Phenotypes associated with this allele

• Allele Symbol: Lepr^db
• Allele Name: diabetes
• Allele ID: MGI:1856009
• Summary: 44 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Lepr^db/Lepr^db	B6.BKS(D)-Lepr^db/J	MGI:4429457
hm2	Lepr^db/Lepr^db	B6.BKS(D)-Lepr^db/JOrlRj	MGI:6356398
hm3	Lepr^db/Lepr^db	B6.Cg-Dock7^m +/+ Lepr^db/J	MGI:3689720
hm4	Lepr^db/Lepr^db	B6NTac.BKS(D)-Lepr^db	MGI:7545550
hm5	Lepr^db/Lepr^db	BKS.Cg-Dock7^m +/+ Lepr^db	MGI:7622052
hm6	Lepr^db/Lepr^db	BKS.Cg-Dock7^m +/+ Lepr^db/J	MGI:3694548
hm7	Lepr^db/Lepr^db	BKS.Cg-Dock7^m +/+ Lepr^db/Jcl	MGI:4418957
hm8	Lepr^db/Lepr^db	BKS.Cg-Dock7^m +/+ Lepr^db/OlaHsd	MGI:3774345
hm9	Lepr^db/Lepr^db	FVB.BKS-Lepr^db	MGI:3655832
hm10	Lepr^db/Lepr^db	involves: 129S2/SvPas * C57BL/6 * C57BLKS/J	MGI:3803206
hm11	Lepr^db/Lepr^db	involves: C57BL/6	MGI:3774853
hm12	Lepr^db/Lepr^db	involves: C57BL/6 * C57BLKS/J	MGI:3822315
hm13	Lepr^db/Lepr^db	involves: C57BLKS/J	MGI:2654708
ht14	Lepr^db/Lepr^+	B6.Cg-Dock7^m +/+ Lepr^db/J	MGI:3697525
ht15	Lepr^db/Lepr^+	involves: C57BLKS/J	MGI:3774843
ht16	Lepr^db/Lepr^db-Nokl	B6NTac.Cg-Lepr^db Lepr^db-Nokl	MGI:7545554
ht17	Lepr^db/Lepr^db-5J	involves: C57BLKS/J * NOD/ShiLtJ	MGI:3699233
cn18	Jaml^tm1Fnyi/Jaml^+ Lepr^db/Lepr^db Tg(NPHS2-cre)295Lbh/0	B6.Cg-Lepr^db Jaml^tm1Fnyi Tg(NPHS2-cre)295Lbh	MGI:6506863
cn19	Jaml^tm1Fnyi/Jaml^tm1Fnyi Lepr^db/Lepr^db Tg(NPHS2-cre)295Lbh/0	B6.Cg-Lepr^db Jaml^tm1Fnyi Tg(NPHS2-cre)295Lbh	MGI:6506864
cn20	Cebpb^tm1.1Maka/Cebpb^tm1.1Maka Lepr^db/Lepr^db Tg(Ins2-cre)23Herr/0	involves: 129P2/OlaHsd * C57BL/6J * C57BLKS/J * CBA/J	MGI:4421499
cn21	Lepr^db/Lepr^db Pten^tm1Hwu/Pten^tm1Hwu Tg(Ins2-cre)25Mgn/0	involves: 129S4/SvJae * C57BL/6 * C57BLKS/J * DBA	MGI:5013485
cx22	Foxo1^tm2.1Dac/Foxo1^tm2.1Dac Lepr^db/Lepr^db	B6.Cg-Foxo1^tm2.1Dac Lepr^db	MGI:5305587
cx23	Dock7^m/Dock7^+ Lepr^db/Lepr^+	BKS.Cg-Dock7^m +/+ Lepr^db/J	MGI:3776095
cx24	Lepr^db/Lepr^db Nos3^tm1Unc/Nos3^tm1Unc	BKS.Cg-Lepr^db Nos3^tm1Unc	MGI:4361710
cx25	Apoe^tm1Unc/Apoe^tm1Unc Lepr^db/Lepr^db	involves: 129P2/OlaHsd * C57BLKS/J	MGI:3775795
cx26	Gdf15^tm1Sjl/Gdf15^tm1Sjl Lepr^db/Lepr^db	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * C57BLKS/J	MGI:5548175
cx27	Lepr^db/Lepr^db Plin1^tm1Chan/Plin1^tm1Chan	involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * C57BLKS/J	MGI:3839678
cx28	Aqp9^tm1Nlsn/Aqp9^tm1Nlsn Lepr^db/Lepr^db	involves: 129S1/Sv * C57BL/6 * C57BLKS/J	MGI:3720617
cx29	Lepr^db/Lepr^db Serpine1^tm1Mlg/Serpine1^tm1Mlg	involves: 129S2/SvPas * C57BL/6 * C57BLKS/J	MGI:3803207
cx30	Lepr^db/Lepr^db Rock1^tm1Leiw/Rock1^tm1Leiw	involves: 129S7/SvEvBrd * C57BLKS/J * FVB/N	MGI:5316083
cx31	Lepr^db/Lepr^db Repin1^tm1.2Arte/Repin1^tm1.2Arte	involves: BALB/c * C57BL/6 * C57BLKS/J	MGI:5903475
cx32	Lepr^db/Lepr^+ Tg(APPswe,PSEN1dE9)85Dbo/0	involves: C3H * C57BL/6 * C57BLKS/J	MGI:5435319
cx33	Dbsq3^C57BLKS/J/Dbsq3^C3H/HeJ Lepr^db/Lepr^+	involves: C3H/HeJ * C57BLKS	MGI:3693608
cx34	Dbsq2^C3H/HeJ/Dbsq2^C3H/HeJ Lepr^db/Lepr^+	involves: C3H/HeJ * C57BLKS	MGI:3693605
cx35	Dbsq1^C57BLKS/J/Dbsq1^C57BLKS/J Lepr^db/Lepr^db	involves: C3H/HeJ * C57BLKS	MGI:3693603
cx36	Dbsq1^C57BLKS/J/Dbsq1^C3H/HeJ Lepr^db/Lepr^db	involves: C3H/HeJ * C57BLKS	MGI:3693604
cx37	Dbsq3^C3H/HeJ/Dbsq3^C3H/HeJ Lepr^db/Lepr^+	involves: C3H/HeJ * C57BLKS	MGI:3693607
cx38	Dbsq2^C57BLKS/J/Dbsq2^C3H/HeJ Lepr^db/Lepr^+	involves: C3H/HeJ * C57BLKS	MGI:3693606
cx39	Ccr2^tm1.1(CCR2)Rodb/Ccr2^tm1.1(CCR2)Rodb Lepr^db/Lepr^db	involves: C57BL/6 * C57BLKS/J	MGI:5552736
cx40	Helz2^tm1Tesa/Helz2^tm1Tesa Lepr^db/Lepr^db	involves: C57BL/6 * C57BLKS/J	MGI:5707502
cx41	Lepr^db/Lepr^db Tg(SHBG)4-aGlha/0	involves: C57BL/6 * C57BLKS/J * CBA	MGI:5828524
cx42	Lepr^db/Lepr^db Tg(Fabp4-Fcor)1Jnak/0	involves: C57BL/6 * C57BLKS/J * DBA/2	MGI:5427610
cx43	Cdkn1b^tm1Kin/Cdkn1b^+ Lepr^db/Lepr^db	involves: C57BL/6J * C57BLKS/J	MGI:3529778
cx44	Cdkn1b^tm1Kin/Cdkn1b^tm1Kin Lepr^db/Lepr^db	involves: C57BL/6J * C57BLKS/J	MGI:3529774

