Thermogenin

Thermogenin (called uncoupling protein by its discoverers and now known as uncoupling protein 1, or UCP1)cite web | title = Entrez Gene: UCP1 uncoupling protein 1 (mitochondrial, proton carrier)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7350| accessdate = ] is an uncoupling protein found in the mitochondria of brown adipose tissue (BAT). It is used to generate heat by non-shivering thermogenesis. Non-shivering thermogenesis is the primary means of heat generation in hibernating mammals and in human infants.

Mechanism

The molecular mechanism of UCP1 mediated uncoupling is reasonably well understood; UCP1 provides an alternative pathway by which protons can reenter the mitochondrial matrix, short-circuiting the 'proton circuit' linking the respiratory chain to the ATP synthase (which generates ATP for the cell) and allowing respiration (and hence heat production) to proceed in the absence of ATP synthesis. 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 fat 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 that are liberated by the following pathway: 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 nucleodides (GDP, ADP). At the termination of thermogenesis, the mitochondria oxidize away the residual fatty acids, UCP1 inactivates and the cell resumes its normal energy-conserving mode.

History

Uncoupling protein 1 was discovered in 1979cite journal | author = Nicholls DG, Bernson VS, Heaton GM | title = The identification of the component in the inner membrane of brown adipose tissue mitochondria responsible for regulating energy dissipation | journal = Experientia Suppl. | volume = 32 | issue = | pages = 89–93 | year = 1978 | pmid = 348493 | doi = | issn = ] and was first cloned in 1988.cite journal | author = Kozak LP, Britton JH, Kozak UC, Wells JM | title = The mitochondrial uncoupling protein gene. Correlation of exon structure to transmembrane domains | journal = J. Biol. Chem. | volume = 263 | issue = 25 | pages = 12274–7 | year = 1988 | pmid = 3410843 | doi = | issn = | url = http://www.jbc.org/cgi/content/abstract/263/25/12274 ] cite journal | author = 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 = Biochem. Biophys. Res. Commun. | volume = 157 | issue = 2 | pages = 783–92 | year = 1988 | pmid = 3202878 | doi = 10.1016/S0006-291X(88)80318-8 ]

Uncoupling protein two (UCP2), a homolog of UCP1, was identified in 1997. In the past decade three additional homologs of UCP1 have been identified, including UCP3, UCP4, and BMCP1 (also known as UCP5).

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Ricquier D, Bouillaud F |title=The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP |journal=Biochem. J. |volume=345 Pt 2 |issue= |pages= 161–79 |year= 2000 |pmid= 10620491 |doi=
*cite journal | author=Muzzin P |title=The uncoupling proteins |journal=Ann. Endocrinol. (Paris) |volume=63 |issue= 2 Pt 1 |pages= 106–10 |year= 2002 |pmid= 11994670 |doi=
*cite journal | author=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 : an official journal of the International Association for the Study of Obesity |volume=1 |issue= 2 |pages= 61–72 |year= 2002 |pmid= 12119988 |doi=
*cite journal | author=Cassard AM, Bouillaud F, Mattei MG, "et al." |title=Human uncoupling protein gene: structure, comparison with rat gene, and assignment to the long arm of chromosome 4 |journal=J. Cell. Biochem. |volume=43 |issue= 3 |pages= 255–64 |year= 1990 |pmid= 2380264 |doi= 10.1002/jcb.240430306
*cite journal | author=Bouillaud F, Villarroya F, Hentz E, "et al." |title=Detection of brown adipose tissue uncoupling protein mRNA in adult patients by a human genomic probe |journal=Clin. Sci. |volume=75 |issue= 1 |pages= 21–7 |year= 1988 |pmid= 3165741 |doi=
*cite journal | author=Oppert JM, Vohl MC, Chagnon M, "et al." |title=DNA polymorphism in the uncoupling protein (UCP) gene and human body fat |journal=Int. J. Obes. Relat. Metab. Disord. |volume=18 |issue= 8 |pages= 526–31 |year= 1994 |pmid= 7951471 |doi=
*cite journal | author=Clément K, Ruiz J, Cassard-Doulcier AM, "et al." |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=Int. J. Obes. Relat. Metab. Disord. |volume=20 |issue= 12 |pages= 1062–6 |year= 1997 |pmid= 8968850 |doi=
*cite journal | author=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 Lett. |volume=404 |issue= 2-3 |pages= 314–8 |year= 1997 |pmid= 9119086| doi=10.1016/S0014-5793(97)00145-2
*cite journal | author=Urhammer SA, Fridberg M, Sørensen TI, "et al." |title=Studies of genetic variability of the uncoupling protein 1 gene in Caucasian subjects with juvenile-onset obesity |journal=J. Clin. Endocrinol. Metab. |volume=82 |issue= 12 |pages= 4069–74 |year= 1998 |pmid= 9398715 |doi=
*cite journal | author=Jezek P, Urbánková E |title=Specific sequence of motifs of mitochondrial uncoupling proteins |journal=IUBMB Life |volume=49 |issue= 1 |pages= 63–70 |year= 2000 |pmid= 10772343 |doi=
*cite journal | author=Mori H, Okazawa H, Iwamoto K, "et al." |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= 373–6 |year= 2001 |pmid= 11317671| doi=10.1007/s001250051629
*cite journal | author=Nibbelink M, Moulin K, Arnaud E, "et al." |title=Brown fat UCP1 is specifically expressed in uterine longitudinal smooth muscle cells |journal=J. Biol. Chem. |volume=276 |issue= 50 |pages= 47291–5 |year= 2002 |pmid= 11572862 |doi= 10.1074/jbc.M105658200
*cite journal | author=Echtay KS, Roussel D, St-Pierre J, "et al." |title=Superoxide activates mitochondrial uncoupling proteins |journal=Nature |volume=415 |issue= 6867 |pages= 96–9 |year= 2002 |pmid= 11780125 |doi= 10.1038/415096a
*cite journal | author=Rousset S, del Mar Gonzalez-Barroso M, Gelly C, "et al." |title=A new polymorphic site located in the human UCP1 gene controls the in vitro binding of CREB-like factor |journal=Int. J. Obes. Relat. Metab. Disord. |volume=26 |issue= 5 |pages= 735–8 |year= 2002 |pmid= 12032762 |doi= 10.1038/sj.ijo.0801973
*cite journal | author=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=J. Biol. Chem. |volume=277 |issue= 37 |pages= 34589–600 |year= 2002 |pmid= 12084707 |doi= 10.1074/jbc.M108866200
*cite journal | author=Kieć-Wilk B, Wybrańska I, Malczewska-Malec M, "et al." |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=J. Physiol. Pharmacol. |volume=53 |issue= 3 |pages= 477–90 |year= 2003 |pmid= 12375583 |doi=
*cite journal | author=Strausberg RL, Feingold EA, Grouse LH, "et al." |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899

External links

* [http://news.bbc.co.uk/2/hi/health/5335176.stm Seaweed anti-obesity tablet hope] (BBC - Thermogenin mentioned as part of process)
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