Mouse Genome Informatics
hm1
    Leprdb/Leprdb
B6.BKS(D)-Leprdb/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• mice treated with leptin fail to exhibit a decrease in food intake unlike similarly treated wild-type mice

behavior/neurological
• faster in food finding trials relative to controls
• during the dark phase

renal/urinary system
• homozygotes develop significant glomerulosclerosis by 18 weeks of age


Mouse Genome Informatics
hm2
    Leprdb/Leprdb
B6.Cg-Dock7m +/+ Leprdb/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size
• increase in body weight becomes apparent at 4-6 weeks of age (J:18161)
• body weight is 2- to 3-fold more than in wild-type mice by 10 weeks of age (J:82334)
• body weight is 10% and 20% more in males and females, respectively, compared to Leprrtm1Mgmj homozygotes (J:82334)
• develop progressive obesity (J:103063)
• snout to anus length is decreased by about 5% compared to wild-type mice

behavior/neurological

cardiovascular system
• exhibit myocyte hypertrophy
• increase in left ventricle wall thickness and mass is seen by 6 months of age but not at 2 months of age
• induced weight loss via leptin infusion, but not via caloric restriction, partially resolves the hypertrophy

muscle
• exhibit myocyte hypertrophy

homeostasis/metabolism
• HDL cholesterol and glucose levels increase concurrently
• Background Sensitivity: plasma lipid levels are similar at 3.5 and 14 months of age on the C57BL/6J background unlike on a C57BL/KsJ background
• fasting plasma total cholesterol concentration is increased 2 fold over controls
• triglyceride levels are elevated 1.5- to 2-fold (J:18161)
• female mice exhibit an increase in hypothalamic gonadotrophin releasing hormone compared to in wild-type mice
• decreased in serum
• elevated levels of eotaxin, keratinocyte cytokine, and monocyte chemotactic protein-1 (also elevated in serum) in bronchoalveolar lavage fluid
• elevated levels of IL-6 in bronchoalveolar lavage fluid
• elevated levels of IL-6 in serum

reproductive system
• atrophy of the reproductive organs (J:82334)
(J:6157)
(J:82334)
• females never show signs of vaginal oestrous (J:82334)
• mice exhibit diestrous vaginal acyclicity or occasional metestrous acyclicity (J:6157)
(J:6157)
• all females fail to reproduce (J:82334)

respiratory system
• elevated levels of eotaxin, Il6, keratinocyte cytokine, monocyte chemotactic protein-1, and neutrophiles in bronchoalveolar lavage as a result of ozone exposure
• ozone induces significantly elevated levels of TNFR1
• ozone induces a nonsignificant elevation of TNFR2 levels
• elevated pulmonary levels of Il1beta mRNA 24 hours after ozone exposure
• elevated pulmonary levels of TNF mRNA 24 hours after ozone exposure but to a lesser extent than in controls
• reduced
• pressure volume curves shifted to the right
• end-expiratory pause increases considerably less than in controls after ozone exposure
• total lung resistance increases much more in response to ozone than in control mice
• responsiveness to methacholine and serotonin is much greater than controls
• ventilation volumes decline with ozone exposure but to a lesser degree than for controls

immune system
• decrease blood leukocyte numbers
• increased numbers in bronchoalveolar lavage
• elevated levels of eotaxin, keratinocyte cytokine, and monocyte chemotactic protein-1 (also elevated in serum) in bronchoalveolar lavage fluid
• elevated levels of IL-6 in bronchoalveolar lavage fluid
• elevated levels of IL-6 in serum
• elevated levels of eotaxin, Il6, keratinocyte cytokine, monocyte chemotactic protein-1, and neutrophiles in bronchoalveolar lavage as a result of ozone exposure
• ozone induces significantly elevated levels of TNFR1
• ozone induces a nonsignificant elevation of TNFR2 levels
• elevated pulmonary levels of Il1beta mRNA 24 hours after ozone exposure
• elevated pulmonary levels of TNF mRNA 24 hours after ozone exposure but to a lesser extent than in controls

tumorigenesis
• increased metastasis to the lung of both melanoma cell lines and lung cancer cell lines initially injected in the tail vein

hematopoietic system
• decrease blood leukocyte numbers
• increased numbers in bronchoalveolar lavage

nervous system

Mouse Models of Human Disease
OMIM IDRef(s)
Obesity 601665 J:18161 , J:82234 , J:103063


Mouse Genome Informatics
hm3
    Leprdb/Leprdb
BKS.Cg-Dock7m +/+ Leprdb/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• increased secreation of glucagon by pancreatic cells in culture
• brain derived neurotrophic factor (BDNF) causes a drop in blood glucose relative to controls 8 weeks after treatment (J:43162)
• affect of BDNF on blood glucose becomes progressively less as mice age (J:43162)
• neurotrophin 3 also causes a drop in blood glucose but the glucose levels return to normal by 24 hours after treatment (J:43162)
• glucose levels are reduced at all times tested when mice are placed on feeding restriction during the dark phase (J:91813)
• blood glucose shows a progressive increase from 5 through 33 weeks
• fasting blood glucose level is significantly higher than control at 26 weeks of age (J:135864)
• BDNF causes a 50% reduction in plasma insulin relative to controls (J:43162)
• morning insulin levels lowered when feeding is restricted during the dark phase (J:91813)
• Background Sensitivity: plasma lipid levels differ between young and old mutants unlike on the C57BL/6J background where levels are similar at both ages; 14-month old mice have lower triglycerides, HDL cholesterol and combined VLDL + LDL cholesterol levels than 14-week old mice, but have significantly higher plasma triglyceride levels
• fasting plasma total cholesterol concentration is increased 2 fold over controls
• triglyceride levels are reduced at all times tested when mice are placed on feeding restriction during the dark phase
• triglyceride levels are elevated 1.5- to 2-fold
• BDNF treatment causes a lower blood glucose level response in a glucose tolerance test
• in diabetic wounds, PGE2 level is consistently less than 50% of wild-type wounds at all times
• mutants treated with sRAGE do not show the increased albumin excretion seen in untreated mutants (0.11 ug albumin/ug creatinine vs 0.20 ug albumin/ ug creatinine); levels are not significantly different from control animals (0.08 ug albumin/ ug creatinine)
• moderate albuminuria is observed at 26 weeks of age
• wound healing is impaired, with an average wound closure time of 22 days, 7 days longer than in controls
• T26A, a prostaglandin transporter inhibitor, topically applied to wounds shortened wound closure to 16 days in mutants, similar to untreated controls; T26A increased re-epithelialization, neovascularization, and blood flow in wounds

growth/size
• body weight drops after 6 days on feeding restriction during the dark phase
• become progressively obese starting at 5 weeks of age
• weight reaches 2.5X that of control mice by 3 months of age

renal/urinary system
• mutants treated with sRAGE do not show the increased albumin excretion seen in untreated mutants (0.11 ug albumin/ug creatinine vs 0.20 ug albumin/ ug creatinine); levels are not significantly different from control animals (0.08 ug albumin/ ug creatinine)
• moderate albuminuria is observed at 26 weeks of age
• moderate mesangial expansion is observed in glomeruli at 26 weeks
• male mutants treated with sRAGE to achieve RAGE blockade display increased creatinine clearance (~5.1 ml/hour/100 x g body weight) compared to PBS-treated mutants (~3 ml/hour/100 x g body weight), approaching wild-type levels (6.7 ml/hour/100 x g body weight)

nervous system
• axonal growth cone extension fails to occur for neurons treated in culture with 100ng/ml of leptin
• myelinated fibers reduced in numbers at 25 weeks in the sural nerve
• unmyelinated fibers reduced in numbers at 25 weeks in the vagus nerve
• myelinated fiber density increases in most nerves (not the peroneal and phrenic nerves)
• unmyelinated fiber density increase in the sural, peroneal, and vagus nerves
• non significant shift toward smaller fiber diameter at 15 weeks of age
• significantly shifted to smaller diameter fibers by 25 weeks in ventral roots, dorsal roots, sural nerve
• smaller diameter nerve fibers in peroneal, phrenic and vagus nerves at 25 weeks but not significant
• small numbers of very large unmyelinated fibers (up to 1.6 micrometers)
• shift of unmyelinated fibers to smaller diameters
• number of myelin lamellae relative to nerve diameter is increased
• motor nerve conductance significantly lower than controls from 7 weeks of age onward
• velocity returns to and is maintained at prediabetic levels by 15 weeks of age whereas control mice show a continuous increase in velocity
• insulin treatment results in improved conductance but only for the duration of treatment and control levels of conductance are never restored
• no conductance improvement is seen in mice over 23 weeks in age due to insulin treatment
• CA1 hippocampal slices indicate brief post tetanic potentiation but no long term potentiation on recordings of excitatory post-synaptic potentials
• CA1 hippocampal slices indicate no long term depression on recordings of excitatory post-synaptic potentials

behavior/neurological
• daily locomotor pattern becomes attenuated in 6-8 week old mice but rhythmicity is retained
• daily locomotor activity rhythmicity severely diminished at 13-14 weeks, 75% fail to show significant rhythmicity
• daily locomotor rhythmicity restored by feeding restriction during dark phase
• food intake is about 60% of control level
• longer swimming distances than control mice in a Morris water maze test
• cross the original platform location less frequently than do controls in a Morris water maze test

vision/eye
• prolonged latency of the b-wave in the retina
• delays in oscillatory potentials 1, 2, 3 although only the delay in "OP1" is significant

endocrine/exocrine glands
• increased secreation of glucagon by pancreatic cells in culture

cardiovascular system
• dense bodies found in the smooth muscle of intramyocardial arteries
• disrupted sarcomeres sometimes
• presence of many lipid droplets
• dense bodies present in places normally occupied by mitochondria

muscle
• presence of many lipid droplets
• dense bodies present in places normally occupied by mitochondria
• disrupted sarcomeres sometimes

cellular
• axonal growth cone extension fails to occur for neurons treated in culture with 100ng/ml of leptin


