Expression of the mitochondrial uncoupling protein gene from the aP2 gene promoter prevents genetic obesity.
The brown fat-specific mitochondrial uncoupling protein (UCP) provides a mechanism for generating heat by uncoupling respiration and oxidative phosphorylation. It has been suggested that this system of thermogenesis can provide a defense against obesity. To test this idea, we created a transgenic mouse in which the fat-specific aP2 gene promoter directed Ucp expression in white fat and provided for the constitutive expression of Ucp in brown fat. Transgenic mice showed both Ucp mRNA and immunoreactive UCP in white fat at 2-10% the level normally measured in brown fat. A reduction in subcutaneous fat of aP2-Ucp C57BL/6J mice was observed at 3 mo of age. When the transgene was expressed in Avy genetically obese mice reductions in total body weight and subcutaneous fat stores were observed. Female transgenic Avy mice at 13 mo of age weighed 35 grams, a weight indistinguishable from nontransgenic C57BL/6J mice. Gonadal fat showed an increase in a novel adipocyte derivative that did not accumulate lipids and that constituted approximately 80% of the mass of the tissue in Avy transgenic. A major effect of aP2-Ucp in brown fat was to reduce endogenous gene expression by as much as 95%. The results suggest that UCP synthesized from the aP2 gene promoter is thermogenically active and capable of reducing fat stores.
Kopecky
J
J
Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Clarke
G
G
Enerbäck
S
S
Spiegelman
B
B
Kozak
L P
LP
D000273:Adipose Tissue / Q000378:metabolism* / Q000502:physiology / Q000503:physiopathology; D002001:Adipose Tissue, Brown / Q000378:metabolism* / Q000502:physiology / Q000503:physiopathology; D000818:Animals; D001483:Base Sequence; D001833:Body Temperature Regulation; D001835:Body Weight; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics*; D017931:DNA Primers; D005091:Exons; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005260:Female; D014644:Genetic Variation; D007473:Ion Channels; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins; D008969:Molecular Sequence Data; D018996:Myelin P2 Protein / Q000235:genetics*; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009765:Obesity / Q000235:genetics* / Q000517:prevention & control*; D009929:Organ Size; D009928:Organ Specificity; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012045:Regulatory Sequences, Nucleic Acid; D015183:Restriction Mapping; D012727:Sex Characteristics; D000071256:Uncoupling Protein 1
D002352:Carrier Proteins; D017931:DNA Primers; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D007473:Ion Channels; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D018996:Myelin P2 Protein; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D000071256:Uncoupling Protein 1