mortality/aging
• pronounced cardiac dysfunction results in premature death for male and female homozygotes; the first mice die around 12 weeks of age
• male mice (50% after 16 weeks) die earlier than female (50% after 20 weeks)
• heterozygous mice have normal life spans
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growth/size/body
• mutant hearts have a 1.4x heart weight because of the excess triglycerides (193 mg for mutant vs 131 mg wild-type)
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• homozygotes display a 2-fold increase in body fat mass
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• homozygotes are heavier than wild-type
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homeostasis/metabolism
• after 5 hours of cold exposure, mutant body temperature is only 25 degrees C
• when mutants are exposed to cold for 5 hours, they suffer from life-threatening hypothermia as a result of impaired catabolism to triglycerides to brown adipose tissue
• after 18 hours of fasting, body temperature drops to 28.4 degrees C vs 35.4 degrees in wild-type with prolonged fasting
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• after a 6-hour fast, mice have significantly lower basal glucose values compared to wild-type
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• in the fed state, plasma insulin levels are reduced by 42% in mutants compared to wild-type
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• plasma leptin levels are elevated by 2.1-fold in fed mutants and by 4.4-fold in fasted mutant mice
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• at death
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• oxygen consumption decreases to 25% of that of wild-type after 18 hours of fasting
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• RQ in mutants deviates from wild-type during fasting; RQ remains constant whereas in wild-type, it decreases with increasing fasting time
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• after a 6-hour fast, null mice show improved glucose tolerance compared to wild-type
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• maximal decline of blood glucose levels is more pronounced (34 mg/dl vs 53 mg/dl in wild-type) in Pnpla-deficient mice and persists for the entire 3 hour observation period
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• total cholesterol (due to decreased HDL levels ) is reduced by 22%
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• in mutants, levels are reduced by 30% in the fed state and by 62% in the fasted state
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• levels are decreased by 66%
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• reduced VLDL levels are found in mutants
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• in non-cardiac tissue the most pronounced accumulation of triglycerides is a >10-fold increase seen in the testis and kidney; smaller (1.5-4-fold) increases are seen in all tissues including the liver
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• there is a 20-fold increase in triglyceride content in cardiac muscle by 12 weeks of age in mutants
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• in mutants there is decreased lipolytic activities in white (-82%) and brown (-85%) adipose tissues, cardiac muscle (-31%), skeletal muscle (-44%), testis (-69%) and liver (-73%)
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adipose tissue
• mutant mice have enlarged lipid droplets (1395 micrometer
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• mutants have an 8.5 fold increase in wet weight of intracapsular brown adipose tissue
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• homozygotes display a 1.6 fold increase in wet weight of gonadal white adipose tissue compared to controls
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• homozygotes display a 2.1 fold increase in wet weight of inguinal white adipose tissue compared to controls
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• mutants have an 8.5 fold increase in wet weight of intracapsular brown adipose tissue
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• mutant mice have enlarged lipid droplets (4690 micrometer
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cardiovascular system
• congestion is observed in pulmonary vessels at death; not observed in mice before 14 weeks of age
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• there is a 20-fold increase in triglyceride content in cardiac muscle by 12 weeks of age in mutants
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• in homozygotes there is severe triglyceride accumulation in cardiac muscle; at 12 weeks of age, mutants have a 20-fold higher triglyceride content in myocytes compared to wild-type
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• lipid droplets show an age-dependent increase in size and number in cardiomyocytes of mutants beginning with microvesicular droplets at 6 weeks and progressing to large droplets by 18 weeks
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• the interventricular septum in mutant hearts is significantly thickened and increases in thickness with age
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• mutant hearts have a 1.4x heart weight because of the excess triglycerides (193 mg for mutant vs 131 mg wild-type)
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• at death; this is not observed in mice before 14 weeks of age
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• at death; this is not observed in mice before 14 weeks of age
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• there is a marked change in cardiac texture and increase in fibrosis
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• massive lipid buildup causes severe cardiac insufficiency in mutants
• at death, cardiac edema and pleural as well as cardiac effusions are observed; these are not observed in mice before 14 weeks of age
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• ejection fraction from left ventricle is drastically reduced compared to wild-type (40.2% vs 80.5% in wild-type)
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• in mutants there is a moderate induction of apoptosis
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• at death, mutants display typical features of congestive heart failure
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muscle
• there is a 20-fold increase in triglyceride content in cardiac muscle by 12 weeks of age in mutants
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• in homozygotes there is severe triglyceride accumulation in cardiac muscle; at 12 weeks of age, mutants have a 20-fold higher triglyceride content in myocytes compared to wild-type
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• lipid droplets show an age-dependent increase in size and number in cardiomyocytes of mutants beginning with microvesicular droplets at 6 weeks and progressing to large droplets by 18 weeks
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• ejection fraction from left ventricle is drastically reduced compared to wild-type (40.2% vs 80.5% in wild-type)
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• in mutants there is a moderate induction of apoptosis
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liver/biliary system
respiratory system
• congestion is observed in pulmonary vessels at death; not observed in mice before 14 weeks of age
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cellular
• in mutants there is a moderate induction of apoptosis
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