All Phenotypes Eif2ak3<tm1.2Drc> MGI Mouse

increased susceptibility to diet-induced obesity ( J:373627 )

• mice fed a high-fat diet (HFD) for 16 weeks show a significant increase in body weight gain at thermoneutrality (30 degrees C) relative to thermoneutral-housed HFD-fed controls

• however, food intake is not significantly altered in HFD-fed mice at thermoneutrality

impaired adaptive thermogenesis ( J:373627 )

• upon cold exposure (4degrees C), 20-week HFD-fed mice show cold sensitivity (lower rectal temperatures) relative to similarly challenged HFD-fed controls

increased isoleucine level ( J:373627 )

• whole interscapular brown adipose tissue (iBAT) samples from HFD-fed mice exhibit increased leucine-isoleucine levels, consistent with reduced insertion of SLC25A44

increased leucine level ( J:373627 )

• whole iBAT tissues from HFD-fed mice exhibit increased leucine-isoleucine levels, consistent with reduced insertion of SLC25A44

increased fasting circulating glucose level ( J:373627 )

• 20-week HFD-fed mice exhibit significantly higher blood glucose levels after a 16-hour fast

increased circulating insulin level ( J:373627 )

• 20-week HFD-fed mice exhibit significantly higher serum insulin levels than HFD-fed controls

increased circulating free fatty acids level ( J:373627 )

• HFD-fed mice exhibit significantly higher serum free fatty acid levels than HFD-fed controls

decreased oxygen consumption ( J:373627 )

• HFD-fed mice chronically housed at thermoneutrality (30 degrees C) show significantly lower oxygen consumption rates than thermoneutral-housed HFD-fed controls

impaired glucose tolerance ( J:373627 )

• 20-week HFD-fed mice exhibit significantly higher blood glucose levels at different time points after intraperitoneal injection of glucose, indicating glucose intolerance

insulin resistance ( J:373627 )

• 20-week HFD-fed mice exhibit significantly higher blood glucose levels at all time points after intraperitoneal injection of insulin

decreased fat cell respiration ( J:373627 )

• HFD-fed mice exhibit reduced respiratory capacity in mitochondria isolated from interscapular brown adipose tissue (iBAT), as indicated by significantly lower oxygen consumption rates after sequential addition of GDP, oligomycin, and FCCP (an uncoupling agent)

abnormal mitochondrial morphology ( J:373627 )

• TEM images from HFD-fed mice show alterations in mitochondrial ultrastructure

abnormal mitochondrial crista morphology ( J:373627 )

• HFD-fed mice show a significant reduction in mitochondrial cristae density

abnormal mitochondrial physiology ( J:373627 )

• iBAT mitochondria isolated from HFD-fed mice show impaired in vitro import of the TOM70-dependent substrate 35S-ANT2 (adenine nucleotide transporter 2), but not the TOM20-dependent substrate 35S-OTC (ornithine transcarbamylase), suggesting a TOM70-dependent defect

• although protein levels of TOMM70 (translocase of outer mitochondrial membrane 70; aka TOM70) are slightly higher in mitochondria isolated from HFD-fed mice, carbonate extraction assays show a decrease in the steady-state levels of TOM70 and carrier substrates such as ANT2 and SLC25A44 in HFD-fed mice, indicating defective TOM70 insertion at the outer mitochondrial membrane (OMM)

• in vitro import of 35S-TOM70 into mitochondria isolated from HFD-fed mice is reduced while import of ANT2 at the inner mitochondrial membrane (IMM) is also defective, consistent with the cold-sensitive phenotype observed in vivo

• moreover, in vitro 14C-amino-acid uptake assays show a reduction in leucine incorporation, but not glutamine incorporation, in iBAT mitochondria isolated from HFD-fed mice

abnormal respiratory electron transport chain ( J:373627 )

• iBAT mitochondria isolated from HFD-fed mice show a significant reduction in relative NAD+/NADH ratios

abnormal brown adipose tissue morphology ( J:373627 )

• whole iBAT tissues from HFD-fed mice exhibit increased leucine-isoleucine levels, consistent with reduced insertion of SLC25A44 -- an IMM carrier characterized as a mitochondrial branched-chain amino acid (BCAA) transporter in iBAT

abnormal brown adipose tissue thermogenesis ( J:373627 )

• mitochondrial dysfunction in HFD-fed mice impairs the insertion of TOM70 at the OMM, causing defective import of essential solute protein carriers that sustain iBAT thermogenesis

decreased fat cell respiration ( J:373627 )

• HFD-fed mice exhibit reduced respiratory capacity in mitochondria isolated from interscapular brown adipose tissue (iBAT), as indicated by significantly lower oxygen consumption rates after sequential addition of GDP, oligomycin, and FCCP (an uncoupling agent)

increased susceptibility to diet-induced obesity ( J:373627 )

• mice fed a high-fat diet (HFD) for 16 weeks show a significant increase in body weight gain at thermoneutrality (30 degrees C) relative to thermoneutral-housed HFD-fed controls

• however, food intake is not significantly altered in HFD-fed mice at thermoneutrality

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

♀	phenotype observed in females
♂	phenotype observed in males
N	normal phenotype

Contributing Projects: Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO)
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