hm1

Lepr^db/Lepr^db
B6.BKS(D)-Lepr^db/J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

homeostasis/metabolism

decreased body temperature ( J:166105 )

decreased carbon dioxide production ( J:166105 )

decreased oxygen consumption ( J:166105 )

impaired glucose tolerance ( J:166105 )

insulin resistance ( J:166105 )

abnormal response/metabolism to endogenous compounds ( J:166105 )

• mice treated with leptin fail to exhibit a decrease in food intake unlike similarly treated wild-type mice

behavior/neurological

abnormal behavior ( J:112820 )

• faster in food finding trials relative to controls

hypoactivity ( J:166105 )

• during the dark phase

renal/urinary system

glomerulosclerosis ( J:160943 )

• homozygotes develop significant glomerulosclerosis by 18 weeks of age

hm2

Lepr^db/Lepr^db
B6.Cg-Dock7^m +/+ Lepr^db/J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

growth/size

decreased body length ( J:82334 )

• snout to anus length is decreased by about 5% compared to wild-type mice

obese ( J:18161 , J:82334 , J:103063 )

• 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 Leprr^tm1Mgmj homozygotes (J:82334)

• develop progressive obesity (J:103063)

behavior/neurological

polyphagia ( J:82334 )

reduced male mating frequency ( J:6157 )

(J:6157)

cardiovascular system

abnormal myocardial fiber morphology ( J:103063 )

• exhibit myocyte hypertrophy

heart left ventricle hypertrophy ( J:103063 )

• 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

abnormal myocardial fiber morphology ( J:103063 )

• exhibit myocyte hypertrophy

homeostasis/metabolism

abnormal circulating lipid level ( J:18161 )

• 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

abnormal circulating cholesterol level ( J:18161 )

increased circulating cholesterol level ( J:18161 )

• fasting plasma total cholesterol concentration is increased 2 fold over controls

increased circulating HDL cholesterol level ( J:18161 )

increased circulating LDL cholesterol level ( J:18161 )

increased circulating VLDL cholesterol level ( J:18161 )

increased circulating triglyceride level ( J:18161 , J:82334 )

• triglyceride levels are elevated 1.5- to 2-fold (J:18161)

abnormal glucose homeostasis ( J:82334 )

increased circulating glucose level ( J:82334 )

hyperglycemia ( J:18161 )

increased circulating insulin level ( J:82334 )

abnormal hormone level ( J:6157 )

• female mice exhibit an increase in hypothalamic gonadotrophin releasing hormone compared to in wild-type mice

increased circulating leptin level ( J:82334 , J:115772 )

decreased adiponectin level ( J:115772 )

• decreased in serum

abnormal chemokine level ( J:115772 )

• elevated levels of eotaxin, keratinocyte cytokine, and monocyte chemotactic protein-1 (also elevated in serum) in bronchoalveolar lavage fluid

abnormal interleukin level ( J:115772 )

• elevated levels of IL-6 in bronchoalveolar lavage fluid

increased circulating interleukin-6 level ( J:115772 )

• elevated levels of IL-6 in serum

reproductive system

abnormal female reproductive system morphology ( J:82334 )

• atrophy of the reproductive organs (J:82334)

small uterus ( J:6157 )

(J:6157)

constricted vagina orifice ( J:6157 )

(J:6157)

anovulation ( J:82334 )

(J:82334)

absent estrus ( J:82334 )

• females never show signs of vaginal oestrous (J:82334)

absent estrous cycle ( J:6157 )

• mice exhibit diestrous vaginal acyclicity or occasional metestrous acyclicity (J:6157)

female infertility ( J:6157 , J:82334 )

(J:6157)

• all females fail to reproduce (J:82334)

respiratory system

lung inflammation ( J:115772 )

• 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

abnormal functional residual capacity ( J:115772 )

• reduced

• pressure volume curves shifted to the right

abnormal respiratory mechanics ( J:115772 )

• end-expiratory pause increases considerably less than in controls after ozone exposure

abnormal lung compliance ( J:115772 )

• total lung resistance increases much more in response to ozone than in control mice

• responsiveness to methacholine and serotonin is much greater than controls

decreased pulmonary ventilation ( J:115772 )