Mouse Genome Informatics
hm4
    Leprdb/Leprdb
BKS.Cg-Dock7m +/+ Leprdb/Jcl
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Increased beta cell mass in Leprdb/Leprdb mice and Leprdb/Leprdb Cebpbtm1.1Maka/Cebpbtm1.1Maka Tg(Ins2-cre)23Herr/0 mice

endocrine/exocrine glands
• at 8 weeks, pancreatic islet cell proliferation is increased compared to in heterozygous mice
• however, pancreatic islet cell proliferation by 16 weeks is normal
• pancreatic islet cell apoptosis is increased compared to in heterozygous mice

homeostasis/metabolism

adipose tissue
• the epididymal fat pad exhibits macrophage infiltration unlike in wild-type mice

cellular
• pancreatic islet cell apoptosis is increased compared to in heterozygous mice


Mouse Genome Informatics
hm5
    Leprdb/Leprdb
BKS.Cg-Dock7m +/+ Leprdb/OlaHsd
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
digestive/alimentary system
• reduced levels of occludin in intestinal sections
• zonula occludens 1 has a discontinuous distribution
• transepithelial resistance in the epithelium is reduced, indictive of a disrupted mucosal barrier function

immune system
• increased release of monocyte chemo attractant protein by hepatic stellate cells
• increased release by hepatic stellate cells
• higher levels of endotoxin are found in portal blood (entotoxemia)
• increased succeptibility of hepatic stellate cells to LPS

liver/biliary system


Mouse Genome Informatics
hm6
    Leprdb/Leprdb
C57BLKS/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• homozygotes subjected to 30, 45, and 60 min of left coronary artery ischemia-reperfusion exhibit survival rates of 71%, 53%, and 18%, respectively, at 24 h after reperfusion, much lower than in controls
• homozygotes subjected to 30 and 45 min of left coronary artery occlusion show survival rates of 58% and 44%, respectively, at 28 days after reperfusion, compared to 100% and 88% in controls

behavior/neurological

endocrine/exocrine glands
• islet mass and density are significantly increased compared to wild-type mice
• individual beta cell size is increased

growth/size
• overweight by 4 weeks of age

homeostasis/metabolism
• homozygotes subjected to 45 min of ischemia display an increase in diastolic dimensions, significant dilatation of left ventricular end-systolic dimensions, a 30% reduction in fractional shortening, and an increase in cardiac hypertrophy, 28 days postreperfusion, indicating decreased tolerance to myocardial infarction
• significant increase in the percentage of plasma glycosylated hemoglobin
• diabetic phenotype appears earlier in males than in females
• by 8 weeks (J:106597)
• hyperinsulinemia by 8 weeks (J:106597)

cardiovascular system
• myocardial triacylglycerol content 2X that of controls at 10-18 weeks of age
• at low fatty acid supply, hearts consume 86% more oxygen (MVO2) for noncontractile purposes compared with control hearts and a further increase in fatty acid supply has no effect on the already elevated unloaded MVO2, indicating reduced cardiac efficiency in unloaded hearts (J:106871)
• reduced aortic flow
• cardiac output is reduced in fatty acid perfused hearts (J:106871)
• reduced recovery of mechanical function after 13 minutes of ischemia and reperfusion
• hypercontractility of smooth muscle in aortic strips due to either phenylephrine or serotonin
• hypercontractility corrollated with the levels of obesity, hyperglycemia, and hyperinsulinemia
• maximal contractions increase with age rather than decrease as in controls
• hearts show a significant increase in the slope of the MVO2-PVA (pressure volume area) regression line after elevation of fatty acids, suggesting a reduction in contractile efficiency
• hearts show a significant increase in the slope of the MVO2-PVA (pressure volume area) regression line after elevation of fatty acids, suggesting a reduction in contractile efficiency
• intrinsic heart rates are reduced at all workloads (J:106871)
• decreased peak systolic pressure
• decreased peak systolic pressure X cardiac output
• decreased peak systolic pressure X heart rate
• homozygotes subjected to 45 min of ischemia display an increase in diastolic dimensions, significant dilatation of left ventricular end-systolic dimensions, a 30% reduction in fractional shortening, and an increase in cardiac hypertrophy, 28 days postreperfusion, indicating decreased tolerance to myocardial infarction

hematopoietic system
• significant increase in the percentage of plasma glycosylated hemoglobin

cellular
• elevation of fatty acids in perfused hearts causes an increase in fatty acid oxidation combined with a reduction in glucose oxidation rates (J:106871)
• carbohydrate oxidation becomes reduced (J:107138)
• palmitate oxidation is elevated (J:107138)
• state 3 respiration is elevated in cardiac mitochondria incubated with palmitoyl-carnitine but not with pyruvate

muscle
• hypercontractility of smooth muscle in aortic strips due to either phenylephrine or serotonin
• hypercontractility corrollated with the levels of obesity, hyperglycemia, and hyperinsulinemia
• maximal contractions increase with age rather than decrease as in controls
• hearts show a significant increase in the slope of the MVO2-PVA (pressure volume area) regression line after elevation of fatty acids, suggesting a reduction in contractile efficiency


