Thermogenin

{{Short description|Mammalian protein found in Homo sapiens}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox gene}} '''Thermogenin''' (called uncoupling protein by its discoverers and now known as uncoupling protein 1, or '''UCP1''')<ref name="entrez">{{cite web | title = Entrez Gene: UCP1 uncoupling protein 1 (mitochondrial, proton carrier) | url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=7350 }}</ref> is a mitochondrial carrier protein found in brown adipose tissue (BAT). It is used to generate heat by non-shivering thermogenesis, and makes a quantitatively important contribution to countering heat loss in babies which would otherwise occur due to their high surface area-volume ratio. Recent findings indicate that the UCP1 protein plays a crucial role in thermogenesis by catalyzing the dissipative production of heat through protons derived from NADH and FADH2. These electron carriers are produced in the TCA cycle from the oxidation of acetyl-CoA, which comes from the breakdown of free fatty acids. Intriguingly, the acetyl-CoA products undergo a recycling process that facilitates their re-utilization, thereby sustaining the cycle known as the HEAT cycle.<ref name="Mirza_2021">{{cite journal | vauthors = Mirza AH, Cui L, Zhang S, Liu P | title = Comparative proteomics reveals that lipid droplet-anchored mitochondria are more sensitive to cold in brown adipocytes | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1866 | issue = 10 | article-number = 158992 | date = 1 October 2021 | pmid = 34147658 | doi = 10.1016/j.bbalip.2021.158992 | issn = 1388-1981 | doi-access = free }}</ref>

==Structure== thumb|left|'''Structure of the human uncoupling protein''' The atomic structure of human uncoupling protein 1 UCP1 has been solved by cryogenic-electron microscopy.<ref name="Jones_2023">{{Cite journal | vauthors = Jones S, Gogoi P, Ruprecht J, King M, Lee Y, Zogg T, Pardon E, Chand D, Steel S, Coperman D, Cotrim C, Steyaert J, Crichton P, Moiseenkova-Bell V, Kunji E | title = Structural basis of purine nucleotide inhibition of human uncoupling protein 1 | journal = Science Advances | volume = 9 | issue = 22 | article-number = eadh4251 | date = 2023 | pmid = 37256948 | pmc = 10413660 | doi = 10.1126/sciadv.adh4251 | bibcode = 2023SciA....9H4251J }}</ref> The structure has the typical fold of a member of the SLC25 family.<ref name="Ruprecht_2020">{{Cite journal | vauthors = Ruprecht J, Kunji E | title = The SLC25 Mitochondrial Carrier Family: Structure and Mechanism | journal = Trends in Biochemical Sciences | volume = 45 | issue = 3 | pages = 244–258 | date = 2020 | pmid = 31787485 | pmc = 7611774 | doi = 10.1016/j.tibs.2019.11.001 }}</ref><ref name="Kunji_2020">{{Cite journal | vauthors = Kunji E, King M, Ruprecht J, Thangaratnarajah C | title = The SLC25 Carrier Family: Important Transport Proteins in Mitochondrial Physiology and Pathology | journal = Physiology | location = Bethesda, Md. | volume = 35 | issue = 5 | pages = 302–327 | date = 2020 | pmid = 32783608 | pmc = 7611780 | doi = 10.1152/physiol.00009.2020 }}</ref> UCP1 is locked in a cytoplasmic-open state by guanosine triphosphate in a pH-dependent manner, preventing proton leak.<ref name="Jones_2023" />

==Mechanism== thumb|Mechanism of thermogenin activation: In a last step thermogenin inhibition is released through the presence of free fatty acids. The cascade is initiated by binding of norepinephrine to the cells β₃-adrenoceptors. UCP1 belongs to the UCP family which are transmembrane proteins that decrease the proton gradient generated in oxidative phosphorylation. They do this by increasing the permeability of the inner mitochondrial membrane, allowing protons that have been pumped into the intermembrane space to return to the mitochondrial matrix and hence dissipating the proton gradient. UCP1-mediated heat generation in brown fat uncouples the respiratory chain, allowing for fast substrate oxidation with a low rate of ATP production. UCP1 is related to other mitochondrial metabolite transporters such as the adenine nucleotide translocator, a proton channel in the mitochondrial inner membrane that permits the translocation of protons from the mitochondrial intermembrane space to the mitochondrial matrix. UCP1 is restricted to brown adipose tissue, where it provides a mechanism for the enormous heat-generating capacity of the tissue.

