Phenotypes associated with this allele

• Allele Symbol: Npy1r^tm1Tped
• Allele Name: targeted mutation 1, Thierry Pedrazzini
• Allele ID: MGI:2158699
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Npy1r^tm1Tped/Npy1r^tm1Tped	B6.129P2-Npy1r^tm1Tped	MGI:3639781
hm2	Npy1r^tm1Tped/Npy1r^tm1Tped	involves: 129P2/OlaHsd * C57BL/6	MGI:3639766

Genotype
MGI:3639781

hm1

• Allelic Composition: Npy1r^tm1Tped/Npy1r^tm1Tped
• Genetic Background: B6.129P2-Npy1r^tm1Tped

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

behavior/neurological

behavior/neurological phenotype ( J:108001 )

N • in response to hippocampal kindling epileptogenesis, homozygotes display similar susceptibility to seizure induction and present no differences in kindling development relative to wild-type mice

increased alcohol consumption ( J:109207 )

• at 8-14 weeks of age (prior to the onset of obesity), male homozygotes show a significantly increased consumption of solutions containing 3, 6, and 10% (v/v) ethanol relative to wild-type males while female homozygotes exhibit increased consumption of a 10% ethanol solution but not of the 3% and 6% ethanol solutions

• in contrast, both male and female homozygotes display normal consumption of solutions containing either sucrose or quinine

• no significant differences in average body weight, food intake or water consumption are noted during the alcohol consumption test

impaired behavioral response to alcohol ( J:109207 )

• male homozygotes are resistant to ethanol-induced sedation, regaining their righting reflex significantly faster than wild-type males after injection of both the 3.5 and 4.0 gm/kg ethanol doses, although plasma ethanol levels do not differ significantly between the genotypes

• however, male homozygotes display normal ethanol-induced ataxia on the rotarod test after administration of a 2.5 gm/kg dose relative to wild-type males

decreased exploration in new environment ( J:101870 )

• 6-month-old male homozygotes exhibit reduced novelty-induced somatomotor activity in the free-choice novelty-preference test; however, mutants spend the same amount of time in the novel environment as wild-type mice

• in the open field, homozygotes habituate more quickly when repeatedly exposed to a familiar environment relative to wild-type mice

• however, when the environment is manipulated by rearrangement or replacement of objects, mutants show a significantly reduced rate of object exploration relative to wild-type mice

• in addition, homozygotes fail to show signs of behavioural arousal directed towards displaced/replaced objects

cardiovascular system

cardiac interstitial fibrosis ( J:101870 )

• 6-month-old male homozygotes exhibit a moderately larger volume fraction of interstitial and reparative fibrosis than wild-type males; however, the total amount of fibrotic damage is limited, involving 1.3% of the entire left ventricular myocardium, and no hypertrophic compensatory response is observed

abnormal cardiovascular system physiology ( J:101870 )

• during social defeat, 6-month-old homozygotes show a higher heart rate reactivity than wild-type mice, as shown by greater area under the curve values of heart rate and heart rate variability parameters

• however, homozygotes show no significant differences in the values of ECG parameters during the test and post-test period, indicating that increased responsiveness is due to differences in starting, baseline levels

decreased heart rate ( J:101870 )

• 6-month-old male homozygotes display reduced heart rate in baseline conditions relative to wild-type males

• however, male homozygotes show increased heart rate responsiveness during acute social defeat

nervous system

abnormal sympathetic system morphology ( J:101870 )

• 6-month-old male homozygotes display an increased number of alpha2-adrenoceptors in the dorsal motor nucleus of the vagus and the locus coeruleus i.e. in brain areas involved in central neural regulation of cardiovascular function

growth/size/body

obese ( J:87424 )

• in response to chronic, central neuropeptide Y infusion, 6-7-month-old male homozygotes display a comparable hyperphagic response and immediate development of an obesity syndrome similar to that observed in wild-type mice

adipose tissue

increased epididymal fat pad weight ( J:102554 )

• at 8-10 weeks, the wet weight of mutant epididymal fat pads is >2-fold higher than that of wild-type fat pads

increased retroperitoneal fat pad weight ( J:87424 )

• in response to chronic, central neuropeptide Y infusion, 6-7-month-old male homozygotes display a further increase in retroperitoneal fat pad mass to levels even higher than those found in NPY-treated wild-type males

increased percent body fat/body weight ( J:102554 )

• at 8-10 weeks, male homozygotes show a significant increase in percent body fat relative to wild-type males (11.5 0.8% vs 7.7 0.6%, respectively)

• notably, circulating leptin levels are not significantly increased in young mutants but do increase with the development of obesity in older mutants

increased adipocyte glucose uptake ( J:102554 )

• during a 6-hr fast, young male homozygotes show a 3-fold increase of glucose uptake in epididymal fat pads

homeostasis/metabolism

increased circulating corticosterone level ( J:87424 )

• in response to chronic, central neuropeptide Y infusion, 6-7-month-old male homozygotes display a comparable increase in plasma corticosterone levels relative to wild-type males

increased circulating leptin level ( J:87424 )

• in response to chronic, central neuropeptide Y infusion, 6-7-month-old male homozygotes display a further increase in plasma leptin to levels even higher than those found in NPY-treated wild-type males

abnormal glucose homeostasis ( J:102554 )