Mouse Genome Informatics
hm7
    Leprdb/Leprdb
FVB.BKS-Leprdb
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size
• mice of both sexes are obese

homeostasis/metabolism
• Background Sensitivity: after a 2-day fast on refeeding with carbohydrate-free diet, female obese mice show a rise in glucose
• Background Sensitivity: obese mice have a prolonged period of hyperglycemia compared to obese B6.BKS-Leprdb mice where glucose levels rarely exceed 250 mg/dl
• fasting mice are hyperglycemic at 3 months of age, while obese B6.BKS-Leprdb fasted mice are euglycemic
• levels increase from 5 to 7 months in obese females to ~500 ng/ml, significantly higher than the males (~40 ng/ml) or obese B6.BKS-Leprdb females (~50 ng/ml)
• Background Sensitivity: at 3 months of age, females show a trend toward higher insulin levels compared to obese B6.BKS-Leprdb females; at 5-7 months insulin levels (~500 ng/ml) are ~10-fold higher than levels in obese female obese B6.BKS-Leprdb mice (~50 ng/ml)
• Background Sensitivity: at 7 months of age obese males are severely glucose intolerant with glucose levels of >400 mg/dl 90 minutes after glucose load compared to obese B6.BKS-Leprdb mice clear glucose load by 90 min
• Background Sensitivity: obese mice show a rapid increase of blood glucose above 400 mg/dl with diminished rate of glucose clearance
• at 7 months of age, 3U/kg of insulin does not alter circulating glucose levels, while in B6.BKS-Lepr mice, glucose decreases by 50% by 40 minutes; 12U/kg insulin does not cause a decrease in glucose in obese female mice on the FVB background
• at a dose of 3U/kg 6-week old mice show a diminished response to insulin
• circulating insulin levels in the fed state show that obese mice have exteme insulin resistance

endocrine/exocrine glands
• obese mice show massive expansion of beta cells (744 insulin +ve cells/islet cross-section in obese vs 165 +ve cells in lean mice); there are 4.5-fold more cells per islet cross-section in obese mice
• some islets in obese mice have more than 1000 cells per cross section; such islets are absent in lean mice

renal/urinary system
• at 7 months of age, obese mice show an increased mesangial matrix in most glomeruli compared to lean controls, resembling diabetic nephropathy; some small glomeruli have separated from the capsule with nearly obliterated microtubules

Mouse Models of Human Disease
OMIM IDRef(s)
Obesity 601665 J:78850


Mouse Genome Informatics
hm8
    Leprdb/Leprdb
involves: 129S2/SvPas * C57BL/6 * C57BLKS/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
renal/urinary system
• total kidney collagen is increased in females by 96%
• glomerular extracellular matrix (ECM) area in females is increased by 31% compared to wild-type female controls and female single Serpine1-deficient animals; however, when expressed as fractional glomerular ECM area, little difference is observed between any genotype


Mouse Genome Informatics
hm9
    Leprdb/Leprdb
involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
• 3 fold increase in bone volume
• rate of new bone formation increased at both 3 and 6 months
• increased numbers of osteoclasts

hematopoietic system
• increased numbers of osteoclasts

immune system
• increased numbers of osteoclasts

cellular
• increased numbers of osteoclasts


Mouse Genome Informatics
hm10
    Leprdb/Leprdb
involves: C57BL/6 * C57BLKS/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
reproductive system
(J:164339)
(J:142218)
(J:164339)

homeostasis/metabolism
• thermoregulation in response to cold exposure is severely impaired compared to wild-type controls
• oxygen consumption normalized to lean mass is increased compared to wild-type controls but oxygen consumption normalized to metabolic size is decreased compared to wild-type controls

growth/size
• early onset obesity starting from 4 weeks of age

adipose tissue

behavior/neurological
• decreased activity in both the light and dark cycle

limbs/digits/tail

skeleton


Mouse Genome Informatics
hm11
    Leprdb/Leprdb
involves: C57BLKS/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Neural-specific STAT3 deletion results in severe obesity in Stat3tm1Flv/Stat3tm1Flv Tg(Nes-cre)1Kln/0 mice similar to that seen in Leprdb/Leprdb mice