Genotype
MGI:4429457

hm1

• Allelic Composition: Lepr^db/Lepr^db
• Genetic Background: B6.BKS(D)-Lepr^db/J

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

decreased locomotor activity ( J:166105 )

• during the dark phase

renal/urinary system

glomerulosclerosis ( J:160943 )

• homozygotes develop significant glomerulosclerosis by 18 weeks of age

Genotype
MGI:6356398

hm2

• Allelic Composition: Lepr^db/Lepr^db
• Genetic Background: B6.BKS(D)-Lepr^db/JOrlRj

growth/size/body

increased body weight ( J:277927 )

♂ • mice exhibit increased body weight at 3 months, but not 1 month, of standard chow diet

increased susceptibility to diet-induced obesity ( J:277927 )

♂ • mice exhibit increased body weight when fed a high-calorie diet for 1 or 3 months

homeostasis/metabolism

increased susceptibility to diet-induced obesity ( J:277927 )

♂ • mice exhibit increased body weight when fed a high-calorie diet for 1 or 3 months

increased circulating ketone body level ( J:277927 )

♂ • plasma beta-hydroxybutyrate levels are greatly increased after 3 months of the high-calorie diet

increased cholesterol level ( J:277927 )

♂ • total cholesterol levels are increased in mice fed a high-calorie diet for 1 month and increased further when fed for 3 months

immune system

liver inflammation ( J:277927 )

♂ • hepatic necroinflammation is not prominent, however it is aggravated after 1 month of high-calorie diet compared to standard diet and tends to alleviate with time

♂ • non-alcoholic steatohepatitis is seen occasionally after 3 months of a standard diet and is seen in 3 of 9 mice after 3 months of the high-calorie diet

liver/biliary system

increased hepatocyte apoptosis ( J:277927 )

♂ • some hepatocyte apoptosis is seen in mice fed the standard diet and apoptosis is not increased by a high-calorie diet and even reduced after 3 months of a high-calorie diet

liver inflammation ( J:277927 )

♂ • hepatic necroinflammation is not prominent, however it is aggravated after 1 month of high-calorie diet compared to standard diet and tends to alleviate with time

♂ • non-alcoholic steatohepatitis is seen occasionally after 3 months of a standard diet and is seen in 3 of 9 mice after 3 months of the high-calorie diet

hepatic steatosis ( J:277927 )

♂ • mice develop steatosis, with steatosis mainly localized in the centrilobular and mediolobular areas; fatty change is milder than in Lep^ob homozygotes

♂ • severity of steatosis is enhanced by the high-calorie diet after 1 month, but is subsequently reduced after 3 months on this diet

macrovesicular hepatic steatosis ( J:277927 )

• macrovacuolar steatosis is similar to that seen in Lep^ob homozygotes

microvesicular hepatic steatosis ( J:277927 )

• microvesicular steatosis is more frequently seen than in Lep^ob homozygotes

liver fibrosis ( J:277927 )

♂ • some portal and perisinusoidal fibrosis is seen in standard diet fed mice at 3 months and is increased when mice are fed the high-calorie diet

cellular

increased hepatocyte apoptosis ( J:277927 )

♂ • some hepatocyte apoptosis is seen in mice fed the standard diet and apoptosis is not increased by a high-calorie diet and even reduced after 3 months of a high-calorie diet

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
metabolic dysfunction-associated steatotic liver disease		DOID:0080208	OMIM:613282 OMIM:613387	J:277927

Genotype
MGI:3689720

hm3

• Allelic Composition: Lepr^db/Lepr^db
• Genetic Background: B6.Cg-Dock7^m +/+ Lepr^db/J

growth/size/body

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

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)

decreased body length ( J:82334 )

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

behavior/neurological

polyphagia ( J:82334 )

reduced male mating frequency ( 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

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

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 )

abnormal hormone level ( J:6157 )

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

increased circulating insulin level ( J:82334 )

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

decreased circulating adiponectin level ( J:115772 )

• decreased adiponectin levels 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

small uterus ( J:6157 )

♀

constricted vagina orifice ( J:6157 )

♀

anovulation ( J:82334 )

♀

absent estrus ( J:82334 )

♀ • females never show signs of vaginal oestrous

absent estrous cycle ( J:6157 )

♀ • mice exhibit diestrous vaginal acyclicity or occasional metestrous acyclicity

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 )

increased neutrophil cell number ( J:115772 )

• increased numbers in bronchoalveolar lavage

decreased leukocyte cell number ( J:115772 )

• decrease blood leukocyte numbers

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

neoplasm

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 )

increased neutrophil cell number ( J:115772 )

• increased numbers in bronchoalveolar lavage

decreased leukocyte cell number ( J:115772 )

• decrease blood leukocyte numbers

nervous system

abnormal hypothalamus physiology ( J:6157 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
obesity		DOID:9970	OMIM:601665	J:18161 , J:82234 , J:103063

Genotype
MGI:7545550

hm4

• Allelic Composition: Lepr^db/Lepr^db
• Genetic Background: B6NTac.BKS(D)-Lepr^db

adipose tissue

increased subcutaneous adipose tissue amount ( J:313303 )

increased body fat mass ( J:313303 )

increased white fat cell size ( J:313303 )

increased gonadal fat pad weight ( J:313303 )

behavior/neurological

increased food intake ( J:313303 )

abnormal locomotor circadian rhythm ( J:313303 )

• no activity, oxygen consumption and carbon dioxide production difference between light and dark periods

decreased locomotor activity ( J:313303 )

• constant low activity regardless of light or dark period

growth/size/body

increased body fat mass ( J:313303 )

obese ( J:313303 )

hematopoietic system

increased glycosylated hemoglobin level ( J:313303 )

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:313303 )

N • normal hepatic glycogen content

N • normal adiponectin serum concentrations

N • normal core body temperature in males

N • normal circulating post-fasting glucose levels in males

increased glycosylated hemoglobin level ( J:313303 )

increased fasting circulating glucose level ( J:313303 )

♀ • increased in females

increased circulating insulin level ( J:313303 )

• higher fasting serum insulin levels

increased circulating leptin level ( J:313303 )

increased circulating cholesterol level ( J:313303 )

increased circulating HDL cholesterol level ( J:313303 )

increased circulating LDL cholesterol level ( J:313303 )

increased circulating triglyceride level ( J:313303 )

decreased core body temperature ( J:313303 )

♀ • reduced in females

abnormal carbon dioxide production ( J:313303 )

• steady production regardless of light or dark period

abnormal oxygen consumption ( J:313303 )

• steady consumption regardless of light or dark period

impaired glucose tolerance ( J:313303 )

