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Cited by 476Mitochondrial Function and PathologyAdipose Tissue and MetabolismAutophagy in Disease and Therapy

Mitochondrial Uncoupling: A Key Controller of Biological Processes in Physiology and Diseases

Open access
Demine, Stéphane, Renard, Patricia, Arnould, Thierry·2019·Cells
DOI 10.3390/cells8080795PMC PMC6721602
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Abstract

Mitochondrial uncoupling can be defined as a dissociation between mitochondrial membrane potential generation and its use for mitochondria-dependent ATP synthesis. Although this process was originally considered a mitochondrial dysfunction, the identification of UCP-1 as an endogenous physiological uncoupling protein suggests that the process could be involved in many other biological processes. In this review, we first compare the mitochondrial uncoupling agents available in term of mechanistic and non-specific effects. Proteins regulating mitochondrial uncoupling, as well as chemical compounds with uncoupling properties are discussed. Second, we summarize the most recent findings linking mitochondrial uncoupling and other cellular or biological processes, such as bulk and specific autophagy, reactive oxygen species production, protein secretion, cell death, physical exercise, metabolic adaptations in adipose tissue, and cell signaling. Finally, we show how mitochondrial uncoupling could be used to treat several human diseases, such as obesity, cardiovascular diseases, or neurological disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

Mitochondrial uncoupling is a dissociation between mitochondrial membrane potential generation and ATP synthesis, and this review argues it is not merely dysfunction but a regulator of autophagy, ROS, secretion, cell death, exercise adaptation, adipose biology, and disease. It surveys natural and synthetic uncouplers and their therapeutic potential, while cautioning that most mechanistic evidence comes from non-specific agents such as DNP and FCCP.

Key findings

  • Basal proton leak can account for up to 30–50% of resting cellular metabolic rate, and ANTs can account for up to 50% of basal mitochondrial membrane proton conductance.
  • UCP-1 is a well-established uncoupling protein, but uncoupling properties of other UCPs remain debated; UCP-3 expression is 200–700-fold lower than UCP-1 in mouse skeletal muscle, so overexpression models may be artefactual.
  • Mitochondrial uncoupling is linked to bulk and specific autophagy/mitophagy, ROS production, protein secretion, cell death, physical exercise, adipose tissue browning, and cell signaling; mitochondrial ROS release can account for 0.1–0.2% of O₂ consumed in rat tissues.
  • Therapeutic potential is discussed for obesity, diabetes, cardiovascular disease, and neurological disorders; controlled-release DNP in rats decreased fasting plasma glucose, fatty acids by 30%, TAG, HDL by 30%, and hyperinsulinemia by 50%, with 50–90% decreases in TAG in plasma, liver, and skeletal muscle. DNP at 30 °C decreased energy expenditure by 17% and weight loss by 23% in female C57BL/6J mice, while no significant effect was observed at 22 °C.

Methods

  • Narrative review comparing mitochondrial uncoupling agents, uncoupling proteins (UCPs and ANTs), and chemical compounds with uncoupling properties.
  • Synthesizes cited literature on cellular and biological processes including autophagy, mitophagy, ROS production, protein secretion, cell death, physical exercise, adipose tissue browning, and cell signaling.
  • Discusses possible use of mitochondrial uncouplers in human diseases such as obesity, cardiovascular diseases, and neurological disorders; no primary experimental data or systematic search strategy is reported.

Limitations

  • The authors state that most mechanistic studies have focused on classical but non-specific uncouplers such as DNP or FCCP, making it difficult to discriminate effects directly imputable to mitochondrial uncoupling from unspecific effects.
  • The authors state that cellular consequences have not been studied rigorously and that continuous development of mitochondria-specific uncoupling agents is needed to improve knowledge and safety.
  • Evident from the text: this is a narrative review without stated systematic search or inclusion criteria, and many findings are described as conflicting or dependent on species, cell type, temperature, membrane composition, and uncoupler used.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/cells8080795

Cites

298 of 298 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 236 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    UCP-3 has no clear uncoupling effect in CHO cells overexpressing it or in rat skeletal muscles.

    “Regarding UCP-3, several groups reported that UCP-3 has no clear uncoupling effect as it does, for instance, in CHO cells overexpressing this protein [19] or in rat skeletal muscles [20].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [19] Mozo, 2006, Expression of UCP3 in CHO cells does not cause uncoupling, but controls mitochondrial activity in the presence of glucose, Biochem. J. source

      Not checked in the free run.

    • cites [20] Cadenas, 1999, UCP2 and UCP3 rise in starved rat skeletal muscle but mitochondrial proton conductance is unchanged, FEBS Lett. source

      Not checked in the free run.

  • Premisecitation

    Purine nucleotides such as GDP directly bind UCP-1 and lead to its inactivation.

    “First, purine nucleotides, such as GDP, directly bind UCP-1 and lead to its inactivation [8].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Rial, 1983, Brown-adipose-tissue mitochondria: The regulation of the 32000-Mr uncoupling protein by fatty acids and purine nucleotides, JBIC J. Biol. Inorg. Chem.

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  • Premisecitation

    UCP-2 can only be activated under circumstances such as massive entry of FFAs into mitochondria.

    “UCP-2 could then only be activated under some circumstances, such as a massive entry of FFAs into mitochondria [18].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Berardi, 2014, Fatty Acid Flippase Activity of UCP2 Is Essential for Its Proton Transport in Mitochondria, Cell Metab. source

      Not checked in the free run.

  • Premisecitation

    ANTs can account for up to 50% of basal mitochondrial membrane proton conductance.

    “Underlining their importance, ANTs can account for up to 50% of basal mitochondrial membrane proton conductance [25].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Brand, 2005, The basal proton conductance of mitochondria depends on adenine nucleotide translocase content, Biochem. J. source

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  • Premisecitation

    Free fatty acids promote UCP-1-dependent proton leak.

    “Second, free fatty acids (FFAs) are well-known to promote UCP-1-dependent protein leak [8,9].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Rial, 1983, Brown-adipose-tissue mitochondria: The regulation of the 32000-Mr uncoupling protein by fatty acids and purine nucleotides, JBIC J. Biol. Inorg. Chem.

      Not checked in the free run.

    • cites [9] Strieleman, 1985, Fatty acid activation of the reconstituted brown adipose tissue mitochondria uncoupling protein, J. Biol. Chem. source

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  • May combine two claims. 63
  • Classified as probably not a substantial claim. 14
  • The quote only partly states this claim. 1

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    Premisecitation

    UCP-1 is a transmembrane protein localized in the inner mitochondrial membrane that catalyzes proton transport across the mitochondrial membrane and thereby induces mitochondrial uncoupling.

    “UCP-1 is a transmembrane protein localized in the inner mitochondrial membrane catalyzing the transport of protons across the mitochondrial membrane and thereby inducing mitochondrial uncoupling [7].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Jacobsson, 1985, Mitochondrial uncoupling protein from mouse brown fat. Molecular cloning, genetic mapping, and mRNA expression, J. Biol. Chem. source

      Not checked in the free run.

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    Premisecitation

    UCP-1 activity is modulated by phosphorylation, which increases in response to cold in rats.

    “In addition, UCP-1 activity is also tightly modulated by phosphorylation, a phenomenon shown to increase in response to cold in rats [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Carroll, 2008, Identification of serine phosphorylation in mitochondrial uncoupling protein 1, Biochim. Biophys. Acta source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    UCP-2 activity can be completely blocked by GDP at basal state (100 μM).

    “The same authors suggested that UCP-2 activity could be completely blocked by GDP at the basal state (100 µM, which corresponds to the basal intracellular GDP/GTP concentration) [18].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Berardi, 2014, Fatty Acid Flippase Activity of UCP2 Is Essential for Its Proton Transport in Mitochondria, Cell Metab. source

      Not checked in the free run.

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    Premisecitation

    Basal proton leak depends on inner mitochondrial membrane composition and can account for up to 30-50% of resting cellular metabolic rate.

    “This process essentially depends on the composition of the inner mitochondrial membrane and could account for up to 30–50% of the resting cellular metabolic rate [3].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Jastroch, 2010, Mitochondrial proton and electron leaks, Essays Biochem. source

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    Premisecitation

    Strong evidence of mitochondrial uncoupling property is clear for UCP-1 but still heavily debated for other UCPs.

    “Importantly, although strong evidence of the mitochondrial uncoupling property is clear for UCP-1 [7,12], it is still heavily debated for the other UCPs [13,14,15].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [7] Jacobsson, 1985, Mitochondrial uncoupling protein from mouse brown fat. Molecular cloning, genetic mapping, and mRNA expression, J. Biol. Chem. source

      Not checked in the free run.

    • cites [12] Nedergaard, 2001, UCP1: The only protein able to mediate adaptive non-shivering thermogenesis and metabolic inefficiency, Biochim. Biophys. Acta source

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    • cites [13] Bouillaud, 2009, UCP2, not a physiologically relevant uncoupler but a glucose sparing switch impacting ROS production and glucose sensing, Biochim. Biophys. Acta source

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    • cites [14] Shabalina, 2011, Mitochondrial (‘mild’) uncoupling and ROS production: Physiologically relevant or not?, Biochem. Soc. Trans. source

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    • cites [15] Stuart, 2001, Physiological Levels of Mammalian Uncoupling Protein 2 Do Not Uncouple Yeast Mitochondria, J. Biol. Chem. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The molecular mechanism of ANT uncoupling is suggested to depend on transport of fatty acids.

    “The molecular mechanism is not entirely clear but has been suggested to depend on the transport of fatty acids [23,24].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] Andreyev, 1989, The ATP/ADP-antiporter is involved in the uncoupling effect of fatty acids on mitochondria, JBIC J. Biol. Inorg. Chem.

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    • cites [24] Sparks, 2016, ANT1-mediated fatty acid-induced uncoupling as a target for improving myocellular insulin sensitivity, Diabetologia source

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    Premisecitation

    BAM15 is a novel mitochondria-specific protonophore uncoupler with similar potency to FCCP or DNP.

    “For instance, BAM15 ((2-fluorophenyl)6-[(2-fluorophenyl)amino](1,2,5-oxadiazolo[3,4-e]pyrazin-5-yl)amine) is a novel mitochondria-specific protonophore uncoupler that possesses a similar potency to FCCP or DNP [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Kenwood, 2014, Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane, Mol. Metab. source

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    Premisecitation

    CCCP can interfere with lysosomal function and inhibit autophagic cargo degradation in both yeast and HeLa cells.

    “For instance, CCCP can interfere with lysosomal function and inhibit autophagic cargo degradation in both yeast and HeLa cells [83].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Padman, 2013, The protonophore CCCP interferes with lysosomal degradation of autophagic cargo in yeast and mammalian cells, Autophagy source

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    Premisecitation

    FCCP triggers a form of autophagy in 3T3-L1 murine white adipocytes, and a low concentration (0.5 μM) reduces adipocyte triacylglycerol content via lipolysis activation independent of HSL and ATGL.

    “In this model, a low concentration (0.5 μM) in this mitochondrial uncoupler is sufficient to reduce adipocyte triacylglycerol (TAG) content, resulting from a lipolysis activation that is independent of the classical cytosolic lipases HSL (Hormone Sensitive Lipase) and ATGL (Adipose Triglyceride Lipase) [91].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] Demine, 2018, Mild mitochondrial uncoupling induces HSL/ATGL-independent lipolysis relying on a form of autophagy in 3T3-L1 adipocytes, J. Cell. Physiol. source

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    Premisecitation

    Catecholamines such as noradrenaline activate β3 adrenergic receptors and upregulate UCP-1 expression in mouse, rat, and human brown adipose tissues.

    “These molecules are also known to upregulate UCP-1 expression in many models, including mouse [40,41], rat [42,43], and human [44] brown adipose tissues.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [40] Rehnmark, 1990, Alpha- and beta-adrenergic induction of the expression of the uncoupling protein thermogenin in brown adipocytes differentiated in culture, J. Biol. Chem. source

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    • cites [41] Champigny, 1992, Regulation of UCP gene expression in brown adipocytes differentiated in primary culture. Effects of a new beta-adrenoceptor agonist, Mol. Cell. Endocrinol. source

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    • cites [42] Silva, 1988, Full Expression of Uncoupling Protein Gene Requires the Concurrence of Norepinephrine and Triiodothyronine, Mol. Endocrinol. source

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    • cites [43] Herron, 1990, Norepinephrine-induced synthesis of the uncoupling protein thermogenin (UCP) and its mitochondrial targeting in brown adipocytes differentiated in culture, FEBS Lett. source

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    • cites [44] Champigny, 1996, Evidence from in vitro differentiating cells that adrenoceptor agonists can increase uncoupling protein mRNA level in adipocytes of adult humans: An RT-PCR study, J. Lipid Res. source

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    Interpretationcitation

    FR58P1 mildly uncouples mitochondria, leading to mitochondrial clearance by mitophagy, activation of the cytoprotective AMPK/Sirt1 axis, and a glycolytic shift.

    “In summary, FR58P1 mildly uncouples mitochondria, leading to a mitochondrial clearance by mitophagy, activation of the cytoprotective AMPK/Sirt1 axis, and a glycolytic shift.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Urra, 2018, FR58P1a; a new uncoupler of OXPHOS that inhibits migration in triple-negative breast cancer cells via Sirt1/AMPK/β1-integrin pathway, Sci. Rep. source

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    Premisecitation

    Mice deficient for LAL exhibit BAT with lysosome and lipid droplet accumulation, reduced UCP-1 expression, and mitochondrial dysfunction.

    “Indeed, mice deficient for LAL (Lysosomal Acid Lipase, lysosomal lipase) exhibit BAT with lysosome and lipid droplet accumulation, reduced UCP-1 expression, and mitochondrial dysfunction [97].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Sachdev, 2018, Lysosomal acid lipase regulates fatty acid channeling in brown adipose tissue to maintain thermogenesis, Biochim. Biophys. Acta Mol. Cell. Biol. Lipids

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    Premisecitation

    Low doses of CCCP (5 μM) or C12TPP (0.2 nM) do not upregulate macroautophagy in human EAhy926 endothelial cells but still induce an anti-inflammatory response, including reduction in expression of E-selectin, ICAM1, and VCAM1 and in adhesion of neutrophils to endothelium induced by TNFα.

    “For instance, low doses of CCCP (5 μM) or C12TPP (0.2 nM) do not upregulate macroautophagy in human EAhy926 endothelial cells but still induce an anti-inflammatory response, including reduction in the expression of E-selectin, ICAM1, and VCAM1 and in the adhesion of neutrophils to endothelium induced by TNFα (Tumor Necrosis Factor α) [95].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Romaschenko, 2015, Low concentrations of uncouplers of oxidative phosphorylation prevent inflammatory activation of endothelial cells by tumor necrosis factor, Biochemistry

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    Premisecitation

    Cloxyquin protects mouse cardiomyocytes against ischemia-reperfusion, an effect requiring autophagy.

    “Indeed, the mitochondrial uncoupler cloxyquin (5-chloro-8-hydroxyquinoline) protects mouse cardiomyocytes against ischemia-reperfusion, an effect requiring autophagy [99].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Zhang, 2016, The cardioprotective compound cloxyquin uncouples mitochondria and induces autophagy, Am. J. Physiol. Heart Circ. Physiol. source

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    Premisecitation

    T3 regulates mitochondrial uncoupling by sympathetic stimulation, by increasing acylcarnitine production, and by directly stimulating transcription of the Ucp1 gene.

    “T3 regulates mitochondrial uncoupling by different mechanisms: (1) by sympathetic stimulation [61], (2) by increasing acylcarnitine production [61], thereby activating mitochondrial respiration/uncoupling, and (3) by directly stimulating the transcription of the Ucp1 gene [37].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [61] Yau, 2019, Thyroid hormone (T3) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy, Autophagy source

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    • cites [37] Villarroya, 2017, Transcriptional regulation of the uncoupling protein-1 gene, Biochimie source

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    Premisecitation

    PUFAs such as EPA and DHA stimulate UCP1 expression and adaptive non-shivering or diet-induced thermogenesis in brown adipocytes, as well as browning of WAT in C57BL/6 mice, Sprague-Dawley rats, and overweight humans.

    “PUFAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also stimulate UCP1 expression and thus adaptive non-shivering or diet-induced thermogenesis in brown adipocytes, as well as the browning of the white adipose tissue (WAT) in C57BL/6 mice [67,68], Sprague-Dawley rats [69,70], and overweight humans [71].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [67] Bargut, T.C.L., Martins, F.F., Santos, L.P., Aguila, M.B., and Mandarim-de-Lacerda, C.A. (2018). Administration of eicosapentaenoic and docosahexaenoic acids may improve the remodeling and browning in subcutaneous white adipose tissue and thermogenic markers in brown adipose tissue in mice. Mol. Cell. Endocrinol. source

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    • cites [68] Zhao, 2014, Eicosapentaenoic acid promotes thermogenic and fatty acid storage capacity in mouse subcutaneous adipocytes, Biochem. Biophys. Res. Commun. source

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    • cites [69] Oudart, 1997, Brown fat thermogenesis in rats fed high-fat diets enriched with n-3 polyunsaturated fatty acids, Int. J. Obes. source

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    • cites [70] Takahashi, 2000, Dietary n-3 fatty acids affect mRNA level of brown adipose tissue uncoupling protein 1, and white adipose tissue leptin and glucose transporter 4 in the rat, Br. J. Nutr. source

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    • cites [71] Laiglesia, 2016, Eicosapentaenoic acid promotes mitochondrial biogenesis and beige-like features in subcutaneous adipocytes from overweight subjects, J. Nutr. Biochem. source

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  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    BAM15 has low or no effect on plasma membrane polarization and exhibits less cytotoxicity.

    “However, BAM15 has low or no effect on plasma membrane polarization, as seen in rat L6 myoblasts [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Kenwood, 2014, Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane, Mol. Metab. source

      Not checked in the free run.

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    Premisecitation

    The uncoupler effect of T3 seems to require autophagy, at least partially; hyperthyroidic Atg5KO mice have lower body temperature and lower mitochondrial uncoupling than WT littermates.

    “Indeed, hyperthyroidic Atg5KO mice are characterized by a lower body temperature and lower mitochondrial uncoupling than WT littermates [61].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Yau, 2019, Thyroid hormone (T3) stimulates brown adipose tissue activation via mitochondrial biogenesis and MTOR-mediated mitophagy, Autophagy source

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    Premisecitation

    Mitochondrial uncoupling is often associated with autophagy activation, and more specifically with mitophagy.

    “Mitochondrial uncoupling has often been associated with autophagy activation, and more specifically, with mitophagy (specific degradation of mitochondria by macroautophagy) (Figure 1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Lyamzaev, 2018, Induction of autophagy by depolarization of mitochondria, Autophagy source

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    Premisecitation

    Rapamycin protects primary murine mesencephalic cells against rotenone-induced cell death and is accompanied by an increase in mitochondrial potential membrane.

    “Interestingly, rapamycin treatment is accompanied by an increase in mitochondrial potential membrane [100], suggesting, again, a link between mitochondrial (un)coupling and autophagy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Radad, 2015, Rapamycin protects dopaminergic neurons against rotenone-induced cell death in primary mesencephalic cell culture, Folia Neuropathol. source

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    Premisecitation

    In humans, physical exercise increases total mitochondrial mass and uncoupling in skeletal muscular cells.

    “In humans, physical exercise increases total mitochondrial mass and uncoupling in skeletal muscular cells [192].”
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    • cites [192] Phielix, 2010, Exercise training increases mitochondrial content and ex vivo mitochondrial function similarly in patients with type 2 diabetes and in control individuals, Diabetologia source

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    Premisecitation

    Use of CCCP or FCCP decreases the Ca2+ buffering capacity of mitochondria and increases global exocytosis in bovine and rat chromaffin cells but not in the same cell type in mice.

    “In accordance with this theory, use of CCCP or FCCP decreases the Ca2+ buffering capacity of mitochondria and increases global exocytosis in bovine [164,165] and rat chromaffin cells [166] but not in the same cell type in mice [167], suggesting species differences.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [164] Giovannucci, 1999, Mitochondria regulate the Ca(2+)-exocytosis relationship of bovine adrenal chromaffin cells, J. Neurosci. source

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    • cites [165] Jurkiewicz, 2013, Novel features on the regulation by mitochondria of calcium and secretion transients in chromaffin cells challenged with acetylcholine at 37°C, Physiol. Rep. source

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    • cites [166] Jurkiewicz, 2009, Role of the Endoplasmic Reticulum and Mitochondria on Quantal Catecholamine Release from Chromaffin Cells of Control and Hypertensive Rats, J. Pharmacol. Exp. Ther. source

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    • cites [167] Fuentealba, 2005, Depolarization evokes different patterns of calcium signals and exocytosis in bovine and mouse chromaffin cells: The role of mitochondria, Eur. J. Neurosci. source

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    Premisecitation

    Physical exercise directly reduces proton leak and ROS production and increases mitochondrial membrane potential, suggesting an improvement of mitochondrial coupling.

    “First, physical exercise by itself directly reduces proton leak and ROS production and increases mitochondrial membrane potential, suggesting an improvement of mitochondrial coupling (Figure 3).”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Irisin is mainly secreted by skeletal muscle cells, although some secretion was also reported in WAT and, to a lesser extent, in BAT.

    “Irisin is mainly secreted by skeletal muscle cells, although some secretion was also reported in WAT [204] and, to a lesser extent, in BAT [204,205].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [204] Roca-Rivada, A., Castelao, C., Senin, L.L., Landrove, M.O., Baltar, J., Crujeiras, A.B., Seoane, L.M., Casanueva, F.F., and Pardo, M. (2013). FNDC5/Irisin Is Not Only a Myokine but Also an Adipokine. PLoS ONE, 8. source

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    • cites [205] 2018, Irisin a Novel Metabolic biomarker: Present knowledge and future directions, Int. J. Endocrinol.

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Brown adipocytes express UCP-1, allowing these cells to oxidize fatty acids in order to dissipate and produce energy as heat, a phenomenon called non-shivering adaptive thermogenesis.

    “Another hallmark of this tissue is the expression of UCP-1, allowing these cells to oxidize fatty acids in order to dissipate and produce energy as heat, a phenomenon called “non-shivering adaptive thermogenesis.””
    Quote in the paperNot a substantial claim

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    Premisecitation

    Overexpression of ANT-1 (but not ANT2) promotes apoptosis.

    “Contrary to UCP-1, the effect of the overexpression of ANT-1 (but not ANT2 [184]) is well-known to promote apoptosis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [184] Zamora, 2004, Recruitment of NF-κB into Mitochondria Is Involved in Adenine Nucleotide Translocase 1 (ANT1)-induced Apoptosis, J. Biol. Chem. source

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    Premisecitation

    Three types of adipose tissues have been identified so far: WAT, BAT, and beige or brite (BIWAT).

    “Three types of adipose tissues have been identified so far: The WAT [218], the BAT [219,220], and the beige or brite (brown in white) adipose tissue (BIWAT) [220].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [218] Rutkowski, 2015, The cell biology of fat expansion, J. Cell Biol. source

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    • cites [219] Schulz, 2013, Brown adipose tissue: Development, metabolism and beyond, Biochem. J. source

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    • cites [220] Harms, 2013, Brown and beige fat: Development, function and therapeutic potential, Nat. Med. source

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    Premisecitation

    Mice treated with DNP present a decrease in mTOR activity, in the insulin-PI3K-MAPK signaling pathways, and a stimulation of the Ca2+-CREB axis accompanied by an increase in autophagy.

    “Indeed, mice treated with DNP present a decrease in mTOR activity, in the insulin-PI3K-MAPK signaling pathways, and a stimulation of the Ca2+-CREB axis accompanied by an increase in autophagy [94].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Liu, 2015, The Mitochondrial Uncoupler DNP Triggers Brain Cell mTOR Signaling Network Reprogramming and CREB Pathway Upregulation, J. Neurochem. source

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    Interpretationcitation

    Mitochondrial uncoupling, by decreasing ATP content, could slow down the energy-demanding steps in protein secretion.

    “To explain this effect, it was suggested that mitochondrial uncoupling, by decreasing ATP content, could slow down the energy-demanding steps in protein secretion [160].”
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    • cites [160] Argon, 1989, Two steps in the intracellular transport of IgD are sensitive to energy depletion, J. Immunol. source

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    Interpretationreasoning

    Induction of mitochondrial uncoupling would theoretically lead to a decrease in ROS production.

    “Based on the simple model described above, the induction of mitochondrial uncoupling would theoretically lead to a decrease in ROS production (Figure 2).”
    Quote in the paperSubstantial claim

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    Premisecitation

    Excessive ROS production damages mitochondria and induces secondary mitochondrial respiration uncoupling.

    “In fine, excessive ROS production damages mitochondria and induces secondary mitochondrial respiration uncoupling [158].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [158] Ma, 2015, Mitochondrial targeted β-lapachone induces mitochondrial dysfunction and catastrophic vacuolization in cancer cells, Bioorg. Med. Chem. Lett. source

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    Premisecitation

    This coupling is not complete and leads to the production of ROS, a process called electron leak.

    “However, this coupling is not complete and leads in fine to the production of ROS, a process called electron leak [3] (Figure 2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Jastroch, 2010, Mitochondrial proton and electron leaks, Essays Biochem. source

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  • May combine two claims.

    Premisecitation

    No increase in the mitochondrial uncoupling rate was found in subcutaneous inguinal WAT of rats exposed to cold, even though UCP-1 protein expression was elevated as expected.

    “Indeed, no increase in the mitochondrial uncoupling rate in subcutaneous inguinal WAT of rats exposed to cold was found, even though UCP-1 protein expression was elevated as expected [223].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [223] Jani, 2019, Cold acclimation enhances UCP1 content, lipolysis, and triacylglycerol resynthesis, but not mitochondrial uncoupling and fat oxidation, in rat white adipocytes, Am. J. Physiol. Physiol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In adipose tissue, IL-18 is released by both macrophages and adipocytes in obese mice and humans.

    “In the adipose tissue, the latest cytokine is released by both macrophages and adipocytes in obese mice and humans [237,238].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [237] Ahmad, 2017, Increased adipose tissue expression of IL-18R and its ligand IL-18 associates with inflammation and insulin resistance in obesity, Immun. Inflamm. Dis. source

      Not checked in the free run.

    • cites [238] Skurk, 2005, The proatherogenic cytokine interleukin-18 is secreted by human adipocytes, Eur. J. Endocrinol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    C57BL7 mice deficient for IL-18 exhibit larger brown adipocytes and higher UCP-1 expression in BAT compared to wild-type littermates.

    “Indeed, C57BL7 mice deficient for IL-18 are extremely sensitive to obesity but also exhibit larger brown adipocytes and a higher UCP-1 expression in BAT compared to wild-type littermates [240].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [240] Yamanishi, 2018, Deficiency in interleukin-18 promotes differentiation of brown adipose tissue resulting in fat accumulation despite dyslipidemia, J. Transl. Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effect of IL-1β on white adipocytes includes an increase in ROS production, a decrease in SOD activity, and mitochondrial depolarization.

    “The effect of IL-1β on white adipocytes includes an increase in ROS production, a decrease in SOD activity, and mitochondrial depolarization [229].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [229] Okla, 2018, Inhibitory effects of toll-like receptor 4, NLRP3 inflammasome, and interleukin-1β on white adipocyte browning, Inflammation source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice KO for IL-18r or for IL-18 are both overweight at the basal state but protected against diet-induced obesity.

    “If both mouse models are overweight at the basal state but protected against diet-induced obesity, only IL-18r KO mice can increase thermogenesis and white browning in response to HFD or cold [241].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [241] Pazos, 2015, Divergent responses to thermogenic stimuli in BAT and subcutaneous adipose tissue from interleukin 18 and interleukin 18 receptor 1-deficient mice, Sci. Rep. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    IL-18 expression seems to be tightly correlated with other proinflammatory markers such as TNFα.

    “IL-18 expression seems to be tightly correlated to other proinflammatory markers, such as TNFα, and a linear correlation between IL-18 and BMI was found in humans [237].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [237] Ahmad, 2017, Increased adipose tissue expression of IL-18R and its ligand IL-18 associates with inflammation and insulin resistance in obesity, Immun. Inflamm. Dis. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The precise action of IL-18 is likely complex and possibly independent of the IL-18 receptor.

    “The precise action of IL-18 is likely to be complex and possibly independent from the IL-18 receptor (IL-18r).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Sestrins are stress-inducible proteins involved in negative regulation of the AMPK/TORC1 axis and in ROS detoxification by restoring the activity of oxidized peroxiredoxins.

    “Sestrins are a family of stress-inducible proteins involved in the negative regulation of the AMPK/TORC1 axis [227] and in ROS detoxifying by restoration of the activity of oxidized peroxiredoxins [227,228].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [227] Budanov, 2010, Stressin’ Sestrins take an aging fight, EMBO Mol. Med. source

      Not checked in the free run.

    • cites [228] Budanov, 2004, Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD, Science source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The reduction of browning by NLRP3 activation seems to be due to IL-1β release by macrophages, as IL-1β blocking antibodies protected human white adipocytes.

    “This effect seems to be due to IL-1β release by macrophages, as IL-1β blocking antibodies protected the human white adipocytes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [229] Okla, 2018, Inhibitory effects of toll-like receptor 4, NLRP3 inflammasome, and interleukin-1β on white adipocyte browning, Inflammation source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In combination with IL-2, IL-18 can promote a Th2 response, while a Th1 response is promoted in response to IL-12.

    “For instance, in combination with IL-2, IL-18 can promote a Th2 response, while a Th1 response will be promoted in response to IL-12 (reviewed here [239]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [239] Seljeflot, 2010, The role of interleukin-18 in the metabolic syndrome, Cardiovasc. Diabetol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    IL-18 enhances both T cell and natural killer cell maturation and promotes proinflammatory cytokine release.

    “IL-18 is known to enhance both T cell and natural killer cell maturation and promote proinflammatory cytokine release [239].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [239] Seljeflot, 2010, The role of interleukin-18 in the metabolic syndrome, Cardiovasc. Diabetol. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Oxidative stress is usually observed in adipocytes during obesity.

    “Oxidative stress is usually observed in adipocytes during obesity.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [230] Costa, 2018, Mitochondrial dysfunction in obesity, Life Sci. source

      Not checked in the free run.

    • cites [231] Engin, 2017, What is lipotoxicity?, Adv. Exp. Med. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exogenous administration of IL-18 in IL-18 deficient mice restores adipocyte size and UCP-1 expression.

    “To support the role of IL-18 in this process, exogenous administration of IL-18 in these mice restores the adipocyte size as well as the expression of UCP-1 [240].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [240] Yamanishi, 2018, Deficiency in interleukin-18 promotes differentiation of brown adipose tissue resulting in fat accumulation despite dyslipidemia, J. Transl. Med. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    BAT is characterized by its own set of non-BAT-specific adipokines, including IL-6, IL-8, and MCP-1.

    “Though most studies often focus on WAT adipokine secretion, BAT is also characterized by its own set of (non-BAT-specific) adipokines, including, for instance, IL-6, IL-8, and MCP-1 [242].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [242] Veress, 2019, Interleukin-6 released from differentiating human beige adipocytes improves browning, Exp. Cell Res. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A linear correlation between IL-18 and BMI was found in humans.

    “IL-18 expression seems to be tightly correlated to other proinflammatory markers, such as TNFα, and a linear correlation between IL-18 and BMI was found in humans [237].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [237] Ahmad, 2017, Increased adipose tissue expression of IL-18R and its ligand IL-18 associates with inflammation and insulin resistance in obesity, Immun. Inflamm. Dis. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reported side effects of DNP include acute cataract, sensory axonal polyneuropathy, fever, tachycardia, sweating, nausea, rash, breathing difficulties, abdominal pain, agitation, headache, and death.

    “The reported side effects of DNP include acute cataract [261,262], sensory axonal polyneuropathy [263], fever, tachycardia, sweating, nausea, rash, breathing difficulties, abdominal pain, agitation, headache, and death [264,265].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [261] Margo, 2014, Diet pills and the cataract outbreak of 1935: Reflections on the evolution of consumer protection legislation, Surv. Ophthalmol. source

      Not checked in the free run.

    • cites [262] Horner, 1936, Cataract following di-nitrophenol treatment for obesity, Arch. Ophthalmol. source

      Not checked in the free run.

    • cites [263] Izumoto, 2017, Sensory axonal polyneuropathy due to 2,4-dinitrophenol, Rinsho Shinkeigaku source

      Not checked in the free run.

    • cites [264] Kamour, 2015, Increasing frequency of severe clinical toxicity after use of 2,4-dinitrophenol in the UK: A report from the National Poisons Information Service, Emerg. Med. J. source

      Not checked in the free run.

    • cites [265] Grundlingh, 2011, 2,4-Dinitrophenol (DNP): A Weight Loss Agent with Significant Acute Toxicity and Risk of Death, J. Med. Toxicol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mice overexpressing UCP-1 and a dominant negative form of AMPKα2 also show similar intolerance to physical activity and degeneration of smooth muscle cells.

    “Moreover, these mice also showed a similar intolerance to physical activity and a degeneration of smooth muscle cells [259].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [259] Ost, M., Werner, F., Dokas, J., Klaus, S., and Voigt, A. (2014). Activation of AMPKα2 Is Not Crucial for Mitochondrial Uncoupling-Induced Metabolic Effects but Required to Maintain Skeletal Muscle Integrity. PLoS ONE, 9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effects of UCP-1 overexpression are fat depot-dependent and can be explained by differences in AMPK subunit activation.

    “Interestingly, the effects of UCP-1 overexpression are fat depot-dependent and can be explained by differences in term of AMPK subunit activation (reviewed here [258]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [258] Klaus, 2012, Augmenting energy expenditure by mitochondrial uncoupling: A role of AMP-activated protein kinase, Genes Nutr. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DNP induces a decrease in energy expenditure by 17% and weight loss by 23% at 30 °C in female C57BL/6J mice.

    “Indeed, DNP induces a decrease in energy expenditure by 17% and weight loss by 23% at 30 °C in female C57BL/6J, while no significant effect has been observed at 22 °C [269].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [269] Goldgof, 2014, The Chemical Uncoupler 2,4-Dinitrophenol (DNP) Protects against Diet-induced Obesity and Improves Energy Homeostasis in Mice at Thermoneutrality, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intermittent fasting is associated with body weight decrease and WAT browning, also by increasing the Firmicutes level.

    “Indeed, intermittent fasting is associated with body weight decrease and WAT browning, also by increasing the Firmicutes level [248].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [248] Li, 2017, Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    More recently, an increase in the use of DNP as self-medication has been observed in China and the United Kingdom, leading to new cases of DNP-associated fatalities.

    “More recently, an increase in the use of DNP as a self-medication has been observed in China [266] and the United Kingdom [267], leading to new cases of DNP-associated fatalities.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [266] Lee, 2014, 2,4-Dinitrophenol: A threat to Chinese body-conscious groups, J. Chin. Med. Assoc. source

      Not checked in the free run.

    • cites [267] Holborow, A., Purnell, R.M., and Wong, J.F. (2016). Beware the yellow slimming pill: Fatal 2,4-dinitrophenol overdose. BMJ Case Rep., 2016. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FCCP leads to an increase in intracellular/cytosolic Ca2+ concentration and secondary opening of Ca2+-activated K+ channels, causing plasma membrane hyperpolarization in mouse sensory neurons.

    “For instance, FCCP leads to an increase in intracellular/cytosolic Ca2+ concentration and to the secondary opening of Ca2+-activated K+ channels, causing a plasma membrane hyperpolarization in mouse sensory neurons [77].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Duchen, 1990, Effects of metabolic inhibition on the membrane properties of isolated mouse primary sensory neurones, J. Physiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Interindividual sensitivity to DNP largely differs, with side effects observed in some patients but not others even at therapeutically efficient doses.

    “Moreover, interindividual sensitivity largely differs, i.e., side effects could be observed in some patients but not in others, even at therapeutically efficient doses, thereby complicating its medical use.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [260] Ingbe, S.Z., and Carlson-Lynch, H. (1995). Toxicological Profile for Dinitrophenols.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The best-known effect of mitochondrial uncouplers is a drop in ATP/AMP levels, which induces activation of the AMPK signaling pathway.

    “In terms of cell signaling, the best-known effect of mitochondrial uncouplers is probably a drop in ATP/AMP levels, which induces the activation of the AMPK signaling pathway (Figure 1).”
    Quote in the paperNot a substantial claim0 of 8 sources checked
    • cites [91] Demine, 2018, Mild mitochondrial uncoupling induces HSL/ATGL-independent lipolysis relying on a form of autophagy in 3T3-L1 adipocytes, J. Cell. Physiol. source

      Not checked in the free run.

    • cites [251] Matejkova, 2004, Possible involvement of AMP-activated protein kinase in obesity resistance induced by respiratory uncoupling in white fat, FEBS Lett. source

      Not checked in the free run.

    • cites [252] Neschen, 2008, Uncoupling protein 1 expression in murine skeletal muscle increases AMPK activation, glucose turnover, and insulin sensitivity in vivo, Physiol. Genom. source

      Not checked in the free run.

    • cites [253] Han, 2004, UCP-mediated energy depletion in skeletal muscle increases glucose transport despite lipid accumulation and mitochondrial dysfunction, Am. J. Physiol. Metab.

      Not checked in the free run.

    • cites [54] Urra, 2018, FR58P1a; a new uncoupler of OXPHOS that inhibits migration in triple-negative breast cancer cells via Sirt1/AMPK/β1-integrin pathway, Sci. Rep. source

      Not checked in the free run.

    • cites [254] Figarola, 2015, SR4 Uncouples Mitochondrial Oxidative Phosphorylation, Modulates AMP-dependent Kinase (AMPK)-Mammalian Target of Rapamycin (mTOR) Signaling, and Inhibits Proliferation of HepG2 Hepatocarcinoma Cells, J. Biol. Chem. source

      Not checked in the free run.

    • cites [255] Singhal, 2012, 1,3-bis(3,5-dichlorophenyl) Urea Compound ‘COH-SR4’ Inhibits Proliferation and Activates Apoptosis in Melanoma, Biochem. Pharmacol. source

      Not checked in the free run.

    • cites [256] Singhal, 2013, Novel Compound 1, 3-bis (3, 5-dichlorophenyl) urea Inhibits Lung Cancer Progression, Biochem. Pharmacol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MCP-1 release was decreased by lower concentrations (1.5 μM) of DNP in murine 3T3-L1 adipocytes, an effect relying on endoplasmic reticulum stress induction and AMPK activation.

    “MCP-1 release was also decreased by lower concentrations (1.5 μM) of DNP in murine 3T3-L1 adipocytes, an effect which relies on endoplasmic reticulum stress induction and AMPK activation [272].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [272] Takahashi, 2012, Induction of mitochondrial uncoupling enhances VEGF₁₂₀ but reduces MCP-1 release in mature 3T3-L1 adipocytes: Possible regulatory mechanism through endogenous ER stress and AMPK-related pathways, Biochem. Biophys. Res. Commun. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rats exposed to 1 mg/kg DNP using an orally available, controlled-release formulation exhibit decreased fasting plasma glucose, fatty acids (by 30%), TAG concentrations, HDL concentrations (by 30%), and hyperinsulinemia (50%).

    “Rats exposed to 1 mg/kg DNP using an orally available, controlled-release formulation of DNP exhibit a decrease in fasting plasma glucose, fatty acids (by 30%), TAG concentrations, HDL concentrations (by 30%) and hyperinsulinemia (50%) [277].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [277] Perry, 2015, Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats, Science source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The mechanism of salsalate seems to depend on direct activation of AMPK via the β1 subunit and an AMPK-independent increase in mitochondrial proton conductance.

    “The mechanism seems to depend on (1) a direct activation of AMPK via the β1 subunit by salsalate and (2) an AMPK-independent increase in mitochondrial proton conductance [281].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [281] Smith, 2016, Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1, Diabetes source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondrial dysfunction, a common hallmark in neurodegenerative diseases, points to mitochondrial uncoupling as a critical player.

    “Indeed, mitochondrial dysfunction, a common hallmark in neurodegenerative diseases, points especially to the mitochondrial uncoupling process as a critical player [288].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [288] Montesanto, 2018, Uncoupling protein 4 (UCP4) gene variability in neurodegenerative disorders: Further evidence of association in Frontotemporal dementia, Aging source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Injectable crystal gel of DNP (DNP-LC-gel) reduces hepatic steatosis development and lowers TAG liver levels and total cholesterol content in rats, while body temperature is not increased.

    “When used in rats, the treatment reduces hepatic steatosis development and lowers TAG liver levels as well as total cholesterol content, while body temperature is not increased [279].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [279] Wei, 2017, Sustained-release mitochondrial protonophore reverses nonalcoholic fatty liver disease in rats, Int. J. Pharm. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A long-chain PUFA-enriched HFD protects C57BL/6J mice against obesity, while an isocaloric diet strongly induces weight gain in the same mouse model.

    “For instance, a long-chain PUFA (PolyUnsaturated Fatty Acids)-enriched HFD protects C57BL/6J mice against obesity, while an isocaloric diet strongly induces weight gain in the same mouse model [282].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [282] Worsch, 2018, Dietary n-3 long-chain polyunsaturated fatty acids upregulate energy dissipating metabolic pathways conveying anti-obesogenic effects in mice, Nutr. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Food consumption of mice housed at 22 °C was higher than at 30 °C, which could counter-balance the effect of DNP.

    “Interestingly, food consumption of mice housed at 22 °C was higher than at 30 °C, which could counter-balance the effect of DNP [269].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [269] Goldgof, 2014, The Chemical Uncoupler 2,4-Dinitrophenol (DNP) Protects against Diet-induced Obesity and Improves Energy Homeostasis in Mice at Thermoneutrality, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Molecular mechanisms of PUFA-enriched HFD include diminished de novo lipogenesis and increased hepatic and intestinal fatty acid oxidation.

    “Molecular mechanisms include diminished de novo lipogenesis and increased hepatic and intestinal fatty acid oxidation [282].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [282] Worsch, 2018, Dietary n-3 long-chain polyunsaturated fatty acids upregulate energy dissipating metabolic pathways conveying anti-obesogenic effects in mice, Nutr. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Although HFD supplemented with n-3 PUFA protects C57BL/6J mice against weight gain, no effect on expression and/or activation of UCP-1 could be found.

    “Indeed, although HFD supplemented with n-3 PUFA protects C57BL/6J mice against weight gain, no effect on the expression and/or activation of the gene encoding the thermogenic UCP-1 could be found [286].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [286] Flachs, 2005, Polyunsaturated fatty acids of marine origin upregulate mitochondrial biogenesis and induce β-oxidation in white fat, Diabetologia source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations in VCP could cause mitochondrial uncoupling and play a role in frontotemporal dementia (IBMPFD) and some familial cases of amyotrophic lateral sclerosis.

    “Mutations in VCP (Valosin-Containing Protein), a type II AAA+ ATPase family, could also cause mitochondrial uncoupling and play a role in frontotemporal dementia (IBMPFD) and some familial cases of amyotrophic lateral sclerosis, as it could sensitize deficient neuronal cells to subsequent stress, such as ischemia and other conditions requiring high energy demand [290].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [290] Wu, 2013, Pathogenic VCP Mutations Induce Mitochondrial Uncoupling and Reduced ATP Levels, Neuron source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The PUFA-enriched HFD treatment seems to induce AMPKα phosphorylation, PPARα activation, and expression of Fgf21.

    “Mechanistically, the treatment seems to induce AMPKα phosphorylation (possibly due to UCP-1 uncoupling/thermogenic activity and a decrease in ATP/AMP level), PPARα activation, and the expression of Fgf21 [282].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [282] Worsch, 2018, Dietary n-3 long-chain polyunsaturated fatty acids upregulate energy dissipating metabolic pathways conveying anti-obesogenic effects in mice, Nutr. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DNP treatment prevents NAFLD development in rats by reducing fasting plasma glucose as well as concentrations of non-esterified fatty acids and insulin, accompanied by a 50-90% decrease in TAG concentrations in plasma, liver, and skeletal muscle.

    “DNP treatment also prevents NAFLD (Non-Alcoholic Fatty Liver Disease) development in rats by reducing fasting plasma glucose as well as concentrations of non-esterified fatty acids and insulin, accompanied by a 50–90% decrease in TAG concentrations in plasma, liver, and skeletal muscle [277].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [277] Perry, 2015, Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DNP can affect melanocortin-secreting neuron activity by inhibiting orexigenic NPY and activating anorexigenic POMC neurons.

    “For instance, DNP can affect melanocortin-secreting neuron activity by inhibiting orexigenic NPY (Neuropeptide Y) and activating anorexigenic POMC (Proopiomelanocortin) neurons [270].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [270] Michael, 2017, Mitochondrial uncoupling in the melanocortin system differentially regulates NPY and POMC neurons to promote weight-loss, Mol. Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Global glucose tolerance was improved in DNP-treated rats, an effect resulting from an increase in liver- and muscle-insulin sensitivity.

    “Global glucose tolerance was also improved in DNP-treated rats, an effect resulting from an increase in liver- and muscle-insulin sensitivity [277].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [277] Perry, 2015, Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats, Science source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Mitochondrial uncoupling has a putative role in stroke, dementia, and depression.

    “Indeed, a putative role in stroke, dementia, and depression has been suggested.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [288] Montesanto, 2018, Uncoupling protein 4 (UCP4) gene variability in neurodegenerative disorders: Further evidence of association in Frontotemporal dementia, Aging source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cholesterol synthesis was reduced, while its reabsorption was increased in EPA/DHA-treated mice.

    “Cholesterol synthesis was also reduced, while its reabsorption was increased [287].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [287] Van Schothorst, E.M., Flachs, P., Hal, N.L.F.-V., Kuda, O., Bunschoten, A., Molthoff, J., Vink, C., Hooiveld, G.J.E.J., Kopecky, J., and Keijer, J. (2009). Induction of lipid oxidation by polyunsaturated fatty acids of marine origin in small intestine of mice fed a high-fat diet. BMC Genom., 10. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    These responses are complex and often rely on the combination of several biological features (species, cell type), physical (temperature), and/or chemical (ion concentration, lipid composition of membranes, nature of the uncoupler) parameters.

    “These responses are complex and often rely on the combination of several biological features (species, cell type), physical (temperature), and/or chemical (ion concentration, lipid composition of membranes, nature of the uncoupler) parameters.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Induction of mitochondrial uncoupling not only impacts mitochondrial respiration but can also activate or hamper multiple cellular mechanisms, including bulk and specific forms of autophagy, ROS production regulation, protein secretion, physical exercise capacity, and adipose tissue biology.

    “However, the induction of such a condition not only impacts mitochondrial respiration but can also activate or hamper multiple cellular mechanisms, including bulk and specific forms of autophagy, ROS production regulation, protein secretion, physical exercise capacity, and adipose tissue biology (Figure 1).”
    Quote in the paperSubstantial claim
74 of 74

  • The paper relies on this without support.

    During browning, UCP-1 must be expressed, imported into mitochondria, and activated; during whitening, UCP-1 protein must be cleared from the mitochondrial population.

    “During browning, UCP-1 must be expressed, imported in mitochondria, and activated; while, conversely, UCP-1 protein must be cleared from the mitochondrial population during whitening (Figure 4).”

  • The paper relies on this without support.

    The beige-to-white adipocyte transition is often associated with mitochondrial disposal by mitophagy.

    “The beige-to-white adipocyte transition is often associated with a mitochondrial disposal by mitophagy.”

  • The paper relies on this without support.

    The cellular consequences of mitochondrial uncoupling have not been studied rigorously.

    “Unfortunately, the cellular consequences have not been studied rigorously.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Under high-workload conditions, mitochondria exhibit increased electrochemical proton gradient across inner mitochondrial membrane, which may initially reduce electron leakage per unit oxygen consumed.

    “Under high-workload conditions, mitochondria exhibit an increased electrochemical (proton) gradient across the inner mitochondrial membrane, which may initially reduce electron leakage per unit of oxygen consumed.”

    From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [31]

    Section 3.6 (Physical Exercise; page unavailable) reports that exercise can increase mitochondrial membrane potential while reducing ROS production, but it also notes studies with opposite results. Section 3.3 (Reactive Oxygen Species Production; page unavailable) discusses electron leak and oxygen consumption. Neither section establishes that high workload increases the proton gradient or that electron leakage initially falls per unit of oxygen consumed. (LLM, conf=0.81)

    Experimental — accuracy not yet measured

  • Because of marked increase in total mitochondrial respiration, absolute number of electrons escaping ETC increases, even if percentage leakage is lower.

    “However, because of the marked increase in total mitochondrial respiration, the absolute number of electrons escaping the electron transport chain (ETC) increases, even if the percentage of leakage is lower [31].”

    From Exercise-Induced Muscle–Fat Crosstalk: Molecular Mediators and Their Pharmacological Modulation for the Maintenance of Metabolic Flexibility in Aging (2025) · cites this paper as [31]

    The Introduction says electrons can leak from the electron transport chain, and §3.3 reports that this produces reactive oxygen species. But §3.3 does not say that increased respiration raises the absolute number of escaping electrons despite a lower leakage percentage; it reports decreases in ROS production in many uncoupling models and increases in some others. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • Higher oxygen consumption together with increased glycolysis while having reduced ATP production is a sign of mitochondrial uncoupling.

    “Higher oxygen consumption together with an increased glycolysis while having reduced ATP production is a sign of mitochondrial uncoupling.”

    From APOE genotype-dependent differences in human astrocytic energy metabolism (2025) · cites this paper as Demine et al., 2019

    Section 2.3 reports that the uncoupler FR58P1 rapidly lowers ATP in MDA-MB-231 cells, followed by a probable glycolytic shift that restores ATP within four hours. The Introduction explains the link between oxygen consumption and mitochondrial electron transfer, but the retrieved passages do not establish increased oxygen consumption alongside those changes as a general sign of uncoupling. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Increased mitochondrial respiration together with decreased ATP levels can be induced by treating cells with mitochondrial uncouplers.

    “Increased mitochondrial respiration together with decreased ATP levels can also be induced by treating cells with mitochondrial uncouplers supporting our hypothesis of APOE4 may induce mitochondrial uncoupling (Demine et al., 2019; Shrestha et al.,”

    From APOE genotype-dependent differences in human astrocytic energy metabolism (2025) · cites this paper as Demine et al., 2019

    In §3.5 (Cell Death), the review reports increased mitochondrial respiration in cardiomyocytes treated with low-dose FCCP. In §2.3 (Synthetic Mitochondrial Uncouplers), it reports a rapid decrease in intracellular ATP after FR58P1 treatment of MDA-MB-231 cells. These passages support each effect, but they do not establish that the two occur together under the same treatment conditions; the reported ATP level was also restored after four hours. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Both increasing and decreasing fission are called prerequisites

    Minor

    The same sentence states that an increase and a decrease in mitochondrial fission are both prerequisites for uncoupling-induced mitophagy, without distinguishing conditions under which each applies.

  • FR58P1 is said to both inhibit and activate Sirt1

    Minor

    The description of FR58P1 reports Sirt1 inhibition, then summarizes the compound's effects as activation of an AMPK/Sirt1 axis.

2 of 2

Cites

1 retracted

Flagged first, then by citations

16 of the 314 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Gnaiger, E., Aasander Frostner, E., Abdul Karim, N., Abdel-Rahman, E.A., Abumrad, N.A., Acuna-Castroviejo, D., Adiele, R.C., Ahn, B., Alencar, M.B., and Ali, S.S. (2019). Mitochondrial respiratory states and rates. MitoFit Preprint Arch.

Cited by

Sorted by citations

Related

Authors
Demine, S., Renard, P., & Arnould, T.
Affiliations
  • Université Libre de Bruxelles (BE)
  • University of Namur (BE)
Corresponding author
Arnould, Thierry
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2019-07-30
Volume
8
Issue
8
Pages
795
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells8080795
PMC
PMC6721602
OpenAlex
W2964584752
Semantic Scholar
5fe753e811e24f270976b9bc449a6cba68aac805
Cited by
476
References
314
Citations by year
2026: 47 · 2025: 77 · 2024: 78 · 2023: 89 · 2022: 70 · 2021: 74 · 2020: 35 · 2019: 5 · 2018: 1
FWCI
4.06
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Repository of the University of Namur (publishedVersion, cc-by)
  • Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Fonds De La Recherche Scientifique - FNRS (Crédit de Recherche J.0034.18, Crédit de Recherche 19497337)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
mitochondrial uncoupling, UCP1, uncoupling proteins, mitochondrial membrane potential, ATP production, autophagy, reactive oxygen species, protein secretion, cell death, physical activity, adipose tissue metabolism, signal transduction, obesity, cardiovascular disease, neurological disorders, disease therapy
MeSH terms
Mitochondrial Uncoupling Proteins, Animals, Autophagy, Humans, Mitochondria, Oxidative Phosphorylation, Uncoupling Agents, Signal Transduction, Reactive Oxygen Species

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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