homeostasis/metabolism
• reduced neointimal area relative to controls 4 weeks after femoral artery injury
• vascular smooth muscle proliferation significantly reduced
• mutants become hypothermic after a 12 hour fast
• mutants housed at 4 degrees C for 3.5 hours cannot maintain their body temperature like wild-type and drop about 1 degree in body temperature every 30 min until they reach 34 degrees C, at which point they stabilize this temperature, indicating decreased sympathetic activity
• mice treated with adenovirus expressing Adipor1 (1.5-fold increase in liver expression), show decreased plasma glucose compared to wild-type
• mice treated with an adenovirus expressing Adipor2 (5-fold increase in liver expression), show decreased plasma glucose compared to wild-type
• plasma fasting glucose is increased (J:89242)
• diabetes is improved after treatment with an adenovirus expressing Adipor1 or Adipor2
• mice treated with an adenovirus expressing Adipor 2 show improved glucose resistance and decreased plasma insulin level
• fasting insulin is increased (J:89242)
• mice treated with an adenovirus expressing Adipor1 or Adipor 2 show improved insulin resistance
• in females when compared to female controls
• levels of protein in urine similar in males and females but levels in males lower than in male controls

growth/size
• increase in total fat content
• by four weeks of age (J:80996)
• mutants are about 5% shorter than controls

reproductive system
• increased volume and density of lipid inclusion vacuoles (J:80996)
• basal membrane of epithelial cells displays a folded contour at locations where lipid accumulates (J:80996)
• tissue norepinephrin levels elevated by 4 weeks of age and remain elevated (J:80996)
• decreased relative to controls by 4 weeks of age (J:80996)
• 1/3 normal tissue weight by 12 weeks (J:80996)

vision/eye
• modest but significant elevation of intraocular pressure

behavior/neurological
• aversion response is more strongly generalized from saccharin to sucrose
• lower aversion threshold for sucrose than in controls
• recovery from conditioned taste aversion is more rapid than in controls

renal/urinary system
• in females when compared to female controls
• levels of protein in urine similar in males and females but levels in males lower than in male controls
• basement membrane becomes thickened with age (J:5257)
• large quantites if immunoglobulin and complement are found in the mesangium (J:30970)
• eventually becomes flattened
• calyceal dilation eventually develops

immune system
• T cells from homozygous mice but not those from heterozygous mice suppressed the beta cell response to glucose + theophylline

nervous system
• hypothalamic uptake of norepinephrine is decreased in males

adipose tissue
• increase in total fat content

cardiovascular system
• reduced neointimal area relative to controls 4 weeks after femoral artery injury
• vascular smooth muscle proliferation significantly reduced


Mouse Genome Informatics
ht12
    Leprdb/Lepr+
B6.Cg-Dock7m +/+ Leprdb/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• increased survival when totally deprived of food than wild-type controls
• Background Sensitivity: survival when deprived of food is not as long as when in a C57BLKsS background

growth/size
• slight but significant increase in body weight compared to wild-type mice


Mouse Genome Informatics
ht13
    Leprdb/Lepr+
BKS.Cg-Dock7m +/+ Leprdb/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• increased survival when totally deprived of food than wild-type controls
• Background Sensitivity: survival when deprived of food is longer rhan when in a C57BL/6 background


Mouse Genome Informatics
ht14
    Leprdb/Lepr+
involves: C57BLKS/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• fasting glucose levels elevated 25% during pregnancy
• profound glucose intolerance during pregnancy
• glucose levels 41% higher in a glucose tolerance test at 30 and at 60 minute time points
• 45-55% higher glucose levels after a glucose challenge but dramatically improved by leptin treatment and glucose levels reduced 33 and 30% in glucose tolerance tests at 30 and 60 minute time points
• elevated placental leptin levels in pregnant females
• 2.2X increase in fasting insulin during pregnancy compared to a 3X increase in controls
• leptin treatment results in a 14% reduction in insulin levels compared to a 45% reduction in controls

behavior/neurological
• food intake 11% greater than controls during pregnancy
• leptin treatment suppresses food intake to near control levels

growth/size
• 20% greater adipose tissue mass during pregnancy than in controls
• 33% greater maternal weight gain
• maternal body weight at term 24% greater than controls
• birth weights significantly heavier than controls and unaffected by maternal leptin treatment unlike controls where maternal leptin treatment causes a decrease in birth weights

adipose tissue
• 20% greater adipose tissue mass during pregnancy than in controls


Mouse Genome Informatics
ht15
    Leprdb/Leprdb-5J
involves: C57BLKS/J * NOD/ShiLtJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size
• 25% of offspring exhibit obesity


