesis by sympathetic innervation, little is known about its cell autonomous effects on BAT mitochondria. We thus examined effects of T on mitochondrial activity, autophagy, and metabolism in primary brown adipocytes and BAT and found that T 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. However, when cells were treated with Atg5 siRNA to block autophagy, induction of mitochondrial respiration by T 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 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 increased short and long chain acylcarnitines in BAT, consistent with increased β-oxidation. T also decreased amino acid levels, and in conjunction with SIRT1 activation, decreased MTOR activity to stimulate autophagy. In summary, T 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. Abbreviations: ACACA: acetyl-Coenzyme A carboxylase alpha; AMPK: AMP-activated protein kinase; Acsl1: acyl-CoA synthetase long-chain family member 1; ATG5: autophagy related 5; ATG7: autophagy related 7; ATP: adenosine triphosphate; BAT: brown adipose tissue; cKO: conditional knockout; COX4I1: cytochrome c oxidase subunit 4I1; Cpt1b: carnitine palmitoyltransferase 1b, muscle; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole; DIO2: deiodinase, iodothyronine, type 2; DMEM: Dulbecco's modified Eagle's medium; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; Fabp4: fatty acid binding protein 4, adipocyte; FBS: fetal bovine serum; FCCP: carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; FGF: fibroblast growth factor; FOXO1: forkhead box O1; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; Gpx1: glutathione peroxidase 1; Lipe: lipase, hormone sensitive; MAP1LC3B: microtubule-associated protein 1 light chain 3; mRNA: messenger RNA; MTORC1: mechanistic target of rapamycin kinase complex 1; NAD: nicotinamide adenine dinucleotide; Nrf1: nuclear respiratory factor 1; OCR: oxygen consumption rate; PBS: phosphate-buffered saline; PCR: polymerase chain reaction; PPARGC1A: peroxisome proliferati...

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Section: Both Cold Exposure and Thyroid Hormone Increase Autophagy Anmentioning

confidence: 98%

Thyroid hormone (T₃) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy

et al. 2018

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“…Mice with an adipose-specific impairment of autophagy have more mitochondria in their adipose tissue [97] suggesting that autophagy is essential for mitochondrial clearance in the BAT. At present, it is still controversial how autophagy in the BAT is regulated during the adaptive thermogenesis, since both autophagy inhibition and induction have been observed upon cold exposure [98][99][100]. Nevertheless, mitophagy in the BAT is important to maintain mitochondrial quality control during thermogenesis [22,99].…”

Section: Th Increases Mitophagymentioning

confidence: 99%

Thermogenesis in Adipose Tissue Activated by Thyroid Hormone

Yau

Yen

2020

IJMS

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Thermogenesis is the production of heat that occurs in all warm-blooded animals. During cold exposure, there is obligatory thermogenesis derived from body metabolism as well as adaptive thermogenesis through shivering and non-shivering mechanisms. The latter mainly occurs in brown adipose tissue (BAT) and muscle; however, white adipose tissue (WAT) also can undergo browning via adrenergic stimulation to acquire thermogenic potential. Thyroid hormone (TH) also exerts profound effects on thermoregulation, as decreased body temperature and increased body temperature occur during hypothyroidism and hyperthyroidism, respectively. We have termed the TH-mediated thermogenesis under thermoneutral conditions “activated” thermogenesis. TH acts on the brown and/or white adipose tissues to induce uncoupled respiration through the induction of the uncoupling protein (Ucp1) to generate heat. TH acts centrally to activate the BAT and browning through the sympathetic nervous system. However, recent studies also show that TH acts peripherally on the BAT to directly stimulate Ucp1 expression and thermogenesis through an autophagy-dependent mechanism. Additionally, THs can exert Ucp1-independent effects on thermogenesis, most likely through activation of exothermic metabolic pathways. This review summarizes thermogenic effects of THs on adipose tissues.

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“…Lipophagy in brown adipocytes is regulated by cold exposure, although the effect appears to be dependent on the length of exposure. Whereas chronic cold exposure inhibits lipophagy and associated autophagy components through the cAMP-PKA signaling pathway (70), acute cold exposure activates autophagy-mediated lipid degradation (71). An aspect of concern is the shortage of tools to monitor lipophagy, making it difficult to assess selective lipophagy.…”

Section: Physiological Regulation Of Autophagy In Adipose Tissuesmentioning

confidence: 99%

Mitochondrial homeostasis in adipose tissue remodeling

Altshuler-Keylin

Kajimura

2017

Sci. Signal.

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Mitochondrial homeostasis is regulated by a balance between mitochondrial biogenesis and degradation. Emerging evidence suggests that mitophagy, a selective form of autophagy that degrades mitochondria, plays a key role in the physiology and pathophysiology of mitochondria-enriched cells, such as brown and beige adipocytes. This review discusses findings regarding the roles of autophagy and mitophagy in cellular development, maintenance, and functions of metabolic organs, including adipose tissue, liver, and pancreas. A better understanding of the molecular links between mitophagy and energy metabolism will help to identify promising targets for the treatment of obesity and obesity-associated disorders.

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Thermogenic activation represses autophagy in brown adipose tissue

Abstract: Our results show a noradrenergic-mediated inverse relationship between autophagy and thermogenic activity in BAT and point toward autophagy repression as a component of brown adipocyte adaptive mechanisms to activate thermogenesis.

Cited by 44 publications

References 46 publications

Thyroid hormone (T₃) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy

Thyroid hormone (T₃) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy

Thermogenesis in Adipose Tissue Activated by Thyroid Hormone

Mitochondrial homeostasis in adipose tissue remodeling

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Thermogenic activation represses autophagy in brown adipose tissue

Abstract: Our results show a noradrenergic-mediated inverse relationship between autophagy and thermogenic activity in BAT and point toward autophagy repression as a component of brown adipocyte adaptive mechanisms to activate thermogenesis.

Cited by 44 publications

References 46 publications

Thyroid hormone (T3) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy

Thyroid hormone (T3) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy

Thermogenesis in Adipose Tissue Activated by Thyroid Hormone

Mitochondrial homeostasis in adipose tissue remodeling

Contact Info

Product

Resources

About

Thyroid hormone (T₃) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy

Thyroid hormone (T₃) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy