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

In the paper

“Of note, some forms of mitophagy triggered by mitochondrial uncoupling do not seem to require Parkin binding to mitochondria [106,119,120].”

What the sources say

• Partly supported

  The “Parkin and PINK1-dependent mitophagy” section states that low levels of mitophagy persist even in the absence of Parkin, supporting the point that mitochondrial Parkin binding is not always required. The passage does not establish that this Parkin-independent mitophagy was triggered specifically by mitochondrial uncoupling; no page number is available in our copy. (LLM, conf=0.82)

  cites [106] Pickles, 2018, Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance, Curr. Biol. sourceExperimental — accuracy not yet measured
• Disputed

  The Results section on ROS-facilitated mitophagy and the Discussion describe Parkin translocation as a prerequisite in the CCCP-triggered process studied here. The paper does not establish a general rule for every form of mitophagy, but its finding runs contrary to the claim attributed to it. (LLM, conf=0.84)

  Checked by a reasoning model — may be wrong.

  cites [119] Xiao, 2017, Superoxide drives progression of Parkin/PINK1-dependent mitophagy following translocation of Parkin to mitochondria, Cell Death Dis. sourceExperimental — accuracy not yet measured
• Disputed

  The Introduction and Fig. 10 model describe uncoupler-induced mitochondrial depolarization as leading to Parkin recruitment to mitochondria, not as bypassing it. The Results section ‘The UPS is essential for removal of depolarized mitochondria’ observes diffuse cytosolic Parkin after Valinomycin-induced clearance, but that endpoint does not establish that recruitment was unnecessary earlier in the process. (LLM, conf=0.82)

  Checked by a reasoning model — may be wrong.

  cites [120] Rakovic, 2018, PINK1-dependent mitophagy is driven by the UPS and can occur independently of LC3 conversion, Cell Death Differ. sourceExperimental — accuracy not yet measured

In the paper

“The positive effect of mitochondrial uncoupling on autophagy has been established in many cellular and animal models, including adipocytes [91], MEFs [92], HeLa cells [93], HepG2 cells [90], SH-SY5Y neuroblastoma cells [93], or C57BL6 mice [94].”

What the sources say

• Supported

  The citation to this paper is attached specifically to “adipocytes,” not the other listed models. In the section “Macroautophagy is stimulated in adipocytes exposed to mitochondrial uncoupling,” the authors report marker changes suggesting increased macroautophagy in uncoupled adipocytes. (LLM, conf=0.93)

  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 yetcites [92] Kwon, 2011, CCCP induces autophagy in an AMPK-independent manner, Biochem. Biophys. Res. Commun. source
• Supported

  The Results section ('The UPS is essential for Parkin-mediated mitophagy') reports CCCP-induced mitophagy in Parkin-expressing SH-SY5Y cells and describes the corresponding response in HeLa cells. Those are the two cell models for which this paper is cited. The evidence concerns mitophagy under Parkin-expressing conditions, rather than autophagy generally. (LLM, conf=0.88)

  cites [93] Chan, 2011, Broad activation of the ubiquitin–proteasome system by Parkin is critical for mitophagy, Hum. Mol. Genet. source

In the paper

“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].”

What the sources say

• Supported

  Among the two knockout models, the Abstract reports that Il18-KO mice failed to develop diet-induced thermogenesis, whereas Il18r1-KO mice showed increased iWAT Ucp1 expression after HFD and stronger browning responses to cold. The Discussion likewise contrasts blocked inducible browning in Il18-KO mice with beige reprogramming in Il18r1-KO mice. The preceding statement about both models being protected against diet-induced obesity is not part of the quoted claim. (LLM, conf=0.90)

  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

In the paper

“By decreasing the Ca2+ buffering capacity of mitochondria, CCCP or FCCP increases global exocytosis in chromaffin cells [164,165,166].”

What the sources say

• Partly supported

  In “Effect of FCCP on the stimulus-evoked Cm response,” the paper reports that FCCP reduces mitochondrial Ca2+ import and increases stimulus-evoked exocytosis in bovine chromaffin cells. It does not establish the same effect for CCCP, and it reports no significant effect of FCCP on basal membrane capacitance. The supported finding is therefore an increase in evoked, rather than unqualified, exocytosis. (LLM, conf=0.86)

  cites [164] Giovannucci, 1999, Mitochondria regulate the Ca(2+)-exocytosis relationship of bovine adrenal chromaffin cells, J. Neurosci. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction says CCCP and FCCP suppress mitochondrial Ca2+ buffering and increase exocytosis in bovine chromaffin cells; the Results also report that FCCP potentiates ACh-evoked secretion. But the Introduction notes that protonophores reduce K+-evoked secretory responses in mouse chromaffin cells, so the unqualified claim about chromaffin cells is too broad. (LLM, conf=0.87)

  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. sourceExperimental — accuracy not yet measured
• Not checked yetcites [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

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [20] Cadenas, 1999, UCP2 and UCP3 rise in starved rat skeletal muscle but mitochondrial proton conductance is unchanged, FEBS Lett. source

In the paper

“First, purine nucleotides, such as GDP, directly bind UCP-1 and lead to its inactivation [8].”

What the sources say

• Not checked yetcites [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.

In the paper

“UCP-2 could then only be activated under some circumstances, such as a massive entry of FFAs into mitochondria [18].”