• ventilation volumes decline with ozone exposure but to a lesser degree than for controls

immune system

abnormal leukocyte morphology ( J:115772 )

decreased leukocyte cell number ( J:115772 )

• decrease blood leukocyte numbers

increased neutrophil cell number ( J:115772 )

• increased numbers in bronchoalveolar lavage

abnormal chemokine level ( J:115772 )

• elevated levels of eotaxin, keratinocyte cytokine, and monocyte chemotactic protein-1 (also elevated in serum) in bronchoalveolar lavage fluid

abnormal interleukin level ( J:115772 )

• elevated levels of IL-6 in bronchoalveolar lavage fluid

increased circulating interleukin-6 level ( J:115772 )

• elevated levels of IL-6 in serum

lung inflammation ( J:115772 )

• 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 metastatic potential ( J:117826 )

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

hematopoietic system

abnormal leukocyte morphology ( J:115772 )

decreased leukocyte cell number ( J:115772 )

• decrease blood leukocyte numbers

increased neutrophil cell number ( J:115772 )

• increased numbers in bronchoalveolar lavage

nervous system

abnormal hypothalamus physiology ( J:6157 )

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

hm3

Lepr^db/Lepr^db
BKS.Cg-Dock7^m +/+ Lepr^db/J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

homeostasis/metabolism

increased glucagon secretion ( J:6264 )

• increased secreation of glucagon by pancreatic cells in culture

abnormal circulating glucose level ( J:43162 )

decreased circulating glucose level ( J:43162 , J:91813 )

• 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)

increased circulating glucose level ( J:6323 )

• blood glucose shows a progressive increase from 5 through 33 weeks

hyperglycemia ( J:135864 , J:185546 )

• fasting blood glucose level is significantly higher than control at 26 weeks of age (J:135864)

decreased circulating insulin level ( J:43162 , J:91813 )

• 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)

abnormal circulating lipid level ( J:18161 )

• 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

abnormal circulating cholesterol level ( J:18161 )

increased circulating cholesterol level ( J:18161 )

• fasting plasma total cholesterol concentration is increased 2 fold over controls

increased circulating HDL cholesterol level ( J:18161 )

increased circulating LDL cholesterol level ( J:18161 )

increased circulating VLDL cholesterol level ( J:18161 )

decreased circulating triglyceride level ( J:91813 )

• triglyceride levels are reduced at all times tested when mice are placed on feeding restriction during the dark phase

increased circulating triglyceride level ( J:18161 )

• triglyceride levels are elevated 1.5- to 2-fold

improved glucose tolerance ( J:43162 )

• BDNF treatment causes a lower blood glucose level response in a glucose tolerance test

decreased prostaglandin level ( J:185546 )

• in diabetic wounds, PGE2 level is consistently less than 50% of wild-type wounds at all times

decreased urine albumin level ( J:82491 )

• 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)

albuminuria ( J:135864 )

• moderate albuminuria is observed at 26 weeks of age

delayed wound healing ( J:185546 )

• 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

weight loss ( J:91813 )

• body weight drops after 6 days on feeding restriction during the dark phase

increased body weight ( J:135864 )

obese ( J:6323 )

• 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

decreased urine albumin level ( J:82491 )

albuminuria ( J:135864 )

• moderate albuminuria is observed at 26 weeks of age

expanded mesangial matrix ( J:135864 )

• moderate mesangial expansion is observed in glomeruli at 26 weeks

increased creatinine clearance ( J:82491 )

• 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

abnormal nervous system morphology ( J:6323 )

abnormal axon outgrowth ( J:112680 )

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

decreased motor neuron number ( J:6323 )

• 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

abnormal axon morphology ( J:6323 )

• 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

abnormal myelin sheath morphology ( J:6323 )

• number of myelin lamellae relative to nerve diameter is increased

abnormal nerve conduction ( J:6323 )

• 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

abnormal CNS synaptic transmission ( J:109401 )

reduced long term potentiation ( J:109401 )

• CA1 hippocampal slices indicate brief post tetanic potentiation but no long term potentiation on recordings of excitatory post-synaptic potentials

absent long term depression ( J:109401 )