UCP1 is activated in the brown fat cell by fatty acids and inhibited by nucleotides.<ref>{{Cite journal | vauthors = Fedorenko A, Lishko PV, Kirichok Y | title = Mechanism of Fatty-Acid-Dependent UCP1 Uncoupling in Brown Fat Mitochondria | journal = Cell | volume = 151 | issue = 2 | pages = 400–413 | date = 2012-10-12 | pmid = 23063128 | pmc = 3782081 | doi = 10.1016/j.cell.2012.09.010 | language = en | issn = 0092-8674 | doi-access = free }}</ref> Fatty acids are released by the following signaling cascade: Sympathetic nervous system terminals release Norepinephrine onto a Beta-3 adrenergic receptor on the plasma membrane. This activates adenylyl cyclase, which catalyses the conversion of ATP to cyclic AMP (cAMP). cAMP activates protein kinase A, causing its active C subunits to be freed from its regulatory R subunits. Active protein kinase A, in turn, phosphorylates triacylglycerol lipase, thereby activating it. The lipase converts triacylglycerols into free fatty acids, which activate UCP1, overriding the inhibition caused by purine nucleotides (GDP and ADP). During the termination of thermogenesis, thermogenin is inactivated and residual fatty acids are disposed of through oxidation, allowing the cell to resume its normal energy-conserving state.

thumb|The Alternating Access Model for UCP1 with H+ as a Substrate UCP1 is very similar to the ATP/ADP Carrier protein, or Adenine Nucleotide Translocator (ANT).<ref name="Crichton_2017">{{Cite journal | vauthors = Crichton PG, Lee Y, Kunji ER | title = The molecular features of uncoupling protein 1 support a conventional mitochondrial carrier-like mechanism | journal = Biochimie | volume = 134 | pages = 35–50 | date = 2017-03-01 | pmid = 28057583 | pmc = 5395090 | doi = 10.1016/j.biochi.2016.12.016 | series = UCP1: 40 years and beyond | issn = 0300-9084 | doi-access = free }}</ref><ref>{{Cite journal | vauthors = Ruprecht J, Kunji E | title = Structural mechanism of transport of mitochondrial carriers | journal = Annual Review of Biochemistry | volume = 90 | pages = 535–558 | date = 2021 | pmid = 33556281 | doi = 10.1146/annurev-biochem-072820-020508 | doi-access = free }}</ref> The proposed alternating access model for UCP1 is based on the similar ANT mechanism.<ref>{{Cite journal | vauthors = Ryan RM, Vandenberg RJ | title = Elevating the alternating-access model | journal = Nature Structural & Molecular Biology | volume = 23 | issue = 3 | pages = 187–189 | date = 2016-03-01 | pmid = 26931415 | doi = 10.1038/nsmb.3179 | language = en | s2cid = 35913348 | issn = 1545-9985 }}</ref> The substrate comes in to the half open UCP1 protein from the cytoplasmic side of the membrane, the protein closes the cytoplasmic side so the substrate is enclosed in the protein, and then the matrix side of the protein opens, allowing the substrate to be released into the mitochondrial matrix. The opening and closing of the protein is accomplished by the tightening and loosening of salt bridges at the membrane surface of the protein. Substantiation for this modelling of UCP1 on ANT is found in the many conserved residues between the two proteins that are actively involved in the transportation of substrate across the membrane. Both proteins are integral membrane proteins, localized to the inner mitochondrial membrane, and they have a similar pattern of salt bridges, proline residues, and hydrophobic or aromatic amino acids that can close or open when in the cytoplasmic or matrix state.<ref name="Crichton_2017" />