What the sources say

• Not checked yetcites [18] Berardi, 2014, Fatty Acid Flippase Activity of UCP2 Is Essential for Its Proton Transport in Mitochondria, Cell Metab. source

In the paper

“Underlining their importance, ANTs can account for up to 50% of basal mitochondrial membrane proton conductance [25].”

What the sources say

• Not checked yetcites [25] Brand, 2005, The basal proton conductance of mitochondria depends on adenine nucleotide translocase content, Biochem. J. source

In the paper

“Second, free fatty acids (FFAs) are well-known to promote UCP-1-dependent protein leak [8,9].”

What the sources say

• Not checked yetcites [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 yetcites [9] Strieleman, 1985, Fatty acid activation of the reconstituted brown adipose tissue mitochondria uncoupling protein, J. Biol. Chem. source

In the paper

“First, they stimulate directly mitochondrial respiration, as seen in intact isolated brown adipocytes or mitochondria isolated from these cells [28,29].”

What the sources say

• Not checked yetcites [28] Bukowiecki, 1981, Metabolic relationships between lipolysis and respiration in rat brown adipocytes. The role of long chain fatty acids as regulators of mitochondrial respiration and feedback inhibitors of lipolysis, J. Biol. Chem. source
• Not checked yetcites [29] Wojtczak, 1993, Effect of fatty acids on energy coupling processes in mitochondria, Biochim. Biophys. Acta source

In the paper

“For instance, UCP-3 expression is expressed at a much lower level than UCP-1 (200–700 fold) in mouse skeletal muscle [21].”

What the sources say

• Not checked yetcites [21] Harper, 2002, Artifactual uncoupling by uncoupling protein 3 in yeast mitochondria at the concentrations found in mouse and rat skeletal-muscle mitochondria, Biochem. J. source

In the paper

“However, others found that UCP-2 could indeed induce mitochondrial uncoupling by essentially acting as a fatty acid flippase transporter [18].”

What the sources say

• Not checked yetcites [18] Berardi, 2014, Fatty Acid Flippase Activity of UCP2 Is Essential for Its Proton Transport in Mitochondria, Cell Metab. source

In the paper

“Besides this activity, ANT also possesses some uncoupling properties.”

In the paper

“Experiments performed on liposomes enriched in UCP-1 showed that FFAs are a required co-factor for UCP-1-catalyzed proton transport [29]”

What the sources say

• Not checked yetcites [29] Wojtczak, 1993, Effect of fatty acids on energy coupling processes in mitochondria, Biochim. Biophys. Acta source

In the paper

“The CCCP effect on lysosomal pH seems to be concentration- and time-dependent.”

What the sources say

• Not checked yetcites [84] Johnson, 2016, The position of lysosomes within the cell determines their luminal pH, J. Cell Biol. source

In the paper

“Capsaicins and their derivatives are red-pepper components and are long known for their capacity to induce the upregulation of uncoupling proteins, even in vivo [62].”

What the sources say

• Not checked yetcites [62] Masuda, 2003, Upregulation of uncoupling proteins by oral administration of capsiate, a nonpungent capsaicin analog, J. Appl. Physiol. source

In the paper

“This effect relies on a non-specific interaction with sulfhydryl groups of enzymes, such as dynein and myosin ATPases [74].”

What the sources say

• Not checked yetcites [74] Hollenbeck, 1985, Effects of the uncoupling agents FCCP and CCCP on the saltatory movements of cytoplasmic organelles, Cell Biol. Int. Rep. source

In the paper

“The most well-known condition to induce Ucp1 expression in both humans and rodents is cold, essentially by activating β-adrenergic receptors and the cAMP-dependent protein kinase (PKA)-dependent signaling pathway [38,39].”

What the sources say

• Not checked yetcites [38] Xu, 2018, Cold exposure induces nuclear translocation of CRTC3 in brown adipose tissue, J. Cell. Biochem. source
• Not checked yetcites [39] Cao, 2004, p38 Mitogen-Activated Protein Kinase Is the Central Regulator of Cyclic AMP-Dependent Transcription of the Brown Fat Uncoupling Protein 1 Gene, Mol. Cell. Biol. source

In the paper

“A micromolar concentration is sufficient to significantly increase mitochondrial respiration in human MNT-1 melanoma cells [73].”

What the sources say

• Not checked yetcites [73] Kleszczyński, K., Bilska, B., Stegemann, A., Flis, D.J., Ziolkowski, W., Pyza, E., Luger, T.A., Reiter, R.J., Böhm, M., and Slominski, A.T. (2018). Melatonin and Its Metabolites Ameliorate UVR-Induced Mitochondrial Oxidative Stress in Human MNT-1 Melanoma Cells. Int. J. Mol. Sci., 19. source

In the paper

“FFAs with a carbon chain between C12 and C16 as well as long unsaturated FFAs (length above one-half of the mitochondrial membrane thickness, ±3.5 nm) seem to have the most potent effect [30].”

What the sources say

• Not checked yetcites [30] Bernardi, 2002, Mitochondrial energy dissipation by fatty acids. Mechanisms and implications for cell death, TRAIL

In the paper

“In the context of mitochondrial uncoupling, this mechanism is mainly dependent on the recruitment of the serine/threonine kinase PINK-1 (Pentaerythritol Tetranitrate–Induced Kinase 1) and the E3 ubiquitin ligase Parkin.”