• higher glucose levels after glucose injection

increased liver triglyceride level ( J:313303 )

increased susceptibility to diet-induced non-insulin dependent diabetes ( J:313303 )

abnormal peptide metabolism ( J:313303 )

integument

increased subcutaneous adipose tissue amount ( J:313303 )

limbs/digits/tail

short tail ( J:313303 )

liver/biliary system

increased liver triglyceride level ( J:313303 )

increased susceptibility to diet-induced hepatic steatosis ( J:313303 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
obesity		DOID:9970	OMIM:601665	J:313303

Genotype
MGI:7622052

hm5

• Allelic Composition: Lepr^db/Lepr^db
• Genetic Background: BKS.Cg-Dock7^m +/+ Lepr^db

growth/size/body

increased body weight ( J:346348 )

• mice show an increase in body weight

• injection with a CCL4 (MIP-1beta) mAb controls the increase in body weight such that no difference in weight is seen

enlarged kidney ( J:346348 )

• increase in kidney-to-body weight ratio indicating renal hypertrophy

• treatment with MIP-1beta mAb reduces renal hypertrophy

homeostasis/metabolism

increased circulating creatinine level ( J:346348 )

• increase in creatinine levels

• treatment with MIP-1beta mAb reduces creatinine levels

increased blood urea nitrogen level ( J:346348 )

• increase in BUN levels

• treatment with MIP-1beta mAb reduces BUN levels

hyperglycemia ( J:346348 )

• increase in blood sugar levels

• injection with MIP-1beta mAb moderately controls the hyperglycemia

increased circulating insulin level ( J:346348 )

• higher levels of serum insulin

• treatment with MIP-1beta mAb shows a time-dependent reduction in serum insulin levels, with significant difference after 3 weeks of mAb injection

increased circulating cholesterol level ( J:346348 )

• serum cholesterol levels are increased

• treatment with MIP-1beta mAb has no effect on serum cholesterol levels

increased circulating triglyceride level ( J:346348 )

• serum triglyceride levels are increased

• injection with MIP-1beta mAb reduces triglyceride levels

renal/urinary system

enlarged kidney ( J:346348 )

• increase in kidney-to-body weight ratio indicating renal hypertrophy

• treatment with MIP-1beta mAb reduces renal hypertrophy

kidney inflammation ( J:346348 )

• inflammatory protein expression levels in the kidneys are elevated

• treatment with MIP-1beta mAb reduces CCL4 (MIP-1beta), TNF-alpha, and IL-6 expression levels in the kidneys

increased glomerular capsule space ( J:346348 )

abnormal podocyte morphology ( J:346348 )

• podocyte injury

• treatment with MIP-1beta mAb reduces podocyte injury

abnormal renal glomerulus morphology ( J:346348 )

• kidneys show advanced vacuole formation and glomerular hypertrophy as early as 8 weeks of age, indicating glomerular damage

• by 12 weeks of age, significant structural changes are seen in the glomeruli, along with larger Bowmans spaces, lower glomerular cellular contents, and increased tubular lumens

• treatment with MIP-1beta mAb prevents renal damage and normalizes glomerular hypertrophy

abnormal glomerular mesangium morphology ( J:346348 )

• expanded mesangial regions

• treatment with MIP-1beta mAb attenuates the expansion of the mesangial regions

expanded mesangial matrix ( J:346348 )

• accumulation of extracellular matrix

• treatment with MIP-1beta mAb attenuates the accumulation of extracellular matrix

glomerulosclerosis ( J:346348 )

• mice develop glomerulosclerosis

• treatment with MIP-1beta mAb reduces renal glomerulosclerosis

renal glomerulus hypertrophy ( J:346348 )

• mice show glomerular hypertrophy as early as 8 weeks of age

• treatment with MIP-1beta mAb normalizes glomerular hypertrophy

renal fibrosis ( J:346348 )

• mice show enhanced collagen-positive areas in kidneys, indicating kidney fibrosis

• treatment with MIP-1beta mAb reduces kidney fibrosis

immune system

kidney inflammation ( J:346348 )

• inflammatory protein expression levels in the kidneys are elevated

• treatment with MIP-1beta mAb reduces CCL4 (MIP-1beta), TNF-alpha, and IL-6 expression levels in the kidneys

behavior/neurological

polydipsia ( J:346348 )

• mice exhibit polydipsia

• treatment with MIP-1beta mAb reduces polydipsia

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
type 2 diabetes mellitus		DOID:9352	OMIM:125853 OMIM:601283 OMIM:601407 OMIM:603694 OMIM:608036	J:346348

Genotype
MGI:3694548

hm6

• Allelic Composition: Lepr^db/Lepr^db
• Genetic Background: BKS.Cg-Dock7^m +/+ Lepr^db/J

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

abnormal enzyme/coenzyme activity ( J:302677 )