Mouse Genome Informatics
cn16
    Cebpbtm1.1Maka/Cebpbtm1.1Maka
Leprdb/Leprdb
Tg(Ins2-cre)23Herr/0

involves: 129P2/OlaHsd * C57BL/6J * C57BLKS/J * CBA/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Increased beta cell mass in Leprdb/Leprdb mice and Leprdb/Leprdb Cebpbtm1.1Maka/Cebpbtm1.1Maka Tg(Ins2-cre)23Herr/0 mice

endocrine/exocrine glands
• pancreatic islet cell apoptosis is decreased compared to in Leprdb homozygotes
• compared to in Leprdb homozygotes

homeostasis/metabolism
• hyperglycemia develops more slowly and is ameliorated compared to in Leprdb homozygotes
• at 12 weeks, plasma insulin levels are increased compared to in Leprdb homozygotes and wild-type mice

cellular
• pancreatic islet cell apoptosis is decreased compared to in Leprdb homozygotes


Mouse Genome Informatics
cn17
    Leprdb/Leprdb
Ptentm1Hwu/Ptentm1Hwu
Tg(Ins2-cre)25Mgn/0

involves: 129S4/SvJae * C57BL/6 * C57BLKS/J * DBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
N
• mutants are protected from developing diabetes, and despite severe insulin resistance, mutants remain euglycemic and show normal glucose tolerance (J:170206)
• mutant islets show increased beta-cell function, showing robust insulin secretion after glucose stimulation compared to diminished insulin secretion in single homozygous Leprdb mice
• mutants exhibit a similar degree of insulin resistance as single Leprdb mice

growth/size
• mutants exhibit a similar degree of weight gain as single homozygous Leprdb mice

endocrine/exocrine glands
• islets show similar degrees of hypertrophy and proliferation as those in single homozygous Leprdb mice and do not show a further increase in beta-cell mass compared to the single Leprdb mice
• mutant islets show increased beta-cell function, showing robust insulin secretion after glucose stimulation compared to diminished insulin secretion in single homozygous Leprdb mice


Mouse Genome Informatics
cx18
    Foxo1tm2.1Dac/Foxo1tm2.1Dac
Leprdb/Leprdb

B6.Cg-Foxo1tm2.1Dac Leprdb
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism


Mouse Genome Informatics
cx19
    Leprdb/Leprdb
Nos3tm1Unc/Nos3tm1Unc

BKS.Cg-Leprdb Nos3tm1Unc
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
renal/urinary system
• albumin/creatinine ratio (ACR) is significantly higher than all controls
• glomerular basement membrane is markedly thickened by 16 weeks in comparison to all controls
• glomerular injury is significantly increased by 24-26 weeks in comparison to all controls
• marked mesangial expansion is observed at 26 weeks of age
• marked mesangiolysis is observed at 26 weeks of age
• focal nodular sclerosis is observed at 26 weeks of age
• substantial fibronectin accumulation is observed in glomeruli
• GFR is decreased in comparison to homozygous Nos3tm1Unc and Leprdb controls

homeostasis/metabolism
• at 26 weeks, serum creatinine is significantly higher than all controls
• hyperglycemia is first observed between 6-8 weeks of age, but is not higher than homozygous Leprdb control
• albumin/creatinine ratio (ACR) is significantly higher than all controls

growth/size
• at 26 weeks, body weight is double that of lean and Nos3tm1Unc controls

cardiovascular system
• hypertension is observed between 24-28 weeks of age, but is not significantly higher than homozygous Nos3tm1Unc controls


Mouse Genome Informatics
cx20
    Apoetm1Unc/Apoetm1Unc
Leprdb/Leprdb

involves: 129P2/OlaHsd * C57BLKS/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
vision/eye
• higher levels of "advanced glycation end products" in the extracellular matrix
• Ager mRNA levels elevated in the retina
• increase of capillary lesions
• significantly higher number of acellular capillaries
• increased capillary outpouching indicative of early microaneurysms

cardiovascular system
• increase of capillary lesions
• significantly higher number of acellular capillaries
• increased capillary outpouching indicative of early microaneurysms


Mouse Genome Informatics
cx21
    Leprdb/Leprdb
Plin1tm1Chan/Plin1tm1Chan

involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * C57BLKS/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size
• mice are resistant to the obesity caused by the Leprdb background
• at a given age, mice weigh significantly less than Leprdb homozygotes but more than wild-type controls
• MRI analysis finds the total lipid signal for these mice at 27% compared to 24% for wild-type and 63% for the Leprdb homozygotes

homeostasis/metabolism
• mice have much higher rates of oxygen consumption compared to controls