In the paper

“For instance, while both FCCP and CCCP increase O2•− production in rat vascular smooth muscle cells [145], BAM15, a mitochondria-specific uncoupler, does not change ROS production in this cell type despite efficient induction of mitochondrial uncoupling [45].”

What the sources say

• Not checked yetcites [145] Zhang, 2016, Mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone induces vasorelaxation without involving K ATP channel activation in smooth muscle cells of arteries, Br. J. Pharmacol. source

In the paper

“These UCP members are known to alleviate oxidative stress by decreasing mitochondrial ROS production [153].”

What the sources say

• Not checked yetcites [153] Cadenas, 2018, Mitochondrial uncoupling, ROS generation and cardioprotection, Biochim. Biophys. Acta Bioenerg. source

In the paper

“The most well-known effect of mitochondrial depolarization induced by protonophores such as FCCP or CCCP is the promotion of mitochondrial degradation by autophagy (mitophagy).”

In the paper

“A mild mitochondrial uncoupling as induced by 3-nitropropionic acid (–30% in TMRM staining, a fluorescent probe used to assess mitochondrial potential membrane) is sufficient to trigger massive mitophagy in mouse neurons.”

What the sources say

• Not checked yetcites [112] Shin, 2019, Inhibition of bioenergetics provides novel insights into recruitment of PINK 1-dependent neuronal mitophagy, J. Neurochem. source

In the paper

“An FCCP concentration that does not impact ATP content is still sufficient to decrease APP secretion in human embryonic kidney 293T cells [161].”

What the sources say

• Not checked yetcites [161] Connop, 1999, Novel effects of FCCP [carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone] on amyloid precursor protein processing, J. Neurochem. source

In the paper

“In terms of cellular signaling, mitochondrial uncoupling-induced mitophagy seems to rely mainly on mTORC1 inhibition, as TSC2-/- MEFs still exhibit mitophagy activation in the presence of mitochondrial uncouplers [130].”

What the sources say

• Not checked yetcites [130] Bartolomé, A., García-Aguilar, A., Asahara, S.-I., Kido, Y., Guillén, C., Pajvani, U.B., and Benito, M. (2017). MTORC1 Regulates both General Autophagy and Mitophagy Induction after Oxidative Phosphorylation Uncoupling. Mol. Cell. Biol. source

In the paper

“For instance, while both FCCP and CCCP increase O2•− production in rat vascular smooth muscle cells [145], BAM15, a mitochondria-specific uncoupler, does not change ROS production in this cell type despite efficient induction of mitochondrial uncoupling [45].”

What the sources say

• Not checked yetcites [45] Kenwood, 2014, Identification of a novel mitochondrial uncoupler that does not depolarize the plasma membrane, Mol. Metab. source

In the paper

“Physical inactivity has the opposite effect and reduces mitochondrial uncoupling in skeletal muscles of humans [193].”

What the sources say

• Not checked yetcites [193] Kenny, 2017, Bed rest and resistive vibration exercise unveil novel links between skeletal muscle mitochondrial function and insulin resistance, Diabetologia source

In the paper

“The main and well-described function of irisin is to induce WAT browning and thus UCP-1-dependent mitochondrial uncoupling [206].”

What the sources say

• Not checked yetcites [206] Wu, 2012, A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis, Nature source

In the paper

“In the rat insulinoma cell line INS-1E and in primary mouse and rat pancreatic beta cells, use of FCCP/CCCP inhibits glucose-stimulated insulin release (GSIS) [168,169,170].”

What the sources say

• Not checked yetcites [168] Jhun, B.S., Lee, H., Jin, Z.-G., and Yoon, Y. (2013). Glucose Stimulation Induces Dynamic Change of Mitochondrial Morphology to Promote Insulin Secretion in the Insulinoma Cell Line INS-1E. PLoS ONE, 8. source
• Not checked yetcites [169] Leloup, 2009, Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion, Diabetes source
• Not checked yetcites [170] Barg, 2001, Priming of insulin granules for exocytosis by granular Cl(-) uptake and acidification, J. Cell Sci. source

In the paper

“The role of AMPK activation, in response to a decrease in the ATP/AMP ratio caused by mitochondrial uncoupling as a requirement for mitophagy activation, has been questioned as CCCP is able to inhibit the activity of mTORC1 independently of AMPK [92].”

What the sources say

• Not checked yetcites [92] Kwon, 2011, CCCP induces autophagy in an AMPK-independent manner, Biochem. Biophys. Res. Commun. source

In the paper

“For instance, pretreatment with low doses of FCCP (100 nM) protects cardiomyocytes against ischemia stress [176].”

What the sources say

• Not checked yetcites [176] Brennan, 2006, FCCP is cardioprotective at concentrations that cause mitochondrial oxidation without detectable depolarisation, Cardiovasc. Res. source

In the paper

“Mitochondrial uncouplers can be cytotoxic, especially at high concentrations, an effect dependent, at least partly, on the drop in the ATP level and on plasma membrane/lysosomal depolarization/permeabilization.”

In the paper

“As expected, shortly after mitophagy initiation by CCCP, the transcription factors Nrf2 (Nuclear factor erythroid 2-related factor 2) and TFEB are both translocated to the nucleus [132].”