• Lypla1 (APT-1) enzyme activity is decreased in lung endothelial cells

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/body

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 )

• 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

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 extension ( 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 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

abnormal food intake ( J:43162 )

• food intake is about 60% of control level

abnormal locomotor 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

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 aorta morphology ( J:302677 )

• aortic tissue shows increased retention of insoluble fibronectin

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 extension ( J:112680 )

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

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
obesity		DOID:9970	OMIM:601665	J:6323
type 2 diabetes mellitus		DOID:9352	OMIM:125853 OMIM:601283 OMIM:601407 OMIM:603694 OMIM:608036	J:185546

Genotype
MGI:4418957

hm7

• Allelic Composition: Lepr^db/Lepr^db
• Genetic Background: BKS.Cg-Dock7^m +/+ Lepr^db/Jcl

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

increased 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

increased pancreatic islet cell apoptosis ( J:156725 )

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

Genotype
MGI:3774345

hm8

• Allelic Composition: Lepr^db/Lepr^db
• Genetic Background: BKS.Cg-Dock7^m +/+ Lepr^db/OlaHsd

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 )

Genotype
MGI:3655832

hm9

• Allelic Composition: Lepr^db/Lepr^db
• Genetic Background: FVB.BKS-Lepr^db

growth/size/body

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		DO ID	OMIM ID(s)	Ref(s)
obesity		DOID:9970	OMIM:601665	J:78850

Genotype
MGI:3803206

hm10

• Allelic Composition: Lepr^db/Lepr^db
• Genetic Background: involves: 129S2/SvPas * C57BL/6 * C57BLKS/J

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

Genotype
MGI:3774853

hm11

• Allelic Composition: Lepr^db/Lepr^db
• Genetic Background: involves: C57BL/6

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

Genotype
MGI:3822315

hm12

• Allelic Composition: Lepr^db/Lepr^db
• Genetic Background: involves: C57BL/6 * C57BLKS/J

reproductive system

abnormal female reproductive system morphology ( J:164339 )

♀

absent estrus ( J:164339 )

♀

absent estrous cycle ( 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/body

decreased lean body mass ( J:164339 )

increased body weight ( J:164339 )

obese ( J:142218 )

• early onset obesity starting from 4 weeks of age

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

adipose tissue

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

behavior/neurological

abnormal eating behavior ( J:164339 )

polyphagia ( J:142218 )

decreased locomotor activity ( J:142218 )

• decreased activity in both the light and dark cycle

limbs/digits/tail

short femur ( J:164339 )

skeleton

short femur ( J:164339 )

Genotype
MGI:2654708

hm13

• Allelic Composition: Lepr^db/Lepr^db
• Genetic Background: involves: C57BLKS/J

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

hematopoietic system

increased glycosylated hemoglobin level ( J:104790 )

• significant increase in the percentage of plasma glycosylated hemoglobin

liver/biliary system

increased liver weight ( J:232827 )

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

abnormal myocardium layer morphology ( J:107138 )

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

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 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

homeostasis/metabolism

abnormal response to cardiac 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

abnormal vascular wound healing ( J:135034 )

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

• vascular smooth muscle proliferation significantly reduced

increased glycosylated hemoglobin level ( J:104790 )

• significant increase in the percentage of plasma glycosylated hemoglobin

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 , J:232827 )

increased circulating cholesterol level ( J:232827 )

increased circulating free fatty acids level ( J:106871 , J:232827 )

increased circulating triglyceride level ( J:232827 )

hyperlipidemia ( J:96047 )

decreased body temperature ( J:96047 )

abnormal glucose homeostasis ( J:80996 , J:107138 )

• diabetic phenotype appears earlier in males than in females (J:107138)

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:96047 , J:104790 , J:106597 , J:106871 , J:117919 , J:210493 , J:232827 )

• by 8 weeks (J:106597)

• diabetes is improved after treatment with an adenovirus expressing Adipor1 or Adipor2 (J:117919)

• at 12 weeks (J:210493)

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 , J:104790 , J:106597 , J:232827 )

• fasting insulin is increased (J:89242)

• hyperinsulinemia by 8 weeks (J:106597)

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

abnormal nucleotide metabolism ( J:260830 )

• subcutaneous white adipose tissue (sWAT) has less uridine content than in wild-type mice

• however, epididymal white adipose tissue (eWAT), interscapular brown adipose tissue (BAT), and liver uridine content are not different

mortality/aging

increased susceptibility 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

growth/size/body

increased body weight ( J:5010 , J:80996 , J:106597 )

• by four weeks of age (J:80996)

• overweight by 4 weeks of age (J:106597)

obese ( J:89242 , J:96047 , J:104790 , J:106871 , J:232827 )

decreased body length ( J:89242 )

• mutants are about 5% shorter than controls

increased kidney weight ( J:232827 )

increased liver weight ( J:232827 )

reproductive system

abnormal uterus morphology ( J:80996 )