== HEAT cycle ==

The '''HEAT Cycle''' is a proposed metabolic pseudo-futile cycle that occurs in the mitochondria of brown adipose tissue (BAT) and is essential for non-shivering thermogenesis. In a recent study on differential temperature-based analysis of cytoplasmic mitochondria (CM) and lipid droplet-anchored mitochondria (LDAM),<ref>{{cite journal | vauthors = Cui L, Mirza A, Zhang S, Liang B, Liu P | title = Lipid droplets and mitochondria are anchored during brown adipocyte differentiation. | journal = Protein & Cell | volume = 10 | issue = 12 | pages = 921–926 | date = December 2019 | pmid = 31667701 | pmc = 6881423 | doi = 10.1007/s13238-019-00661-1 }}</ref> it was observed that LDAM generate heat through uncoupling proteins, while CM not only produce heat but also enhance the overall cellular metabolism of brown fat cells (BFCs). At lower temperatures or during cold acclimation, brown fat cells (BFCs) initiate thermogenesis at the indirect cost of ATP. Free fatty acids (FFAs) are moved from the cytoplasm to the mitochondria where they undergo β-oxidation, producing one NADH and one FADH per cycle. Instead of entering the TCA cycle, acetyl-CoA from β-oxidation combines with oxaloacetate to form citrate. This citrate returns to the cytoplasm, where it is converted back into oxaloacetate and acetyl-CoA. The cytosolic acetyl-CoA is then used for fatty acid synthesis, fueled by NADPH. The newly synthesized FFAs can be transported back to the mitochondria, creating a cyclical process known as the HEAT cycle,<ref name="Mirza_2021" /> which illustrates the interplay of fatty acid synthesis and breakdown. The glycerol-3-phosphate (G3P) shuttle has been shown to be active at lower temperatures; it transfers cytoplasmic NADH to the mitochondria in the form of FADH. The HEAT cycle provides a comprehensive overview of the bioenergetics of brown fat cells (BFCs), highlighting the intricate interconnections within metabolic processes. Proteomic analysis of two mitochondrial subpopulations (cytoplasmic mitochondria; CM, lipid droplet-anchored mitochondria; LDAM) of BATs revealed that (BFCs) exhibit heightened expression of key proteins involved in several metabolic pathways, including glycolysis, gluconeogenesis, glyceroneogenesis, the pentose phosphate pathway related to nucleotide metabolism, fatty acid β-oxidation, fatty acid synthesis, and the tricarboxylic acid (TCA) cycle, as well as the electron transport chain. Pyruvate, the end product of glycolysis, is transported into the mitochondria where it is converted to acetyl-CoA, linking glycolytic and mitochondrial metabolism. This acetyl-CoA—derived from either glycolytic or β-oxidative sources—then condenses with oxaloacetate to form citrate. Notably, the citrate is shuttled back to the cytoplasm, where it plays a crucial role in fatty acid synthesis. In summary, the HEAT cycle serves as a cyto-mitochondrial pathway that integrates the breakdown and synthesis of fatty acids, ultimately facilitating themogenesis.

The NADH donates its protons to complex I (C-I) of the electron transport chain (ETC). The protons from NADH then move to ubiquinone, then to complex III (C-III), and finally to complex IV (C-IV), resulting in the production of water and ATP. ATP is synthesized by ATP synthase at each step of proton movement. Meanwhile, FADH donates its protons directly to C-III through ubiquinone in the ETC, also contributing to ATP and water production. It is known that in isolated mitochondrial samples of the ETC, 2.5 ATP molecules are produced from NADH and 1.5 ATP molecules from FADH.<ref>{{cite journal | vauthors = Hinkle P, Kumar M, Resetar A, Harris D | title = Mechanistic stoichiometry of mitochondrial oxidative phosphorylation. | journal = Biochemistry | volume = 30 | issue = 14 | pages = 3576–3582 | date = 9 April 1991 | pmid = 2012815 | doi = 10.1021/bi00228a031 | url = https://pubs.acs.org/doi/10.1021/bi00228a031 | access-date = 2 June 2025 | url-access = subscription }}</ref><ref>{{cite journal | vauthors = Hinkle PC | title = P/O ratios of mitochondrial oxidative phosphorylation | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1706 | issue = 1–2 | pages = 1–11 | date = 7 January 2005 | pmid = 15620362 | doi = 10.1016/j.bbabio.2004.09.004 | url = https://www.sciencedirect.com/science/article/pii/S0005272804002701 | access-date = 2 June 2025 | url-access = subscription }}</ref> Uncoupling protein (UCP1) disrupts the electron transport chain (ETC) by uncoupling protons, diverting them towards heat production instead of ATP synthesis.