• during a 6-hr fast, young (8-10-wk-old) male homozygotes show a ~50% increase in whole body glucose turnover relative to wild-type mice; the glucose metabolic clearance rate is also increased

hyperglycemia ( J:102554 )

• in the fed state, young male homozygotes show a moderate but significant hyperglycemia, associated with severe hypoinsulinemia and significantly reduced lactate levels

increased circulating insulin level ( J:87424 , J:102554 )

• in response to chronic, central neuropeptide Y infusion, 6-7-month-old male homozygotes display a higher increase in plasma insulin to levels even higher than those found in NPY-treated wild-type males (J:87424)

• in the fasted state, young male homozygotes show a ~2-fold increase in plasma insulin levels relative to wild-type males; glucose levels remain normal while lactate levels are reduced (J:102554)

• fasting hyperinsulinemia is associated with increased whole body and adipose tissue glucose utilization and glycogen synthesis but normal glycolysis (J:102554)

• leptin infusion in 6-hr fasted homozygotes normalizes hyperinsulinemia as well as whole body glucose turnover and glycogen synthesis rates (J:102554)

abnormal glycogen level ( J:102554 )

• during a 6-hr fast, young male homozygotes show a significant increase in the rate of whole body glycogen synthesis while the glycolytic rate remains unaltered

cellular

increased adipocyte glucose uptake ( J:102554 )

• during a 6-hr fast, young male homozygotes show a 3-fold increase of glucose uptake in epididymal fat pads

cardiac interstitial fibrosis ( J:101870 )

• 6-month-old male homozygotes exhibit a moderately larger volume fraction of interstitial and reparative fibrosis than wild-type males; however, the total amount of fibrotic damage is limited, involving 1.3% of the entire left ventricular myocardium, and no hypertrophic compensatory response is observed

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
obesity		DOID:9970	OMIM:601665	J:87424

Genotype
MGI:3639766

hm2

• Allelic Composition: Npy1r^tm1Tped/Npy1r^tm1Tped
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

mortality/aging

mortality/aging ( J:47972 )

N • breeding of heterozygotes generates homozygous mutant mice at a slightly reduced Mendelian frequency (13.4% vs expected 25%); however, specific stage at which lethality occurs has not been determined

N • both female and male homozygotes are viable and fertile with no apparent organ abnormalities

cardiovascular system

abnormal vasoconstriction ( J:47972 )

• homozygotes show no significant differences in baseline mean arterial blood pressure and heart rate relative to wild-type and heterozygous mutant mice

• however, homozygotes display complete absence of blood pressure and heart rate responses to neuropeptide Y but retain normal responses to other vasoconstrictors such as norepinephrine and angiotensin II

• in vitro, aortas from homozygous mutant mice show loss of NPY-mediated potentiation of norepinephrine-induced vasoconstriction

homeostasis/metabolism

increased circulating insulin level ( J:47972 )

• at 30 weeks, homozygotes display slightly increased plasma insulin levels relative to wild-type mice while glucose levels remain normal

increased circulating leptin level ( J:47972 )

• at 30 weeks, homozygotes display increased plasma leptin levels that are proportional to body fat

increased circulating free fatty acids level ( J:47972 )

• at 30 weeks, homozygotes display slightly increased plasma free fatty acid levels relative to wild-type mice

abnormal energy expenditure ( J:47972 )

• adult homozygotes display reduced energy expenditure

decreased oxygen consumption ( J:47972 )

• at 30 weeks, homozygotes show only a slight reduction in resting metabolic rate during the lights-on period

• however, homozygotes show a ~20% reduction in metabolic rate during the activity period (lights-off)

• in contrast, cold-induced thermogenesis as well as basal and norepinephrine-induced stimulation of oxygen consumption of BAT remain unaffected

adipose tissue

increased total body fat amount ( J:47972 )

• at 30 weeks, homozygotes exhibit an increased body fat, which is more prominent in females than in males; however, protein content remains normal

growth/size/body

obese ( J:47972 )

• at weaning, both male and female homozygotes are slightly lighter than wild-type mice; however, their body weight progressively increases due to fat accumulation

• male homozygotes recover from their weight deficit in ~15 weeks, whereas female homozygotes are heavier than wild-type females by 6 weeks, and ~30% heavier by 30 weeks

behavior/neurological

decreased food intake ( J:47972 )

• at 12-14 weeks, homozygotes show a modest but significant reduction in daily food intake relative to wild-type mice

• in addition, homozygotes display a slightly reduced feeding response after i.c.v. NPY injection

decreased compensatory feeding amount ( J:47972 )

• homozygotes show a significant decrease in the refeeding response after a 24-hr fasting period

decreased locomotor activity ( J:47972 )

• at 12 weeks, male and female homozygotes travel a significantly shorter home-caged distance during the night

• homozygotes show more frequent and longer inactivity periods during both the lights-on and -off periods

muscle

abnormal vasoconstriction ( J:47972 )

• homozygotes show no significant differences in baseline mean arterial blood pressure and heart rate relative to wild-type and heterozygous mutant mice

• however, homozygotes display complete absence of blood pressure and heart rate responses to neuropeptide Y but retain normal responses to other vasoconstrictors such as norepinephrine and angiotensin II

• in vitro, aortas from homozygous mutant mice show loss of NPY-mediated potentiation of norepinephrine-induced vasoconstriction