• CA1 hippocampal slices indicate no long term depression on recordings of excitatory post-synaptic potentials

behavior/neurological

abnormal circadian rhythm ( J:91813 )

• 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

abnormal food intake ( J:43162 )

• food intake is about 60% of control level

abnormal learning/memory/conditioning ( J:109401 )

abnormal spatial learning ( J:109401 )

• longer swimming distances than control mice in a Morris water maze test

abnormal spatial reference memory ( J:109401 )

• cross the original platform location less frequently than do controls in a Morris water maze test

vision/eye

abnormal eye electrophysiology ( J:103714 )

• 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 glucagon secretion ( J:6264 )

• increased secreation of glucagon by pancreatic cells in culture

cardiovascular system

abnormal vascular development ( J:6115 )

• dense bodies found in the smooth muscle of intramyocardial arteries

abnormal myocardial fiber morphology ( J:6115 )

• presence of many lipid droplets

• dense bodies present in places normally occupied by mitochondria

• disrupted sarcomeres sometimes

muscle

abnormal myocardial fiber morphology ( J:6115 )

• presence of many lipid droplets

• dense bodies present in places normally occupied by mitochondria

• disrupted sarcomeres sometimes

cellular

abnormal axon outgrowth ( J:112680 )

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

Mouse Models of Human Disease	OMIM ID	Ref(s)
Diabetes Mellitus, Noninsulin-Dependent; NIDDM	125853	J:185546
Obesity	601665	J:6323

hm4

Lepr^db/Lepr^db
BKS.Cg-Dock7^m +/+ Lepr^db/Jcl

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

Increased beta cell mass in Lepr^db/Lepr^db mice and Lepr^db/Lepr^db Cebpb^tm1.1Maka/Cebpb^tm1.1Maka Tg(Ins2-cre)23Herr/0 mice

endocrine/exocrine glands

increased pancreatic beta cell mass ( J:156725 )

abnormal pancreas physiology ( J:156725 )

• at 8 weeks, pancreatic islet cell proliferation is increased compared to in heterozygous mice

• however, pancreatic islet cell proliferation by 16 weeks is normal

abnormal pancreatic islet cell apoptosis ( J:156725 )

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

homeostasis/metabolism

hyperglycemia ( J:156725 )

increased circulating insulin level ( J:156725 )

adipose tissue

abnormal epididymal fat pad morphology ( J:110277 )

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

cellular

abnormal pancreatic islet cell apoptosis ( J:156725 )

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

hm5

Lepr^db/Lepr^db
BKS.Cg-Dock7^m +/+ Lepr^db/OlaHsd

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

digestive/alimentary system

abnormal intestinal epithelium morphology ( J:124815 )

• reduced levels of occludin in intestinal sections

• zonula occludens 1 has a discontinuous distribution

abnormal digestive system physiology ( J:124815 )

• transepithelial resistance in the epithelium is reduced, indictive of a disrupted mucosal barrier function

immune system

abnormal chemokine secretion ( J:124815 )

• increased release of monocyte chemo attractant protein by hepatic stellate cells

increased interleukin-6 secretion ( J:124815 )

• increased release by hepatic stellate cells

abnormal acute inflammation ( J:124815 )

• higher levels of endotoxin are found in portal blood (entotoxemia)

increased susceptibility to endotoxin shock ( J:124815 )

• increased succeptibility of hepatic stellate cells to LPS

liver inflammation ( J:124815 )

liver/biliary system

liver inflammation ( J:124815 )

hm6

Lepr^db/Lepr^db
C57BLKS/J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

mortality/aging

increased sensitivity to induced morbidity/mortality ( J:104790 )

• 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

polyphagia ( J:96047 )

endocrine/exocrine glands

abnormal pancreatic islet morphology ( J:96047 )

• islet mass and density are significantly increased compared to wild-type mice

abnormal pancreatic beta cell morphology ( J:96047 )

• individual beta cell size is increased

growth/size

increased body weight ( J:106597 )

• overweight by 4 weeks of age

obese ( J:96047 , J:104790 , J:106871 )

homeostasis/metabolism

altered response to myocardial infarction ( J:104790 )

