Thermogenic responses in brown fat cells are fully UCP1-dependent. UCP2 or UCP3 do not substitute for UCP1 in adrenergically or fatty scid-induced thermogenesis.
To examine the thermogenic significance of the classical uncoupling protein-1 (UCP1), the thermogenic potential of brown adipocytes isolated from UCP1-ablated mice was investigated. Ucp1(-/-) cells had a basal metabolic rate identical to wild-type; the mitochondria within them were coupled to the same degree. The response to norepinephrine in wild-type cells was robust ( approximately 10-fold increase in thermogenesis); Ucp1(-/-) cells only responded approximately 3% of this. Ucp1(-/-) cells were as potent as wild-type in norepinephrine-induced cAMP accumulation and lipolysis and had a similar mitochondrial respiratory complement. In wild-type cells, fatty acids induced a thermogenic response similar to norepinephrine, but fatty acids (and retinoate) were practically without effect in Ucp1(-/-) cells. It is concluded that no other adrenergically induced thermogenic mechanism exists in brown adipocytes except that mediated by UCP1 and that entopic expression of UCP1 does not lead to overt innate uncoupling, and it is suggested that fatty acids are transformed to an intracellular physiological activator of UCP1. High expression of UCP2 and UCP3 in the tissue was not associated with an overt innate highly uncoupled state of mitochondria within the cells, nor with an ability of norepinephrine or endo- or exogenous fatty acids to induce uncoupled respiration in the cells. Thus, UCP1 remains the only physiologically potent thermogenic uncoupling protein in these cells.
Matthias
A
A
Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, Sweden.
Ohlson
K B
KB
Fredriksson
J M
JM
Jacobsson
A
A
Nedergaard
J
J
Cannon
B
B
D017667:Adipocytes / Q000378:metabolism*; D002001:Adipose Tissue, Brown / Q000378:metabolism*; D000322:Adrenergic Agonists / Q000378:metabolism*; D000818:Animals; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D005091:Exons; D005227:Fatty Acids / Q000378:metabolism*; D005990:Glycerol / Q000378:metabolism; D007473:Ion Channels; D007848:Laurates / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins; D008954:Models, Biological; D009638:Norepinephrine / Q000378:metabolism; D019301:Oleic Acid / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011995:Recombination, Genetic; D013696:Temperature; D014212:Tretinoin / Q000494:pharmacology; D014475:Uncoupling Agents / Q000494:pharmacology; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3
D000322:Adrenergic Agonists; D002352:Carrier Proteins; D005227:Fatty Acids; D007473:Ion Channels; D007848:Laurates; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; C000604372:Ucp1 protein, mouse; C000604390:Ucp2 protein, mouse; C000604393:Ucp3 protein, mouse; D014475:Uncoupling Agents; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000071247:Uncoupling Protein 3; D019301:Oleic Acid; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D014212:Tretinoin; D000242:Cyclic AMP; D005990:Glycerol; D009638:Norepinephrine