==Evolution== UCP1 is expressed in brown adipose tissue, which is functionally found only in eutherians. The UCP1, or thermogenin, gene likely arose in an ancestor of modern vertebrates, but did not initially allow for our vertebrate ancestor to use non-shivering thermogenesis for warmth. It wasn't until heat generation was adaptively selected for in placental mammal descendants of this common ancestor that UCP1 evolved its current function in brown adipose tissue to provide additional warmth.<ref>{{Cite journal | vauthors = Klingenspor M, Fromme T, Hughes DA, Manzke L, Polymeropoulos E, Riemann T, Trzcionka M, Hirschberg V, Jastroch M | title = An ancient look at UCP1 | journal = Biochimica et Biophysica Acta (BBA) - Bioenergetics | volume = 1777 | issue = 7–8 | pages = 637–641 | date = 2008-07-01 | pmid = 18396149 | doi = 10.1016/j.bbabio.2008.03.006 | series = 15th European Bioenergetics Conference 2008 | issn = 0005-2728 | doi-access = free }}</ref> While UCP1 plays a key thermogenic role in a wide range of placental mammals, particularly those with small body size and those that hibernate, the UCP1 gene has lost functionality in several large-bodied lineages (e.g. horses, elephants, sea cows, whales and hyraxes) and lineages with low metabolic rates (e.g. pangolins, armadillos, sloths and anteaters).<ref>{{Cite journal | vauthors = Gaudry MJ, Jastroch M, Treberg JR, Hofreiter M, Paijmans JL, Starrett J, Wales N, Signore AV, Springer MS, Campbell KL | title = Inactivation of thermogenic UCP1 as a historical contingency in multiple placental mammal clades | journal = Science Advances | volume = 3 | issue = 7 | article-number = e1602878 | date = 2017-07-12 | pmid = 28706989 | pmc = 5507634 | doi = 10.1126/sciadv.1602878 | bibcode = 2017SciA....3E2878G }}</ref> Recent discoveries of non-heat-generating orthologues of UCP1 in fish and marsupials, other descendants of the ancestor of modern vertebrates, show that this gene was passed on to all modern vertebrates, but aside from placental mammals, none have heat producing capability.<ref>{{Cite journal | vauthors = Saito S, Saito CT, Shingai R | title = Adaptive evolution of the uncoupling protein 1 gene contributed to the acquisition of novel nonshivering thermogenesis in ancestral eutherian mammals | journal = Gene | volume = 408 | issue = 1–2 | pages = 37–44 | date = 2008-01-31 | pmid = 18023297 | doi = 10.1016/j.gene.2007.10.018 | issn = 0378-1119 }}</ref> This further suggests that UCP1 had a different original purpose and in fact phylogenetic and sequence analyses indicate that UCP1 is likely a mutated form of a dicarboxylate carrier protein that adapted for thermogenesis in placental mammals.<ref>{{Cite journal | vauthors = Robinson AJ, Overy C, Kunji ER | title = The mechanism of transport by mitochondrial carriers based on analysis of symmetry | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 46 | pages = 17766–17771 | date = 2008-11-18 | pmid = 19001266 | pmc = 2582046 | doi = 10.1073/pnas.0809580105 | language = en | issn = 0027-8424 | bibcode = 2008PNAS..10517766R | doi-access = free }}</ref>