• 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

increased glycosylated hemoglobin level ( J:104790 )

• significant increase in the percentage of plasma glycosylated hemoglobin

increased circulating free fatty acid level ( J:106871 )

hyperlipidemia ( J:96047 )

decreased body temperature ( J:96047 )

abnormal glucose homeostasis ( J:107138 )

• diabetic phenotype appears earlier in males than in females

hyperglycemia ( J:96047 , J:104790 , J:106597 , J:106871 )

• by 8 weeks (J:106597)

increased circulating insulin level ( J:104790 , J:106597 )

• hyperinsulinemia by 8 weeks (J:106597)

cardiovascular system

abnormal myocardium layer morphology ( J:107138 )

• myocardial triacylglycerol content 2X that of controls at 10-18 weeks of age

abnormal cardiovascular system physiology ( J:106871 , J:107138 )

• at low fatty acid supply, hearts consume 86% more oxygen (MV_O2) for noncontractile purposes compared with control hearts and a further increase in fatty acid supply has no effect on the already elevated unloaded MV_O2, indicating reduced cardiac efficiency in unloaded hearts (J:106871)

abnormal blood circulation ( J:107138 )

• reduced aortic flow

decreased cardiac output ( J:106871 , J:107138 )

• cardiac output is reduced in fatty acid perfused hearts (J:106871)

cardiac ischemia ( J:107138 )

• reduced recovery of mechanical function after 13 minutes of ischemia and reperfusion

increased vasoconstriction ( J:106597 )

• 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

decreased cardiac muscle contractility ( J:106871 )

• hearts show a significant increase in the slope of the MV_O2-PVA (pressure volume area) regression line after elevation of fatty acids, suggesting a reduction in contractile efficiency

increased left ventricle diastolic pressure ( J:106871 )

• hearts show a significant increase in the slope of the MV_O2-PVA (pressure volume area) regression line after elevation of fatty acids, suggesting a reduction in contractile efficiency

decreased heart rate ( J:106871 , J:107138 )

• intrinsic heart rates are reduced at all workloads (J:106871)

decreased systemic arterial systolic blood pressure ( J:107138 )

• decreased peak systolic pressure

• decreased peak systolic pressure X cardiac output

• decreased peak systolic pressure X heart rate

altered response to myocardial infarction ( J:104790 )

hematopoietic system

increased glycosylated hemoglobin level ( J:104790 )

• significant increase in the percentage of plasma glycosylated hemoglobin

cellular

abnormal aerobic respiration ( J:106871 , J:107138 )

• 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)

abnormal respiratory electron transport chain ( J:106871 )

• state 3 respiration is elevated in cardiac mitochondria incubated with palmitoyl-carnitine but not with pyruvate

muscle

increased vasoconstriction ( J:106597 )

• 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

decreased cardiac muscle contractility ( J:106871 )

• hearts show a significant increase in the slope of the MV_O2-PVA (pressure volume area) regression line after elevation of fatty acids, suggesting a reduction in contractile efficiency

Mouse Models of Human Disease	OMIM ID	Ref(s)
Diabetes Mellitus, Noninsulin-Dependent; NIDDM	125853	J:104790
Obesity	601665	J:96047 , J:104790 , J:106871

hm7

Lepr^db/Lepr^db
FVB.BKS-Lepr^db

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

growth/size

obese ( J:78850 )

• mice of both sexes are obese

homeostasis/metabolism

abnormal circulating glucose level ( J:78850 )

• Background Sensitivity: after a 2-day fast on refeeding with carbohydrate-free diet, female obese mice show a rise in glucose

hyperglycemia ( J:78850 )

• Background Sensitivity: obese mice have a prolonged period of hyperglycemia compared to obese B6.BKS-Lepr^db mice where glucose levels rarely exceed 250 mg/dl

• fasting mice are hyperglycemic at 3 months of age, while obese B6.BKS-Lepr^db 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-Lepr^db females (~50 ng/ml)

increased circulating insulin level ( J:78850 )