What the sources say

• Not checked yetcites [132] Ivankovic, 2016, Mitochondrial and lysosomal biogenesis are activated following PINK1/parkin-mediated mitophagy, J. Neurochem. source

In the paper

“As an example, acute physical exercise leads to an increase in BAT UCP-1 protein expression in HFD-treated (High Fat Diet) Swiss mice [194] and ICR (Institute of Cancer Research) mice [195].”

What the sources say

• Not checked yetcites [194] Gaspar, 2019, Acute physical exercise increases leptin-induced hypothalamic extracellular signal-regulated kinase1/2 phosphorylation and thermogenesis of obese mice, J. Cell. Biochem. source
• Not checked yetcites [195] Kim, 2018, Effect of acute mid-intensity treadmill exercise on the androgen hormone level and uncoupling protein-1 expression in brown fat tissue of mouse, J. Exerc. Nutr. Biochem. source

In the paper

“According to Mitchell’s chemiosmotic theory, mitochondrial ATP production relies on the coupling between the proton gradient on either side of the inner mitochondrial membrane and the use of this proton-motive force to feed the mitochondrial ATP synthase complex [1].”

What the sources say

• Not checked yetcites [1] Mitchell, 1967, Chemiosmotic Hypothesis of Oxidative Phosphorylation, Nature source

In the paper

“For instance, FCCP inhibits the transport of immunoglobulins from the Golgi apparatus to the plasma membrane by 80% [159].”

What the sources say

• Not checked yetcites [159] Antoine, 1986, Multiple effects of the phenylhydrazone derivative FCCP on the secretory pathway in rat plasma cells, Eur. J. Cell Biol.

In the paper

“This hypothesis was confirmed in many models, including, for example, isolated rat and pigeon liver mitochondria (decrease in H2O2) [143], human monoblastic ML-1 cells (decrease in O2•(−) and ONOO−), and rat brains, hearts, kidneys, livers, and skeletal muscles [137].”

What the sources say

• Not checked yetcites [143] Boveris, 1973, The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen, Biochem. J. source
• Not checked yetcites [137] Tahara, 2009, Tissue-, substrate-, and site-specific characteristics of mitochondrial reactive oxygen species generation, Free. Radic. Biol. Med. source

In the paper

“Low concentrations (1–5 μM) of FCCP also promote cancer cell survival in response to topoisomerase inhibitors [178] or other chemotherapeutic agents, such as gemcitabine [179], reducing apoptosis triggered by these molecules.”

What the sources say

• Not checked yetcites [178] Derdak, 2008, The mitochondrial uncoupling protein-2 promotes chemoresistance in cancer cells, Cancer Res. source
• Not checked yetcites [179] Pozza, 2012, Role of mitochondrial uncoupling protein 2 in cancer cell resistance to gemcitabine, Biochim. Biophys. Acta source

In the paper

“Browning is induced by many physiological or experimental conditions, including cold exposure, physical exercise, or exposure to capsaicin, resveratrol, berberine, quercetin, thiazolidinediones, prostaglandin E2, beta-lapachone, retinoic acid, and cytokines (IL-4, IL-6, (para)thyroid hormone T3, GLP-1, leptin, melatonin, Fgf21, apelin) (Figure 4).”

In the paper

“To illustrate this statement, TLR4 (Toll Like Receptor 4) activation by injection of lipopolysaccharide in C57BL6 mice increases massive ROS production and decreases WAT browning [229].”

What the sources say

• Not checked yetcites [229] Okla, 2018, Inhibitory effects of toll-like receptor 4, NLRP3 inflammasome, and interleukin-1β on white adipocyte browning, Inflammation source

In the paper

“Moreover, in the same mouse strain, cold does not upregulate UCP-1 abundance.”

What the sources say

• Not checked yetcites [227] Budanov, 2010, Stressin’ Sestrins take an aging fight, EMBO Mol. Med. source

In the paper

“Indeed, during obesity, excessive accumulation of triglycerides in adipocytes leads to cellular and organelle dysfunction [230,231].”

What the sources say

• Not checked yetcites [230] Costa, 2018, Mitochondrial dysfunction in obesity, Life Sci. source
• Not checked yetcites [231] Engin, 2017, What is lipotoxicity?, Adv. Exp. Med. Biol. source

In the paper

“To illustrate this statement, TLR4 (Toll Like Receptor 4) activation by injection of lipopolysaccharide in C57BL6 mice increases massive ROS production and decreases WAT browning [229].”

What the sources say

• Not checked yetcites [229] Okla, 2018, Inhibitory effects of toll-like receptor 4, NLRP3 inflammasome, and interleukin-1β on white adipocyte browning, Inflammation source

In the paper

“Indeed, sustained blockage of IL-6 inhibits BAT differentiation in isolated human beige adipocytes [242].”

What the sources say

• Not checked yetcites [242] Veress, 2019, Interleukin-6 released from differentiating human beige adipocytes improves browning, Exp. Cell Res. source

In the paper

“Moreover, the palmitate oxidation rate was not increased in these cells [223].”

What the sources say

• Not checked yetcites [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

In the paper

“As proof of the importance of (mito)autophagy in the process, Ucp1 conditional deletion of Atg5 or Atg12 is sufficient to prevent the dedifferentiation of beige adipocytes [224].”