Mouse Genome Informatics
cx22
    Gdf15tm1Sjl/Gdf15tm1Sjl
Leprdb/Leprdb

involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * C57BLKS/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological
• water intake and urine output are increased at week 9 compared to single Lepr mutants (J:202996)
• food intake is increased over single Gdf15 mutants but is similar to single Lepr mutants (J:202996)

cardiovascular system
• increase in heart weight compared to controls, including that in single Lepr mutants (J:202996)

growth/size
• body weight is increased over nondiabetic single Gdf15 mutants but is similar to single Lepr mutants (J:202996)

homeostasis/metabolism
• increase in serum creatinine levels compared to controls, including that in single Lepr mutants (J:202996)
• nonfasting blood glucose and HbA1c are higher in double mutants than in single Lepr mutants at the final time point of 18 weeks but are similar at earlier time points but higher than in single Gdf15 mutants (J:202996)
• urinary glucose loss is higher than in single Lepr mutants at week 14 (J:202996)
• similar increase in cholesterol level as in single Lepr mutants (J:202996)
• similar increase in HDL levels as in single Lepr mutants (J:202996)
• similar increase in urinary albumin excretion as in single Lepr mutants (J:202996)

liver/biliary system
• liver weight is increased to a similar extent as in single Lepr mutants (J:202996)

renal/urinary system
• urinary glucose loss is higher than in single Lepr mutants at week 14 (J:202996)
• similar increase in urinary albumin excretion as in single Lepr mutants (J:202996)
• marker analysis indicates that double mutants show an increase in renal damage and in interstitial and tubular damage in the kidney compared to single Lepr mutants (J:202996)
• glomerulosclerosis is similar as in single Lepr mutants (J:202996)
• kidney weight is increased to a similar extent as in single Lepr mutants (J:202996)
• water intake and urine output are increased at week 9 compared to single Lepr mutants (J:202996)


Mouse Genome Informatics
cx23
    Aqp9tm1Nlsn/Aqp9tm1Nlsn
Leprdb/Leprdb

involves: 129S1/Sv * C57BL/6 * C57BLKS/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• after fasting blood glucose levels are moderately lower than those in Leprdb homozygotes
• 939+/-43 compared to 553+/-35 in Leprdb homozygotes


Mouse Genome Informatics
cx24
    Leprdb/Leprdb
Serpine1tm1Mlg/Serpine1tm1Mlg

involves: 129S2/SvPas * C57BL/6 * C57BLKS/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 23% of females and 44% of males in the F3 generation died prematurely, of indeterminate cause

growth/size
• female mice are obese relative to wild-type and Serpine1-deficient single mutant controls
• 63% of males in F3 generation are runts with body weight ranging from 20-40 grams compared to 60-100 grams for littermates not displaying runt phenotype

renal/urinary system
• present with slightly higher urinary albumin to creatinine ratios relative to Lepr single homozygotes
• total kidney collagen is increased in females by 47% compared to female single Serpine1-deficient animals
• glomerular extracellular matrix (ECM) areas are reduced 10% in females compared to female single Serpine1-deficient animals; however, when expressed as fractional glomerular ECM area, little difference is observed between any genotype

homeostasis/metabolism
• significantly higher BUN levels compared to Serpine1-deficient single mutants
• hyperglycemia is less severe than observed in Serpine1-sufficient, Lepr-deficient controls at 10, 14, and 34 weeks of age
• present with slightly higher urinary albumin to creatinine ratios relative to Lepr single homozygotes
• total urokinase plasminogen activator (uPA) activity is significantly higher than wild-type compared to Serpine1-sufficient diabetic controls


Mouse Genome Informatics
cx25
    Leprdb/Leprdb
Rock1tm1Leiw/Rock1tm1Leiw

involves: 129S7/SvEvBrd * C57BLKS/J * FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
renal/urinary system
N
• mice treated with streptozotocin to induce diabetes do not exhibit podocyte loss unlike similarly treated Leprdb homozygotes (J:182287)
• mice treated with streptozotocin to induce diabetes exhibit glomerular apoptosis but not as much as in similarly treated Leprdb homozygotes
• in mice treated with streptozotocin to induce diabetes but not as much as in similarly treated Leprdb homozygotes
• in mice treated with streptozotocin to induce diabetes but not as much as in similarly treated Leprdb homozygotes
• in mice treated with streptozotocin to induce diabetes as in similarly treated Leprdb homozygotes
• in mice treated with streptozotocin to induce diabetes as in similarly treated Leprdb homozygotes
• in mice treated with streptozotocin to induce diabetes as in similarly treated Leprdb homozygotes

homeostasis/metabolism
• in mice treated with streptozotocin to induce diabetes as in similarly treated Leprdb homozygotes
• in mice treated with streptozotocin to induce diabetes but not as much as in similarly treated Leprdb homozygotes

growth/size
• in mice treated with streptozotocin to induce diabetes as in similarly treated Leprdb homozygotes
• in mice treated with streptozotocin to induce diabetes as in similarly treated Leprdb homozygotes

cellular
• mice treated with streptozotocin to induce diabetes exhibit glomerular apoptosis but not as much as in similarly treated Leprdb homozygotes
• mice treated with streptozotocin to induce diabetes exhibit mitochondrial reactive oxygen species production but not as much as in similarly treated Leprdb homozygotes
• mice treated with streptozotocin to induce diabetes exhibit mitochondrial fission but not as much as in similarly treated Leprdb homozygotes
• mice treated with streptozotocin to induce diabetes exhibit mitochondrial reactive oxygen species production but not as much as in similarly treated Leprdb homozygotes