• Background Sensitivity: at 3 months of age, females show a trend toward higher insulin levels compared to obese B6.BKS-Lepr^db females; at 5-7 months insulin levels (~500 ng/ml) are ~10-fold higher than levels in obese female obese B6.BKS-Lepr^db mice (~50 ng/ml)

impaired glucose tolerance ( J:78850 )

• 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-Lepr^db 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

insulin resistance ( J:78850 )

• 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

increased pancreatic beta cell number ( J:78850 )

• 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

pancreatic islet hyperplasia ( J:78850 )

• some islets in obese mice have more than 1000 cells per cross section; such islets are absent in lean mice

renal/urinary system

abnormal renal glomerulus morphology ( J:78850 )

• 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 ID	Ref(s)
Obesity		601665	J:78850

hm8

Lepr^db/Lepr^db
involves: 129S2/SvPas * C57BL/6 * C57BLKS/J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

renal/urinary system

abnormal kidney morphology ( J:127478 )

• total kidney collagen is increased in females by 96%

abnormal renal glomerulus morphology ( J:127478 )

• 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

hm9

Lepr^db/Lepr^db
involves: C57BL/6

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

skeleton

increased bone volume ( J:60001 )

• 3 fold increase in bone volume

abnormal skeleton development ( J:60001 )

• rate of new bone formation increased at both 3 and 6 months

abnormal osteoclast differentiation ( J:60001 )

• increased numbers of osteoclasts

hematopoietic system

abnormal osteoclast differentiation ( J:60001 )

• increased numbers of osteoclasts

immune system

abnormal osteoclast differentiation ( J:60001 )

• increased numbers of osteoclasts

cellular

abnormal osteoclast differentiation ( J:60001 )

• increased numbers of osteoclasts

hm10

Lepr^db/Lepr^db
involves: C57BL/6 * C57BLKS/J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

reproductive system

abnormal female reproductive system morphology ( J:164339 )

(J:164339)

absent estrus ( J:164339 )

(J:164339)

female infertility ( J:142218 , J:164339 )

(J:142218)

(J:164339)

homeostasis/metabolism

impaired adaptive thermogenesis ( J:142218 )

• thermoregulation in response to cold exposure is severely impaired compared to wild-type controls

increased circulating glucose level ( J:164339 )

hyperglycemia ( J:142218 )

increased circulating insulin level ( J:164339 )

increased circulating leptin level ( J:142218 )

abnormal oxygen consumption ( J:142218 )

• 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

impaired glucose tolerance ( J:142218 , J:164339 )

insulin resistance ( J:142218 , J:164339 )

growth/size

decreased body length ( J:142218 , J:164339 )

increased body weight ( J:164339 )

obese ( J:142218 )

• early onset obesity starting from 4 weeks of age

decreased lean body mass ( J:164339 )

adipose tissue

increased percent body fat ( J:142218 , J:164339 )

behavior/neurological

polyphagia ( J:142218 )

increased eating behavior ( J:164339 )

hypoactivity ( J:142218 )

• decreased activity in both the light and dark cycle

limbs/digits/tail

short femur ( J:164339 )

skeleton

short femur ( J:164339 )

hm11

Lepr^db/Lepr^db
involves: C57BLKS/J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

Neural-specific STAT3 deletion results in severe obesity in Stat3^tm1Flv/Stat3^tm1Flv Tg(Nes-cre)1Kln/0 mice similar to that seen in Lepr^db/Lepr^db mice

homeostasis/metabolism

abnormal vascular wound healing ( J:135034 )

• reduced neointimal area relative to controls 4 weeks after femoral artery injury

• vascular smooth muscle proliferation significantly reduced

impaired adaptive thermogenesis ( J:89242 )

• 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

increased circulating corticosterone level ( J:89242 )

increased circulating leptin level ( J:89242 )

abnormal glucose homeostasis ( J:80996 )

decreased circulating glucose level ( J:117919 )

• 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

increased circulating glucose level ( J:5010 , J:80996 , J:89242 )

• plasma fasting glucose is increased (J:89242)

hyperglycemia ( J:117919 )

• diabetes is improved after treatment with an adenovirus expressing Adipor1 or Adipor2

decreased circulating insulin level ( J:117919 )