What the sources say

• Not checked yetcites [224] Shinoda, 2016, Beige adipocyte maintenance is regulated by autophagy-induced mitochondrial clearance, Cell Metab. source

In the paper

“In addition to its immune role, IL-18 also seems to regulate UCP-1 expression in adipose tissues.”

What the sources say

• Not checked yetcites [240] Yamanishi, 2018, Deficiency in interleukin-18 promotes differentiation of brown adipose tissue resulting in fat accumulation despite dyslipidemia, J. Transl. Med. source

In the paper

“Conversely, glycerol kinase, phosphoenolpyruvate carboxykinase levels, as well as glycerol and palmitate incorporation into lipid levels were increased in these cells [223].”

What the sources say

• Not checked yetcites [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

In the paper

“Mechanistically, the effect seems to be dependent on Sestrin2.”

What the sources say

• Not checked yetcites [227] Budanov, 2010, Stressin’ Sestrins take an aging fight, EMBO Mol. Med. source

In the paper

“UCP-1 expression in BAT seems to be regulated by oxidative stress.”

What the sources say

• Not checked yetcites [227] Budanov, 2010, Stressin’ Sestrins take an aging fight, EMBO Mol. Med. source

In the paper

“In addition, gut microbiota also seems to play an important role as a regulator of WAT browning.”

What the sources say

• Not checked yetcites [246] Fabbiano, 2015, Microbiota depletion promotes browning of white adipose tissue and reduces obesity, Nat. Med. source
• Not checked yetcites [247] Moreno-Navarrete, J.M., Serino, M., Blasco-Baque, V., Azalbert, V., Barton, R.H., Cardellini, M., Latorre, J., Ortega, F., Sabater-Masdeu, M., and Burcelin, R. (2018). Gut microbiota interacts with markers of adipose tissue browning, insulin action and plasma acetate in morbid obesity. Mol. Nutr. Food Res., 62. source
• Not checked yetcites [248] Li, 2017, Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota, Cell Metab. source

In the paper

“However, once again, the role of ROS could be dependent on the quantity produced.”

In the paper

“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].”

What the sources say

• Not checked yetcites [240] Yamanishi, 2018, Deficiency in interleukin-18 promotes differentiation of brown adipose tissue resulting in fat accumulation despite dyslipidemia, J. Transl. Med. source

In the paper

“In addition, mitophagy also seems to be continuously activated in brown adipocytes, possibly in order to degrade dysfunctional mitochondria exposed to prolonged mitochondrial uncoupling (and possible damages induced by oxidative stress) [109].”

What the sources say

• Not checked yetcites [109] Lu, 2018, Mitophagy is required for brown adipose tissue mitochondrial homeostasis during cold challenge, Sci. Rep. source

In the paper

“In accordance with its role, Sestrin2 defective mice are characterized by a decrease in BAT UCP-1 expression [227].”

What the sources say

• Not checked yetcites [227] Budanov, 2010, Stressin’ Sestrins take an aging fight, EMBO Mol. Med. source

In the paper

“The importance of mitochondrial uncoupling in mitophagy activation is illustrated by the attenuation of autophagy and mitophagy flows in Ucp1-/- murine brown adipocytes [109].”

What the sources say

• Not checked yetcites [109] Lu, 2018, Mitophagy is required for brown adipose tissue mitochondrial homeostasis during cold challenge, Sci. Rep. source

In the paper

“In addition, mitophagy also seems to be continuously activated in brown adipocytes, possibly in order to degrade dysfunctional mitochondria exposed to prolonged mitochondrial uncoupling (and possible damages induced by oxidative stress) [109].”

What the sources say

• Not checked yetcites [109] Lu, 2018, Mitophagy is required for brown adipose tissue mitochondrial homeostasis during cold challenge, Sci. Rep. source

In the paper

“The effect is totally counter-balanced by microbial recolonization of the gastrointestinal tract [246].”

What the sources say

• Not checked yetcites [246] Fabbiano, 2015, Microbiota depletion promotes browning of white adipose tissue and reduces obesity, Nat. Med. source

In the paper

“Surprisingly, UCP-1 is not required for cold-induced mitophagy in beige adipocytes [225].”

What the sources say

• Not checked yetcites [225] Lu, 2018, Mitophagy controls beige adipocyte maintenance through a Parkin-dependent and UCP1-independent mechanism, Sci. Signal. source

In the paper

“Indeed, total depletion of gut microbiota via antibiotics or germ-free conditions promotes WAT browning in subcutaneous and perigonadal WAT in mice [246].”

What the sources say

• Not checked yetcites [246] Fabbiano, 2015, Microbiota depletion promotes browning of white adipose tissue and reduces obesity, Nat. Med. source

In the paper

“In line with this theory, the use of antioxidant molecules (butylated hydroxyanisole or N-acetylcysteine) decreases UCP-1 expression (both at mRNA and protein levels) in mouse BAT [227].”

What the sources say

• Not checked yetcites [227] Budanov, 2010, Stressin’ Sestrins take an aging fight, EMBO Mol. Med. source

In the paper

“Conversely, glycerol kinase, phosphoenolpyruvate carboxykinase levels, as well as glycerol and palmitate incorporation into lipid levels were increased in these cells [223].”

What the sources say

• Not checked yetcites [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

In the paper

“In accordance with this theory, many proinflammatory cytokines have been found to be increased in obese patients, including IFN-γ, TNF-α, MCP-1, IL-1β, IL-5, IL-6, IL-10, IL-12, IL-13, and IL-18 [235,236].”