==History== Researchers in the 1960s investigating brown adipose tissue, found that in addition to producing more heat than typical of other tissues, brown adipose tissue seemed to short circuit, or uncouple, respiration coupling.<ref>{{Cite journal | vauthors = Ricquier D | title = UCP1, the mitochondrial uncoupling protein of brown adipocyte: A personal contribution and a historical perspective | journal = Biochimie | volume = 134 | pages = 3–8 | date = 2017-03-01 | pmid = 27916641 | doi = 10.1016/j.biochi.2016.10.018 | series = UCP1: 40 years and beyond | issn = 0300-9084 }}</ref> Uncoupling protein 1 was discovered in 1976 by David G. Nicholls, Vibeke Bernson, and Gillian Heaton, and the discovery was published in 1978 and shown to be the protein responsible for this uncoupling effect.<ref name="Nicholls_1978">{{cite book | vauthors = Nicholls DG, Bernson VS, Heaton GM | chapter = The Identification of the Component in the Inner Membrane of Brown Adipose Tissue Mitochondria Responsible for Regulating Energy Dissipation | title = Effectors of Thermogenesis | series = Experientia Supplementum | journal = Experientia | issue = Supplementum | volume = 32 | pages = 89–93 | year = 1978 | pmid = 348493 | doi = 10.1007/978-3-0348-5559-4_9 | isbn = 978-3-0348-5561-7 }}</ref> UCP1 was later purified for the first time in 1980 and was first cloned in 1988.<ref name="Kozak_1988">{{cite journal | vauthors = Kozak LP, Britton JH, Kozak UC, Wells JM | title = The mitochondrial uncoupling protein gene. Correlation of exon structure to transmembrane domains | journal = The Journal of Biological Chemistry | volume = 263 | issue = 25 | pages = 12274–12277 | date = Sep 1988 | pmid = 3410843 | doi = 10.1016/S0021-9258(18)37751-2 | doi-access = free }}</ref><ref name="Bouillaud_1988">{{cite journal | vauthors = Bouillaud F, Raimbault S, Ricquier D | title = The gene for rat uncoupling protein: complete sequence, structure of primary transcript and evolutionary relationship between exons | journal = Biochemical and Biophysical Research Communications | volume = 157 | issue = 2 | pages = 783–792 | date = Dec 1988 | pmid = 3202878 | doi = 10.1016/S0006-291X(88)80318-8 | bibcode = 1988BBRC..157..783B }}</ref>

Uncoupling protein two (UCP2), a homolog of UCP1, was identified in 1997. UCP2 localizes to a wide variety of tissues, and is thought to be involved in regulating reactive oxygen species (ROS). In the past decade, three additional homologs of UCP1 have been identified, including UCP3, UCP4, and UCP5 (also known as BMCP1 or SLC25A14).

== Clinical relevance == Methods of delivering UCP1 to cells by gene transfer therapy or methods of its upregulation have been an important line of enquiry in research into the treatment of obesity, due to their ability to dissipate excess metabolic stores.<ref>{{cite journal | vauthors = Kozak LP, Anunciado-Koza R | title = UCP1: its involvement and utility in obesity | journal = International Journal of Obesity | volume = 32 | issue = Suppl 7 | pages = S32–S38 | date = Dec 2008 | pmid = 19136989 | pmc = 2746324 | doi = 10.1038/ijo.2008.236 }}</ref>

== See also == * 2,4-Dinitrophenol (A synthetic small-molecule proton shuttle with similar effects)