• mice treated with an adenovirus expressing Adipor 2 show improved glucose resistance and decreased plasma insulin level

increased circulating insulin level ( J:5010 , J:80996 , J:89242 )

• fasting insulin is increased (J:89242)

impaired glucose tolerance ( J:89242 )

insulin resistance ( J:117919 )

• mice treated with an adenovirus expressing Adipor1 or Adipor 2 show improved insulin resistance

increased urine protein level ( J:5257 )

• 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

decreased body length ( J:89242 )

• mutants are about 5% shorter than controls

increased body weight ( J:5010 , J:80996 )

• by four weeks of age (J:80996)

obese ( J:89242 )

reproductive system

abnormal uterus morphology ( J:80996 )

(J:80996)

abnormal endometrium morphology ( J:80996 )

• 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 uterus weight ( 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

abnormal intraocular pressure ( J:82879 )

• modest but significant elevation of intraocular pressure

behavior/neurological

polydipsia ( J:5010 )

polyphagia ( J:5010 )

abnormal conditioned taste aversion behavior ( J:85127 )

• 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

increased urine protein level ( J:5257 )

• 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

abnormal renal glomerulus morphology ( J:5257 , J:30970 )

• basement membrane becomes thickened with age (J:5257)

• large quantites if immunoglobulin and complement are found in the mesangium (J:30970)

abnormal kidney papilla morphology ( J:5257 )

• eventually becomes flattened

abnormal kidney calyx morphology ( J:5257 )

• calyceal dilation eventually develops

polyuria ( J:5010 )

immune system

increased susceptibility to autoimmune diabetes ( J:7005 )

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

nervous system

abnormal hypothalamus physiology ( J:1325 )

• hypothalamic uptake of norepinephrine is decreased in males

adipose tissue

increased total body fat amount ( J:89242 )

• increase in total fat content

cardiovascular system

abnormal vascular wound healing ( J:135034 )

• reduced neointimal area relative to controls 4 weeks after femoral artery injury

• vascular smooth muscle proliferation significantly reduced

decreased systemic arterial blood pressure ( J:135034 )

ht12

Lepr^db/Lepr⁺
B6.Cg-Dock7^m +/+ Lepr^db/J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

mortality/aging

extended life span ( J:6081 )

• 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

increased body weight ( J:82334 )

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

ht13

Lepr^db/Lepr⁺
BKS.Cg-Dock7^m +/+ Lepr^db/J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

mortality/aging

extended life span ( J:6081 )

• 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

ht14

Lepr^db/Lepr⁺
involves: C57BLKS/J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

homeostasis/metabolism

abnormal glucose homeostasis ( J:71934 )

increased circulating glucose level ( J:71934 )

• fasting glucose levels elevated 25% during pregnancy

abnormal circulating insulin level ( J:71934 )

• 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

impaired glucose tolerance ( J:71934 )

• 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

abnormal hormone level ( J:71934 )

• elevated placental leptin levels in pregnant females

behavior/neurological

increased food intake ( J:71934 )

• food intake 11% greater than controls during pregnancy

• leptin treatment suppresses food intake to near control levels

growth/size

increased susceptibility to weight gain ( J:71934 )

• 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

increased total body fat amount ( J:71934 )

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

ht15

Lepr^db/Lepr^db-5J
involves: C57BLKS/J * NOD/ShiLtJ

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

growth/size

obese ( J:118305 )

• 25% of offspring exhibit obesity

cn16

Cebpb^tm1.1Maka/Cebpb^tm1.1Maka
Lepr^db/Lepr^db
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	Euro	Europhenome
N	normal phenotype

Increased beta cell mass in Lepr^db/Lepr^db mice and Lepr^db/Lepr^db Cebpb^tm1.1Maka/Cebpb^tm1.1Maka Tg(Ins2-cre)23Herr/0 mice

endocrine/exocrine glands

abnormal pancreatic islet cell apoptosis ( J:156725 )

• pancreatic islet cell apoptosis is decreased compared to in Lepr^db homozygotes

increased pancreatic beta cell mass ( J:156725 )

• compared to in Lepr^db homozygotes

homeostasis/metabolism

hyperglycemia ( J:156725 )