What the sources say

• Not checked yetcites [235] Schmidt, F.M., Weschenfelder, J., Sander, C., Minkwitz, J., Thormann, J., Chittka, T., Mergl, R., Kirkby, K.C., Faßhauer, M., and Stumvoll, M. (2015). Inflammatory Cytokines in General and Central Obesity and Modulating Effects of Physical Activity. PLoS ONE, 10. source
• Not checked yetcites [236] Kang, Y.E., Kim, J.M., Joung, K.H., Lee, J.H., You, B.R., Choi, M.J., Ryu, M.J., Ko, Y.B., Lee, M.A., and Lee, J. (2016). The Roles of Adipokines, Proinflammatory Cytokines, and Adipose Tissue Macrophages in Obesity-Associated Insulin Resistance in Modest Obesity and Early Metabolic Dysfunction. PLoS ONE, 11. source

In the paper

“Indeed, activation of the NLRP3 inflammasome in macrophages was recently shown to be sufficient to reduce browning in white human adipocytes differentiated from human adipose-derived stem cells [229].”

What the sources say

• Not checked yetcites [229] Okla, 2018, Inhibitory effects of toll-like receptor 4, NLRP3 inflammasome, and interleukin-1β on white adipocyte browning, Inflammation source

In the paper

“The importance of mitochondrial uncoupling in mitophagy activation is illustrated by the attenuation of autophagy and mitophagy flows in Ucp1-/- murine brown adipocytes [109].”

What the sources say

• Not checked yetcites [109] Lu, 2018, Mitophagy is required for brown adipose tissue mitochondrial homeostasis during cold challenge, Sci. Rep. source

In the paper

“In some obese insulin-sensitive patients, a decreased level in Firmicutes is associated with the downregulation of WAT browning.”

What the sources say

• Not checked yetcites [247] Moreno-Navarrete, J.M., Serino, M., Blasco-Baque, V., Azalbert, V., Barton, R.H., Cardellini, M., Latorre, J., Ortega, F., Sabater-Masdeu, M., and Burcelin, R. (2018). Gut microbiota interacts with markers of adipose tissue browning, insulin action and plasma acetate in morbid obesity. Mol. Nutr. Food Res., 62. source

In the paper

“Altogether, these data suggest that UCP-1 could mainly control fatty acid export and triacylglycerol in these cells, not just mitochondrial uncoupling [223].”

What the sources say

• Not checked yetcites [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

In the paper

“Therefore, under particular circumstances and intensity, mitochondrial uncoupling can have beneficial effects.”

In the paper

“Increased intracellular Ca2+ concentration-dependent CREB (cAMP-response element-binding protein) signaling was also found activated in mice injected with DNP [94].”

What the sources say

• Not checked yetcites [94] Liu, 2015, The Mitochondrial Uncoupler DNP Triggers Brain Cell mTOR Signaling Network Reprogramming and CREB Pathway Upregulation, J. Neurochem. source

In the paper

“To our knowledge, the activation of this signaling pathway by a mitochondrial uncoupler was only found in that model.”

What the sources say

• Not checked yetcites [94] Liu, 2015, The Mitochondrial Uncoupler DNP Triggers Brain Cell mTOR Signaling Network Reprogramming and CREB Pathway Upregulation, J. Neurochem. source

In the paper

“Akt, a protein positively controlled by AMPK, was also activated in these conditions [252].”

What the sources say

• Not checked yetcites [252] Neschen, 2008, Uncoupling protein 1 expression in murine skeletal muscle increases AMPK activation, glucose turnover, and insulin sensitivity in vivo, Physiol. Genom. source

In the paper

“In rat insulinoma cells and primary mouse and rat pancreatic beta cells, FCCP/CCCP inhibits glucose-stimulated (and Ca2+-dependent) insulin release (GSIS) [168,169,170].”

What the sources say

• Not checked yetcites [168] Jhun, B.S., Lee, H., Jin, Z.-G., and Yoon, Y. (2013). Glucose Stimulation Induces Dynamic Change of Mitochondrial Morphology to Promote Insulin Secretion in the Insulinoma Cell Line INS-1E. PLoS ONE, 8. source
• Not checked yetcites [169] Leloup, 2009, Mitochondrial reactive oxygen species are obligatory signals for glucose-induced insulin secretion, Diabetes source
• Not checked yetcites [170] Barg, 2001, Priming of insulin granules for exocytosis by granular Cl(-) uptake and acidification, J. Cell Sci. source

In the paper

“Finally, cold exposure also impacts gut microbiota composition in mice, again by increasing the Firmicutes level [250].”

What the sources say

• Not checked yetcites [250] Chevalier, 2015, Gut Microbiota Orchestrates Energy Homeostasis during Cold, Cell source

In the paper

“Underlining once again the role of gut microbiota, intermittent fasting does not promote WAT browning in germ-free mice [248].”

What the sources say

• Not checked yetcites [248] Li, 2017, Intermittent Fasting Promotes White Adipose Browning and Decreases Obesity by Shaping the Gut Microbiota, Cell Metab. source

In the paper

“Interestingly, even if activated, AMPK phosphorylation does not seem to be required for mitochondrial-induced metabolic effects in skeletal muscle cells.”