♀

abnormal endometrium morphology ( J:80996 )

♀ • increased volume and density of lipid inclusion vacuoles

♀ • basal membrane of epithelial cells displays a folded contour at locations where lipid accumulates

♀ • tissue norepinephrin levels elevated by 4 weeks of age and remain elevated

decreased uterus weight ( J:80996 )

♀ • decreased relative to controls by 4 weeks of age

♀ • 1/3 normal tissue weight by 12 weeks

vision/eye

abnormal intraocular pressure ( J:82879 )

• modest but significant elevation of intraocular pressure

behavior/neurological

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

polydipsia ( J:5010 )

polyphagia ( J:5010 , J:96047 )

renal/urinary system

increased kidney weight ( J:232827 )

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 )

• basement membrane becomes thickened with age

renal glomerular protein deposits ( J:30970 )

• large quantites of immunoglobulin and complement are found in the mesangium

renal glomerular immunoglobulin deposits ( 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

abnormal adipose tissue morphology ( J:232827 )

• increase in adipose tissue weight in both males and females

increased total body fat amount ( J:89242 )

• increase in total fat content

abnormal white adipose tissue morphology ( J:260830 )

• subcutaneous white adipose tissue (sWAT) has less uridine content than in wild-type mice

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

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)

abnormal response to cardiac 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

decreased systemic arterial blood pressure ( J:135034 )

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

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

abnormal vascular wound healing ( J:135034 )

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

• vascular smooth muscle proliferation significantly reduced

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

abnormal pancreatic beta cell physiology ( J:210493 )

• beta cells exhibit DNA damage unlike control cells

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
obesity		DOID:9970	OMIM:601665	J:96047 , J:104790 , J:106871
type 2 diabetes mellitus		DOID:9352	OMIM:125853 OMIM:601283 OMIM:601407 OMIM:603694 OMIM:608036	J:104790

Genotype
MGI:3697525

ht14

• Allelic Composition: Lepr^db/Lepr⁺
• Genetic Background: B6.Cg-Dock7^m +/+ Lepr^db/J

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/body

increased body weight ( J:82334 )

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

Genotype
MGI:3774843

ht15

• Allelic Composition: Lepr^db/Lepr⁺
• Genetic Background: involves: C57BLKS/J

homeostasis/metabolism

abnormal glucose homeostasis ( J:71934 )

increased circulating glucose level ( J:71934 )

♀ • fasting glucose levels elevated 25% during pregnancy

impaired glucose tolerance ( J:71934 , J:219658 )

• profound glucose intolerance during pregnancy (J:71934)

• glucose levels 41% higher in a glucose tolerance test at 30 and at 60 minute time points (J:71934)

• 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 (J:71934)

• females exhibit impaired glucose tolerance during pregnancy (J:219658)

• both male and female heterozygous offspring have impaired glucose tolerance irrespective of maternal environment (heterozygous or wild-type mothers) (J:219658)

abnormal hormone level ( J:71934 )

♀ • elevated placental leptin levels in pregnant females

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

decreased circulating insulin level ( J:219658 )

♀ • pregnant dams exhibit lower fasting insulin levels than wild-type mothers

increased circulating leptin level ( J:219658 )

• mothers exhibit higher circulating leptin levels than wild-type mothers

• heterozygous offspring exhibit an increase in leptin levels at 6 months of age

decreased response to leptin ( J:71934 )

• birth weights significantly heavier than controls and unaffected by maternal leptin treatment unlike controls where maternal leptin treatment causes a decrease in birth weights

• leptin treatment results in a 14% reduction in insulin levels compared to a 45% reduction in controls

embryo

enlarged placenta ( J:219658 )

• placentas from heterozygous fetuses are larger than those of wild-type fetuses, irrespective of maternal genotype

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/body

increased birth weight ( J:219658 )

• heterozygous fetuses carried by wild-type dams exhibit a 5% higher birth weight than wild-type littermates

• heterozygous fetuses from heterozygous mothers are 3% bigger than wild-type littermates

• however, wild-type pups from heterozygous mothers are no bigger than wild-type fetuses carried by wild-type mothers

increased body weight ( J:219658 )

• heterozygous pregnant dams are heavier than wild-type mothers at E18.5

• male and female heterozygous offspring from both normal and complicated pregnancies, are heavier than wild-type littermates at 3 and 6 months of age

increased susceptibility to weight gain ( J:71934 )

♀ • 33% greater maternal weight gain

♀ • maternal body weight at term 24% greater than controls

adipose tissue

increased total body fat amount ( J:71934 )

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

cellular

maternal effect ( J:219658 )

• wild-type males born to heterozygous mothers are heavier than wild-type mice born to wild-type mothers, but postnatal weight gain of female offspring is not affected by the maternal environment