• hyperglycemia develops more slowly and is ameliorated compared to in Lepr^db homozygotes

increased circulating insulin level ( J:156725 )

• at 12 weeks, plasma insulin levels are increased compared to in Lepr^db homozygotes and wild-type mice

cellular

abnormal pancreatic islet cell apoptosis ( J:156725 )

• pancreatic islet cell apoptosis is decreased compared to in Lepr^db homozygotes

cn17

Lepr^db/Lepr^db
Pten^tm1Hwu/Pten^tm1Hwu
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	Euro	Europhenome
N	normal phenotype

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:170206 )

N	• mutants are protected from developing diabetes, and despite severe insulin resistance, mutants remain euglycemic and show normal glucose tolerance (J:170206)

increased insulin secretion ( J:170206 )

• mutant islets show increased beta-cell function, showing robust insulin secretion after glucose stimulation compared to diminished insulin secretion in single homozygous Lepr^db mice

insulin resistance ( J:170206 )

• mutants exhibit a similar degree of insulin resistance as single Lepr^db mice

growth/size

increased body weight ( J:170206 )

• mutants exhibit a similar degree of weight gain as single homozygous Lepr^db mice

endocrine/exocrine glands

abnormal pancreatic islet morphology ( J:170206 )

• islets show similar degrees of hypertrophy and proliferation as those in single homozygous Lepr^db mice and do not show a further increase in beta-cell mass compared to the single Lepr^db mice

increased insulin secretion ( J:170206 )

• mutant islets show increased beta-cell function, showing robust insulin secretion after glucose stimulation compared to diminished insulin secretion in single homozygous Lepr^db mice

cx18

Foxo1^tm2.1Dac/Foxo1^tm2.1Dac
Lepr^db/Lepr^db
B6.Cg-Foxo1^tm2.1Dac Lepr^db

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

homeostasis/metabolism

increased circulating insulin level ( J:179687 )

• in fasted mice

impaired glucose tolerance ( J:179687 )

cx19

Lepr^db/Lepr^db
Nos3^tm1Unc/Nos3^tm1Unc
BKS.Cg-Lepr^db Nos3^tm1Unc

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

renal/urinary system

albuminuria ( J:135864 )

• albumin/creatinine ratio (ACR) is significantly higher than all controls

abnormal nephron morphology ( J:135864 )

abnormal kidney afferent arteriole morphology ( J:135864 )

• arteriolar hyalinosis

increased renal glomerulus basement membrane thickness ( J:135864 )

• glomerular basement membrane is markedly thickened by 16 weeks in comparison to all controls

abnormal renal glomerulus morphology ( J:135864 )

• glomerular injury is significantly increased by 24-26 weeks in comparison to all controls

expanded mesangial matrix ( J:135864 )

• marked mesangial expansion is observed at 26 weeks of age

mesangiolysis ( J:135864 )

• marked mesangiolysis is observed at 26 weeks of age

glomerulosclerosis ( J:135864 )

• focal nodular sclerosis is observed at 26 weeks of age

renal glomerulus fibrosis ( J:135864 )

• substantial fibronectin accumulation is observed in glomeruli

decreased renal glomerular filtration rate ( J:135864 )

• GFR is decreased in comparison to homozygous Nos3^tm1Unc and Lepr^db controls

homeostasis/metabolism

increased circulating creatinine level ( J:135864 )

• at 26 weeks, serum creatinine is significantly higher than all controls

hyperglycemia ( J:135864 )

• hyperglycemia is first observed between 6-8 weeks of age, but is not higher than homozygous Lepr^db control

albuminuria ( J:135864 )

• albumin/creatinine ratio (ACR) is significantly higher than all controls

growth/size

increased body weight ( J:135864 )

• at 26 weeks, body weight is double that of lean and Nos3^tm1Unc controls

cardiovascular system

abnormal kidney afferent arteriole morphology ( J:135864 )

• arteriolar hyalinosis

increased systemic arterial systolic blood pressure ( J:135864 )

• hypertension is observed between 24-28 weeks of age, but is not significantly higher than homozygous Nos3^tm1Unc controls

cx20

Apoe^tm1Unc/Apoe^tm1Unc
Lepr^db/Lepr^db
involves: 129P2/OlaHsd * C57BLKS/J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

vision/eye

abnormal retina morphology ( J:103714 )