Mouse Genome Informatics
cx26
    Leprdb/Lepr+
Tg(APPswe,PSEN1dE9)85Dbo/0

involves: C3H * C57BL/6 * C57BLKS/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
other phenotype
• mutants exhibit an increase in expression of amyloid beta protein in plasma compared to Leprdb heterozygotes, however they do not show amyloid beta plaques yet at 5-7 weeks of age

homeostasis/metabolism
• nonfasting blood glucose levels are elevated compared to control Leprdb heterozygotes
• however, fasting blood glucose is normal at 5-7 weeks of age
• nonfasting and fasting hyperinsulinemia
• elevation in nonfasting plasma cholesterol levels
• however, fasting cholesterol levels are normal
• mutants exhibit decreased insulin sensitivity

endocrine/exocrine glands
• increase in beta cell mass and beta cell area compared to control Leprdb heterozygotes

growth/size
N
• body weight is normal at 5-7 weeks of age (J:186924)


Mouse Genome Informatics
cx27
    Dbsq1BKS/Dbsq1BKS
Leprdb/Leprdb

involves: C3H/HeJ * C57BLKS
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
adipose tissue
• increased fat pad weight in males


Mouse Genome Informatics
cx28
    Dbsq1BKS/Dbsq1C3H/HeJ
Leprdb/Leprdb

involves: C3H/HeJ * C57BLKS
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
adipose tissue
• increased fat pad weight in males


Mouse Genome Informatics
cx29
    Dbsq2C3H/HeJ/Dbsq2C3H/HeJ
Leprdb/Lepr+

involves: C3H/HeJ * C57BLKS
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size
• increased body weight in males at 7, 8, 9, 10 weeks of age and at sacrifice


Mouse Genome Informatics
cx30
    Dbsq2BKS/Dbsq2C3H/HeJ
Leprdb/Lepr+

involves: C3H/HeJ * C57BLKS
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size
• increased body weight in males at 7, 8, 9, 10 weeks of age and at sacrifice


Mouse Genome Informatics
cx31
    Dbsq3C3H/HeJ/Dbsq3C3H/HeJ
Leprdb/Lepr+

involves: C3H/HeJ * C57BLKS
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• increased blood glucose concentration in males at 30, 60, and 120 minutes during the intraperitoneal glucose tolerance test


Mouse Genome Informatics
cx32
    Dbsq3BKS/Dbsq3C3H/HeJ
Leprdb/Lepr+

involves: C3H/HeJ * C57BLKS
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• increased blood glucose concentration in males at 30, 60, and 120 minutes during the intraperitoneal glucose tolerance test


Mouse Genome Informatics
cx33
    Ccr2tm1.1(CCR2)Rodb/Ccr2tm1.1(CCR2)Rodb
Leprdb/Leprdb

involves: C57BL/6 * C57BLKS/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• CCX140-B treatment improves albuminuria

renal/urinary system
• CCX140-B treatment improves albuminuria


Mouse Genome Informatics
cx34
    Leprdb/Leprdb
Tg(Fabp4-Fcor)1Jnak/0

involves: C57BL/6 * C57BLKS/J * DBA/2
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• compared with Leprdb homozygotes
• compared with Leprdb homozygotes
• compared with Leprdb homozygotes

adipose tissue
• decreased visceral fat compared with Leprdb homozygotes
• however, subcutaneous and total adipose mass are normal
• compared with Leprdb homozygotes

growth/size
• compared with Leprdb homozygotes


Mouse Genome Informatics
cx35
    Cdkn1btm1Kin/Cdkn1btm1Kin
Leprdb/Leprdb

involves: C57BL/6J * C57BLKS/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological

endocrine/exocrine glands
• islet mass, but not islet density, is significantly increased compared to Lepr single homozygotes
• beta cell proliferation and the total number of beta cells are increased compared to Lepr single homozygotes; however the size of individual beta cells is similar to Lepr single homozygotes

growth/size

homeostasis/metabolism
• hyperlipidemia similar to Lepr single homozygotes is seen; however, double homozygotes do not develop hyperglycemia


Mouse Genome Informatics
cx36
    Cdkn1btm1Kin/Cdkn1b+
Leprdb/Leprdb

involves: C57BL/6J * C57BLKS/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
behavior/neurological

endocrine/exocrine glands
• islet mass, but not islet density, is significantly increased compared to Lepr single homozygotes
• beta cell proliferation and the total number of beta cells are increased compared to Lepr single homozygotes; however the size of individual beta cells is similar to Lepr single homozygotes

growth/size

homeostasis/metabolism
• developed more slowly and to a reduced extent compared to Lepr single homozygotes