• offspring born from heterozygous mothers with gestational diabetes have lower fasting insulin levels and worse glucose tolerance than offspring born from wild-type mothers

Genotype
MGI:7545554

ht16

• Allelic Composition: Lepr^db/Lepr^db-Nokl
• Genetic Background: B6NTac.Cg-Lepr^db Lepr^db-Nokl

adipose tissue

increased subcutaneous adipose tissue amount ( J:313303 )

increased body fat mass ( J:313303 )

increased white fat cell size ( J:313303 )

increased gonadal fat pad weight ( J:313303 )

behavior/neurological

increased food intake ( J:313303 )

abnormal locomotor circadian rhythm ( J:313303 )

• no activity, oxygen consumption and carbon dioxide production difference between light and dark periods

decreased locomotor activity ( J:313303 )

• constant low activity regardless of light or dark period

growth/size/body

increased body fat mass ( J:313303 )

obese ( J:313303 )

hematopoietic system

increased glycosylated hemoglobin level ( J:313303 )

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:313303 )

N • normal circulating adiponectin and post-fasting glucose levels in males

N • normal core body temperature in males

N • normal hepatic glycogen content in males and females

increased glycosylated hemoglobin level ( J:313303 )

increased fasting circulating glucose level ( J:313303 )

♀ • higher post-fasting circulating glucose levels in females

increased circulating insulin level ( J:313303 )

• higher fasting serum insulin levels

increased circulating leptin level ( J:313303 )

increased circulating cholesterol level ( J:313303 )

increased circulating HDL cholesterol level ( J:313303 )

increased circulating LDL cholesterol level ( J:313303 )

increased circulating triglyceride level ( J:313303 )

decreased core body temperature ( J:313303 )

♀ • lower core body temperature in females

abnormal carbon dioxide production ( J:313303 )

• steady production regardless of light or dark period

abnormal oxygen consumption ( J:313303 )

• steady consumption regardless of light or dark period

impaired glucose tolerance ( J:313303 )

• higher glucose levels after glucose injection

decreased circulating adiponectin level ( J:313303 )

♀ • lower circulating adiponectin levels in females

increased liver triglyceride level ( J:313303 )

increased susceptibility to diet-induced non-insulin dependent diabetes ( J:313303 )

abnormal peptide metabolism ( J:313303 )

integument

increased subcutaneous adipose tissue amount ( J:313303 )

limbs/digits/tail

short tail ( J:313303 )

liver/biliary system

increased liver triglyceride level ( J:313303 )

increased susceptibility to diet-induced hepatic steatosis ( J:313303 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
obesity		DOID:9970	OMIM:601665	J:313303

Genotype
MGI:3699233

ht17

• Allelic Composition: Lepr^db/Lepr^db-5J
• Genetic Background: involves: C57BLKS/J * NOD/ShiLtJ

growth/size/body

obese ( J:118305 )

• 25% of offspring exhibit obesity

Genotype
MGI:6506863

cn18

• Allelic Composition: Jaml^tm1Fnyi/Jaml⁺; Lepr^db/Lepr^db; Tg(NPHS2-cre)295Lbh/0
• Genetic Background: B6.Cg-Lepr^db Jaml^tm1Fnyi Tg(NPHS2-cre)295Lbh

renal/urinary system

increased urine protein level ( J:300243 )

• intermediate but not as severe as in mice with wild-type Jaml

abnormal podocyte morphology ( J:300243 )

• podocyte injury that is as severe as in mice with wild-type Jaml

expanded mesangial matrix ( J:300243 )

• not as severe as in mice with wild-type Jaml

homeostasis/metabolism

increased urine protein level ( J:300243 )

• intermediate but not as severe as in mice with wild-type Jaml

Genotype
MGI:6506864

cn19

• Allelic Composition: Jaml^tm1Fnyi/Jaml^tm1Fnyi; Lepr^db/Lepr^db; Tg(NPHS2-cre)295Lbh/0
• Genetic Background: B6.Cg-Lepr^db Jaml^tm1Fnyi Tg(NPHS2-cre)295Lbh

renal/urinary system

increased urine protein level ( J:300243 )

• not as severe as in mice with wild-type Jaml

abnormal podocyte morphology ( J:300243 )

• podocyte injury that is as severe as in mice with wild-type Jaml

expanded mesangial matrix ( J:300243 )

• not as severe as in mice with wild-type Jaml

renal glomerulus lipidosis ( J:300243 )

• not as severe as in mice with wild-type Jaml

homeostasis/metabolism

increased urine protein level ( J:300243 )

• not as severe as in mice with wild-type Jaml

Genotype
MGI:4421499

cn20

• Allelic Composition: Cebpb^tm1.1Maka/Cebpb^tm1.1Maka; Lepr^db/Lepr^db; Tg(Ins2-cre)23Herr/0
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J * C57BLKS/J * CBA/J