== References == {{Reflist|2}}

== Further reading == {{refbegin | 2}} * {{cite journal | vauthors = Macher G, Koehler M, Rupprecht A, Kreiter J, Hinterdorfer P, Pohl EE | title = Inhibition of mitochondrial UCP1 and UCP3 by purine nucleotides and phosphate | journal = Biochimica et Biophysica Acta (BBA) - Biomembranes | volume = 1860 | issue = 3 | pages = 664–672 | date = March 2018 | pmid = 29212043 | pmc = 6118327 | doi = 10.1016/j.bbamem.2017.12.001 }} * {{cite journal | vauthors = Urbánková E, Voltchenko A, Pohl P, Ježek P, Pohl EE | title = Transport Kinetics of Uncoupling Proteins | journal = The Journal of Biological Chemistry | volume = 278 | issue = 35 | pages = 32497–32500 | date = 29 August 2003 | pmid = 12826670 | doi = 10.1074/jbc.M303721200 | doi-access = free }} * {{cite journal | vauthors = Ricquier D, Bouillaud F | title = The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP | journal = The Biochemical Journal | volume = 345 Pt 2 | issue = Pt 2 | pages = 161–179 | date = Jan 2000 | pmid = 10620491 | pmc = 1220743 | doi = 10.1042/0264-6021:3450161 }} * {{cite journal | vauthors = Muzzin P | title = The uncoupling proteins | journal = Annales d'Endocrinologie | volume = 63 | issue = 2 Pt 1 | pages = 106–110 | date = Apr 2002 | pmid = 11994670 }} * {{cite journal | vauthors = Del Mar Gonzalez-Barroso M, Ricquier D, Cassard-Doulcier AM | title = The human uncoupling protein-1 gene (UCP1): present status and perspectives in obesity research | journal = Obesity Reviews| volume = 1 | issue = 2 | pages = 61–72 | date = Oct 2000 | pmid = 12119988 | doi = 10.1046/j.1467-789x.2000.00009.x | s2cid = 30231289 }} * {{cite journal | vauthors = Cassard AM, Bouillaud F, Mattei MG, Hentz E, Raimbault S, Thomas M, Ricquier D | title = Human uncoupling protein gene: structure, comparison with rat gene, and assignment to the long arm of chromosome 4 | journal = Journal of Cellular Biochemistry | volume = 43 | issue = 3 | pages = 255–264 | date = Jul 1990 | pmid = 2380264 | doi = 10.1002/jcb.240430306 | s2cid = 31128860 }} * {{cite journal | vauthors = Bouillaud F, Villarroya F, Hentz E, Raimbault S, Cassard AM, Ricquier D | title = Detection of brown adipose tissue uncoupling protein mRNA in adult patients by a human genomic probe | journal = Clinical Science | location = London, England | volume = 75 | issue = 1 | pages = 21–27 | date = Jul 1988 | pmid = 3165741 | doi = 10.1042/cs0750021 }} * {{cite journal | vauthors = Oppert JM, Vohl MC, Chagnon M, Dionne FT, Cassard-Doulcier AM, Ricquier D, Pérusse L, Bouchard C | title = DNA polymorphism in the uncoupling protein (UCP) gene and human body fat | journal = International Journal of Obesity and Related Metabolic Disorders | volume = 18 | issue = 8 | pages = 526–531 | date = Aug 1994 | pmid = 7951471 }} * {{cite journal | vauthors = Clément K, Ruiz J, Cassard-Doulcier AM, Bouillaud F, Ricquier D, Basdevant A, Guy-Grand B, Froguel P | title = Additive effect of A-->G (-3826) variant of the uncoupling protein gene and the Trp64Arg mutation of the beta 3-adrenergic receptor gene on weight gain in morbid obesity | journal = International Journal of Obesity and Related Metabolic Disorders | volume = 20 | issue = 12 | pages = 1062–1066 | date = Dec 1996 | pmid = 8968850 }} * {{cite journal | vauthors = Schleiff E, Shore GC, Goping IS | title = Human mitochondrial import receptor, Tom20p. Use of glutathione to reveal specific interactions between Tom20-glutathione S-transferase and mitochondrial precursor proteins | journal = FEBS Letters | volume = 404 | issue = 2–3 | pages = 314–318 | date = Mar 1997 | pmid = 9119086 | doi = 