What the sources say

• Not checked yetcites [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

In the paper

“In addition to AMPK activation (AMPKα1/α2 phosphorylation on Thr172), the mTOR-PI3K-MAPK axis is suppressed in response to mitochondrial uncoupling.”

What the sources say

• Not checked yetcites [94] Liu, 2015, The Mitochondrial Uncoupler DNP Triggers Brain Cell mTOR Signaling Network Reprogramming and CREB Pathway Upregulation, J. Neurochem. source
• Not checked yetcites [251] Matejkova, 2004, Possible involvement of AMP-activated protein kinase in obesity resistance induced by respiratory uncoupling in white fat, FEBS Lett. source

In the paper

“Injection of DNP in C57BL/6 mice leads to the suppression of this pathway [94,251] and to the upregulation of genes involved in autophagy, such as LC3B, p62, or Ulk1 [94].”

What the sources say

• Not checked yetcites [94] Liu, 2015, The Mitochondrial Uncoupler DNP Triggers Brain Cell mTOR Signaling Network Reprogramming and CREB Pathway Upregulation, J. Neurochem. source
• Not checked yetcites [251] Matejkova, 2004, Possible involvement of AMP-activated protein kinase in obesity resistance induced by respiratory uncoupling in white fat, FEBS Lett. source

In the paper

“As suggested by the very first use of DNP in humans, obesity and its complications can also be limited by using uncoupling agents [268].”

What the sources say

• Not checked yetcites [268] Geisler, J.G. (2019). 2,4 Dinitrophenol as Medicine. Cells, 8. source

In the paper

“Specific overexpression of UCP-1 in white adipocytes (aP2-UCP-1 mice) also activates AMPK in this cell type.”

What the sources say

• Not checked yetcites [258] Klaus, 2012, Augmenting energy expenditure by mitochondrial uncoupling: A role of AMP-activated protein kinase, Genes Nutr. source

In the paper

“As we have seen in this review, mitochondrial uncoupling could induce multiple cellular mechanisms, including autophagy, ROS production/detoxification, cell death, and metabolism.”

In the paper

“Injection of DNP in C57BL/6 mice leads to the suppression of this pathway [94,251] and to the upregulation of genes involved in autophagy, such as LC3B, p62, or Ulk1 [94].”

What the sources say

• Not checked yetcites [94] Liu, 2015, The Mitochondrial Uncoupler DNP Triggers Brain Cell mTOR Signaling Network Reprogramming and CREB Pathway Upregulation, J. Neurochem. source

In the paper

“However, recent findings still indicate that the induction of mitochondrial uncoupling could be beneficial in some human diseases.”

In the paper

“The interindividual sensitivity also varies according to time [260].”

What the sources say

• Not checked yetcites [260] Ingbe, S.Z., and Carlson-Lynch, H. (1995). Toxicological Profile for Dinitrophenols.

In the paper

“For instance, DNP’s effect on obesity seems to be dependent on environmental temperature, a well-known phenomenon in mice.”

What the sources say

• Not checked yetcites [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

In the paper

“Activation of AMPK signaling was also found in mice overexpressing UCP-1 specifically in skeletal muscle cells [252,253].”

What the sources say

• Not checked yetcites [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 yetcites [253] Han, 2004, UCP-mediated energy depletion in skeletal muscle increases glucose transport despite lipid accumulation and mitochondrial dysfunction, Am. J. Physiol. Metab.

In the paper

“By decreasing ATP levels, mitochondrial uncoupling will also hamper mitochondrial calcium homeostasis.”

In the paper

“Interestingly, the Firmicutes level was found to be directly correlated with PRDM16 mRNA expression (a key transcription factor involved in BAT differentiation) and UCP-1 expression in subcutaneous and visceral WAT [247].”

What the sources say

• Not checked yetcites [247] Moreno-Navarrete, J.M., Serino, M., Blasco-Baque, V., Azalbert, V., Barton, R.H., Cardellini, M., Latorre, J., Ortega, F., Sabater-Masdeu, M., and Burcelin, R. (2018). Gut microbiota interacts with markers of adipose tissue browning, insulin action and plasma acetate in morbid obesity. Mol. Nutr. Food Res., 62. source

In the paper

“This effect has been found in multiple models and species, including white adipocytes [91,251], skeletal muscle cells [252,253], cancer cells [54,254,255,256], and neurons [257].”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [256] Singhal, 2013, Novel Compound 1, 3-bis (3, 5-dichlorophenyl) urea Inhibits Lung Cancer Progression, Biochem. Pharmacol. source

In the paper

“Proinflammatory adipokine release (TNF-α, IL-1β, IL-6, MCP-1, and IFNγ) also seems to be decreased by high DNP concentrations (100 μM) in isolated murine RAW 264.7 macrophages [271].”

What the sources say

• Not checked yetcites [271] Lee, 2017, Intracellular ATP in balance of pro- and anti-inflammatory cytokines in adipose tissue with and without tissue expansion, Int. J. Obes. source

In the paper

“Other reports suggest that PUFA supplementation indeed protects against diet-induced obesity by decreasing the expression and/or activity of SREBP-1c and PPARα [285].”