• higher levels of "advanced glycation end products" in the extracellular matrix

• Ager mRNA levels elevated in the retina

abnormal retinal vasculature morphology ( J:103714 )

• increase of capillary lesions

• significantly higher number of acellular capillaries

• increased capillary outpouching indicative of early microaneurysms

cardiovascular system

abnormal retinal vasculature morphology ( J:103714 )

• increase of capillary lesions

• significantly higher number of acellular capillaries

• increased capillary outpouching indicative of early microaneurysms

cx21

Lepr^db/Lepr^db
Plin1^tm1Chan/Plin1^tm1Chan
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * C57BLKS/J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

growth/size

decreased susceptibility to age related obesity ( J:66267 )

• mice are resistant to the obesity caused by the Lepr^db background

• at a given age, mice weigh significantly less than Lepr^db 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 Lepr^db homozygotes

homeostasis/metabolism

increased oxygen consumption ( J:66267 )

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

cx22

Aqp9^tm1Nlsn/Aqp9^tm1Nlsn
Lepr^db/Lepr^db
involves: 129S1/Sv * C57BL/6 * C57BLKS/J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

homeostasis/metabolism

decreased circulating glucose level ( J:123742 )

• after fasting blood glucose levels are moderately lower than those in Lepr^db homozygotes

increased circulating glycerol level ( J:123742 )

• 939+/-43 compared to 553+/-35 in Lepr^db homozygotes

cx23

Lepr^db/Lepr^db
Serpine1^tm1Mlg/Serpine1^tm1Mlg
involves: 129S2/SvPas * C57BL/6 * C57BLKS/J

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

mortality/aging

premature death ( J:127478 )

• 23% of females and 44% of males in the F3 generation died prematurely, of indeterminate cause

growth/size

obese ( J:127478 )

• female mice are obese relative to wild-type and Serpine1-deficient single mutant controls

decreased body size ( J:127478 )

• 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

albuminuria ( J:127478 )

• present with slightly higher urinary albumin to creatinine ratios relative to Lepr single homozygotes

abnormal kidney morphology ( J:127478 )

• total kidney collagen is increased in females by 47% compared to female single Serpine1-deficient animals

abnormal renal glomerulus morphology ( J:127478 )

• 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

increased blood urea nitrogen level ( J:127478 )

• significantly higher BUN levels compared to Serpine1-deficient single mutants

hyperglycemia ( J:127478 )

• hyperglycemia is less severe than observed in Serpine1-sufficient, Lepr-deficient controls at 10, 14, and 34 weeks of age

albuminuria ( J:127478 )

• present with slightly higher urinary albumin to creatinine ratios relative to Lepr single homozygotes

abnormal enzyme/coenzyme activity ( J:127478 )

• total urokinase plasminogen activator (uPA) activity is significantly higher than wild-type compared to Serpine1-sufficient diabetic controls

cx24

Lepr^db/Lepr^db
Rock1^tm1Leiw/Rock1^tm1Leiw
involves: 129S7/SvEvBrd * C57BLKS/J * FVB

Key:
♀	phenotype observed in females	WTSI	Wellcome Trust Sanger Institute
♂	phenotype observed in males	Euro	Europhenome
N	normal phenotype

renal/urinary system

renal/urinary system phenotype ( J:182287 )

N	• mice treated with streptozotocin to induce diabetes do not exhibit podocyte loss unlike similarly treated Lepr^db homozygotes (J:182287)

increased renal glomerulus apoptosis ( J:182287 )

• mice treated with streptozotocin to induce diabetes exhibit glomerular apoptosis but not as much as in similarly treated Lepr^db homozygotes

albuminuria ( J:182287 )

• in mice treated with streptozotocin to induce diabetes but not as much as in similarly treated Lepr^db homozygotes

increased renal glomerulus basement membrane thickness ( J:182287 )

• in mice treated with streptozotocin to induce diabetes but not as much as in similarly treated Lepr^db homozygotes

expanded mesangial matrix ( J:182287 )