10.1016/S0014-5793(97)00145-2 | s2cid = 29177508 | doi-access = free | bibcode = 1997FEBSL.404..314S }} * {{cite journal | vauthors = Urhammer SA, Fridberg M, Sørensen TI, Echwald SM, Andersen T, Tybjaerg-Hansen A, Clausen JO, Pedersen O | title = Studies of genetic variability of the uncoupling protein 1 gene in Caucasian subjects with juvenile-onset obesity | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 82 | issue = 12 | pages = 4069–4074 | date = Dec 1997 | pmid = 9398715 | doi = 10.1210/jcem.82.12.4414 | doi-access = free }} * {{cite journal | vauthors = Jezek P, Urbánková E | title = Specific sequence of motifs of mitochondrial uncoupling proteins | journal = IUBMB Life | volume = 49 | issue = 1 | pages = 63–70 | date = Jan 2000 | pmid = 10772343 | doi = 10.1080/713803586 | s2cid = 8541209 | doi-access = free }} * {{cite journal | vauthors = Mori H, Okazawa H, Iwamoto K, Maeda E, Hashiramoto M, Kasuga M | title = A polymorphism in the 5' untranslated region and a Met229-->Leu variant in exon 5 of the human UCP1 gene are associated with susceptibility to type II diabetes mellitus | journal = Diabetologia | volume = 44 | issue = 3 | pages = 373–376 | date = Mar 2001 | pmid = 11317671 | doi = 10.1007/s001250051629 | doi-access = free }} * {{cite journal | vauthors = Nibbelink M, Moulin K, Arnaud E, Duval C, Pénicaud L, Casteilla L | title = Brown fat UCP1 is specifically expressed in uterine longitudinal smooth muscle cells | journal = The Journal of Biological Chemistry | volume = 276 | issue = 50 | pages = 47291–47295 | date = Dec 2001 | pmid = 11572862 | doi = 10.1074/jbc.M105658200 | doi-access = free }} * {{cite journal | vauthors = Echtay KS, Roussel D, St-Pierre J, Jekabsons MB, Cadenas S, Stuart JA, Harper JA, Roebuck SJ, Morrison A, Pickering S, Clapham JC, Brand MD | title = Superoxide activates mitochondrial uncoupling proteins | journal = Nature | volume = 415 | issue = 6867 | pages = 96–99 | date = Jan 2002 | pmid = 11780125 | doi = 10.1038/415096a | bibcode = 2002Natur.415...96E | s2cid = 4349744 }} * {{cite journal | vauthors = Rousset S, del Mar Gonzalez-Barroso M, Gelly C, Pecqueur C, Bouillaud F, Ricquier D, Cassard-Doulcier AM | title = A new polymorphic site located in the human UCP1 gene controls the in vitro binding of CREB-like factor | journal = International Journal of Obesity and Related Metabolic Disorders | volume = 26 | issue = 5 | pages = 735–738 | date = May 2002 | pmid = 12032762 | doi = 10.1038/sj.ijo.0801973 | doi-access = free }} * {{cite journal | vauthors = Rim JS, Kozak LP | title = Regulatory motifs for CREB-binding protein and Nfe2l2 transcription factors in the upstream enhancer of the mitochondrial uncoupling protein 1 gene | journal = The Journal of Biological Chemistry | volume = 277 | issue = 37 | pages = 34589–34600 | date = Sep 2002 | pmid = 12084707 | doi = 10.1074/jbc.M108866200 | doi-access = free }} * {{cite journal | vauthors = Kieć-Wilk B, Wybrańska I, Malczewska-Malec M, Leszczyńska-Gołabek L, Partyka L, Niedbał S, Jabrocka A, Dembińska-Kieć A | title = Correlation of the -3826A >G polymorphism in the promoter of the uncoupling protein 1 gene with obesity and metabolic disorders in obese families from southern Poland | journal = Journal of Physiology and Pharmacology| volume = 53 | issue = 3 | pages = 477–490 | date = Sep 2002 | pmid = 12375583 }} {{refend}}

== External links == * [https://news.bbc.co.uk/2/hi/health/5335176.stm Seaweed anti-obesity tablet hope] (BBC - Thermogenin mentioned as part of process) * {{MeshName|thermogenin}} {{Solute carrier family|bg|bg0}}

Category:Cellular respiration Category:Mitochondria