What the sources say

• Not checked yetcites [285] Dossi, 2014, Reversal of high-fat diet-induced hepatic steatosis by n-3 LCPUFA: Role of PPAR-α and SREBP-1c, J. Nutr. Biochem. source

In the paper

“By acting on white adipocyte mass, mitochondrial uncouplers could protect against diabetes, as limiting hyperaccumulation of triacyglycerol (TAG) in these cells might limit organelle stress [91,273,274,275] and modifications in the expression pattern of genes encoding adipokines, which are known to communicate the level of adiposity to other organs [221,276].”

What the sources say

• Not checked yetcites [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 yetcites [273] Tejerina, 2009, Mild mitochondrial uncoupling induces 3T3-L1 adipocyte de-differentiation by a PPARgamma-independent mechanism, whereas TNFalpha-induced de-differentiation is PPARgamma dependent, J. Cell Sci. source
• Not checked yetcites [274] Demine, 2012, Mild mitochondrial uncoupling does not affect mitochondrial biogenesis but downregulates pyruvate carboxylase in adipocytes: Role for triglyceride content reduction, Am. J. Physiol. Metab.
• Not checked yetcites [275] Rossmeisl, 2005, Triglyceride-lowering Effect of Respiratory Uncoupling in White Adipose Tissue, Obes. Res. source
• Not checked yetcites [221] Cao, 2014, Adipocytokines in Obesity and Metabolic Disease, J. Endocrinol. source
• Not checked yetcites [276] Ouchi, 2011, Adipokines in inflammation and metabolic disease, Nat. Rev. Immunol. source

In the paper

“These authors identified an intronic variant of the neuronal UCP4 (UCP4/SLC25A27) gene that affects the risk of late-onset Alzheimer’s disease (LOAD) and late-onset familial and sporadic cases of frontotemporal dementia [289].”

What the sources say

• Not checked yetcites [289] Montesanto, 2016, The Genetic Variability of UCP4 Affects the Individual Susceptibility to Late-Onset Alzheimer’s Disease and Modifies the Disease’s Risk in APOE-ɛ4 Carriers, J. Alzheimers Dis. source

In the paper

“Whole genome microarray analysis performed on intestinal cells of C57BL/6J mice treated with EPA and DHA confirmed that the main biological process affected by such treatment is lipid metabolism (increase in the expression of Acaa1, Acacb, CPT-1A) [287].”

What the sources say

• Not checked yetcites [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

In the paper

“Importantly, we must note that some anti-obesity effects of PUFAs could be independent of UCP-1-dependent mitochondrial uncoupling.”

What the sources say

• Not checked yetcites [286] Flachs, 2005, Polyunsaturated fatty acids of marine origin upregulate mitochondrial biogenesis and induce β-oxidation in white fat, Diabetologia source

In the paper

“Indeed, salsalate, a prodrug of salicylate, was shown to lower blood glucose in type 2 diabetic patients [280].”

What the sources say

• Not checked yetcites [280] Fakhri, 2014, The effect of salsalate on biochemical factors and endothelial dysfunction of prediabetic patients: A randomized clinical trial, J. Res. Med. Sci.

In the paper

“An increase in UCP-1 protein expression and activity (acting as an efficient monocarboxylic FA anion flippase and regulated by GDP [283]) accounted for the promoted thermogenic capacity [282].”

What the sources say

• Not checked yetcites [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 yetcites [283] Skulachev, 1991, Fatty acid circuit as a physiological mechanism of uncoupling of oxidative phosphorylation, FEBS Lett. source

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“A clear role of UCP2 in the reduction of ROS generation allowing protection against reperfusion damage comes from a study showing that -866G/A polymorphism in the promoter of the UCP2 gene (enhancing its transcription) is associated with functional prognosis in patients with embolic ischemic stroke after early recanalization [291].”

What the sources say

• Not checked yetcites [291] Montaner, 2017, The UCP2-866G/A Polymorphism Could be Considered as a Genetic Marker of Different Functional Prognosis in Ischemic Stroke after Recanalization, NeuroMol. Med. source

In the paper

“The DNP effect requires, at least partially, the melanocortin-4 receptor (MC4R) as observed in C57BL/6 MC4R KO mice [270].”

What the sources say

• Not checked yetcites [270] Michael, 2017, Mitochondrial uncoupling in the melanocortin system differentially regulates NPY and POMC neurons to promote weight-loss, Mol. Metab. source

In the paper

“The direct effect of Fgf21 on adipocyte browning has also been demonstrated by others [284].”

What the sources say

• Not checked yetcites [284] Fisher, 2012, FGF21 regulates PGC-1α and browning of white adipose tissues in adaptive thermogenesis, Genes Dev. source

In the paper

“Similar effects of this treatment have also been reported by the same group in lipodystrophic mice (AZIP/F-1), a mouse model expressing the A-ZIP/F gene under the control of the Fabp4 promoter characterized by a virtually complete absence of white adipose tissue [278].”

What the sources say

• Not checked yetcites [278] Abulizi, 2017, A controlled-release mitochondrial protonophore reverses hypertriglyceridemia, nonalcoholic steatohepatitis, and diabetes in lipodystrophic mice, FASEB J. source

In the paper

“This study clearly demonstrates that, in humans, increased expression of UCP2 is neuroprotective [291].”

What the sources say

• Not checked yetcites [291] Montaner, 2017, The UCP2-866G/A Polymorphism Could be Considered as a Genetic Marker of Different Functional Prognosis in Ischemic Stroke after Recanalization, NeuroMol. Med. source