129S-Ucp1^tm1Kz/J

Stock number: 017476
Product name: Ucp1^-
Research areas: Cardiovascular Research, Diabetes and Obesity Research, Endocrine Deficiency Research, Internal/Organ Research, Metabolism Research, Research Tools

Description

These Ucp knockout mice are sensitive to cold temperatures, exhibit altered metabolism and are resistant to diet induced obesity when maintained at 20°C. This mutant mouse strain may be useful in studies of obesity, metabolic homeostasis, and adaptive thermogenesis.

Detailed description

Mice that are homozygous for this knockout allele are viable and fertile, but exhibit sensitivity to cold temperatures. The Donating Investigator notes that homozygous offspring have increased survival rates to weaning age when maintained at 25°C to 28°C. No gene product (mRNA or protein) is detected by Northern or Western blot analysis of brown adipose tissue from homozygotes. When maintained at 20°C, homozygotes are resistant to diet induced obesity with reduced white fat depot weights, exhibit a 0.1-0.3°C higher body temperature, and a slightly lowered respiratory quotient compared to controls. Notably, when maintained at 27°C, homozygous mutant mice are no longer resistant to diet induced obesity and gain weight at a rate similar to wildtype controls. An increase in the number of brown adipocytes in the inguinal fat depots is observed in mutant mice maintained at 20°C, on either diet. Homozygotes have reduced levels of plasma fatty acids, circulating triglyceride levels, and T4 levels. Spleen cell numbers are reduced by approximately 3-fold, CD8 single positive cells are reduced to approximately half and CD4/CD8 double positive cells in both the spleen and thymus are increased in homozygous animals. Homozygotes have no heat production from brown adipose tissue. Mitochondria isolated from the muscles of cold-acclimated homozygotes display an increased total ATP production capacity, a metabolic shift for increased lipid oxidation and reduced carbohydrate catabolism capacity with a corresponding increased serum level of beta-hydroxybuterate, and decreased sensitivity to fatty acids as uncoupling agents. Mitochondria isolated from brown adipose tissue from homozygotes exhibit increased rate of reactive oxygen species (ROS) production when compared to wildtype controls. The Donating Investigator reports that mice carrying this allele are less cold sensitive on the C57BL/6 genetic background compared to the 129 genetic background.

Development

A targeting vector was used to replace a BamHI/BglII fragment carrying exon 2 and part of exon 3 with the neo^r gene thereby deleting an essential membrane-spanning domain. The construct was electroporated into 129S2/SvPas derived D3 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric animals were crossed to 129Sv/ImJ mice, and then backcrossed to 129Sv/ImJ for 25 generations. Upon arrival at The Jackson Laboratory, the mice were crossed to 129S1/SvImJ (Stock No. 002448) at least once to establish the colony.

Allele

Symbol: Ucp1^tm1Kz
Name: targeted mutation 1, Leslie Kozak
MGI accession ID: MGI:1857471
Generation method: Targeted
Attributes: Null/Knockout
Marker symbol: Ucp1
Marker name: uncoupling protein 1 (mitochondrial, proton carrier)
Chromosome: 8
Strain of origin: 129S2/SvPas
Molecular note: All of exon 2 and a portion of exon 3 were replaced by a neomycin selection cassette. The deleted region encoded an essential transmembrane domain. Transcript was undetected in homozygous mutant mice via Northern blot analysis. Western blot analysis confirmed the absence of encoded protein.