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

Genotype
MGI:5013485

cn21

• Allelic Composition: Lepr^db/Lepr^db; Pten^tm1Hwu/Pten^tm1Hwu; Tg(Ins2-cre)25Mgn/0
• Genetic Background: involves: 129S4/SvJae * C57BL/6 * C57BLKS/J * DBA

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

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/body

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

Genotype
MGI:5305587

cx22

• Allelic Composition: Foxo1^tm2.1Dac/Foxo1^tm2.1Dac; Lepr^db/Lepr^db
• Genetic Background: B6.Cg-Foxo1^tm2.1Dac Lepr^db

homeostasis/metabolism

increased circulating insulin level ( J:179687 )

• in fasted mice

impaired glucose tolerance ( J:179687 )

Genotype
MGI:3776095

cx23

• Allelic Composition: Dock7^m/Dock7⁺; Lepr^db/Lepr⁺
• Genetic Background: BKS.Cg-Dock7^m +/+ Lepr^db/J

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

Genotype
MGI:4361710

cx24

• Allelic Composition: Lepr^db/Lepr^db; Nos3^tm1Unc/Nos3^tm1Unc
• Genetic Background: BKS.Cg-Lepr^db Nos3^tm1Unc

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/body

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

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
type 2 diabetes mellitus		DOID:9352	OMIM:125853 OMIM:601283 OMIM:601407 OMIM:603694 OMIM:608036	J:135864

Genotype
MGI:3775795

cx25

• Allelic Composition: Apoe^tm1Unc/Apoe^tm1Unc; Lepr^db/Lepr^db
• Genetic Background: involves: 129P2/OlaHsd * C57BLKS/J

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 retina vasculature morphology ( J:103714 )

• increase of capillary lesions

• significantly higher number of acellular capillaries

• increased capillary outpouching indicative of early microaneurysms

cardiovascular system

abnormal retina vasculature morphology ( J:103714 )

• increase of capillary lesions

• significantly higher number of acellular capillaries

• increased capillary outpouching indicative of early microaneurysms

Genotype
MGI:5548175

cx26

• Allelic Composition: Gdf15^tm1Sjl/Gdf15^tm1Sjl; Lepr^db/Lepr^db
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * C57BLKS/J

behavior/neurological

increased fluid intake ( J:202996 )

♂ • water intake and urine output are increased at week 9 compared to single Lepr mutants

increased food intake ( J:202996 )

♂ • food intake is increased over single Gdf15 mutants but is similar to single Lepr mutants

cardiovascular system

increased heart weight ( J:202996 )

♂ • increase in heart weight compared to controls, including that in single Lepr mutants

growth/size/body

increased heart weight ( J:202996 )

♂ • increase in heart weight compared to controls, including that in single Lepr mutants

increased body weight ( J:202996 )

♂ • body weight is increased over nondiabetic single Gdf15 mutants but is similar to single Lepr mutants

increased kidney weight ( J:202996 )

♂ • kidney weight is increased to a similar extent as in single Lepr mutants

increased liver weight ( J:202996 )

♂ • liver weight is increased to a similar extent as in single Lepr mutants

homeostasis/metabolism

increased circulating creatinine level ( J:202996 )

♂ • increase in serum creatinine levels compared to controls, including that in single Lepr mutants

hyperglycemia ( 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

increased urine glucose level ( J:202996 )

♂ • urinary glucose loss is higher than in single Lepr mutants at week 14

increased cholesterol level ( J:202996 )

♂ • similar increase in cholesterol level as in single Lepr mutants

increased circulating HDL cholesterol level ( J:202996 )

♂ • similar increase in HDL levels as in single Lepr mutants

albuminuria ( J:202996 )

♂ • similar increase in urinary albumin excretion as in single Lepr mutants

liver/biliary system

increased liver weight ( J:202996 )

♂ • liver weight is increased to a similar extent as in single Lepr mutants

renal/urinary system

increased urine glucose level ( J:202996 )

♂ • urinary glucose loss is higher than in single Lepr mutants at week 14

albuminuria ( J:202996 )

♂ • similar increase in urinary albumin excretion as in single Lepr mutants

abnormal kidney morphology ( 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

increased kidney weight ( J:202996 )

♂ • kidney weight is increased to a similar extent as in single Lepr mutants

glomerulosclerosis ( J:202996 )

♂ • glomerulosclerosis is similar as in single Lepr mutants

polyuria ( J:202996 )

♂ • water intake and urine output are increased at week 9 compared to single Lepr mutants

Genotype
MGI:3839678

cx27

• Allelic Composition: Lepr^db/Lepr^db; Plin1^tm1Chan/Plin1^tm1Chan
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * C57BLKS/J

growth/size/body

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

Genotype
MGI:3720617

cx28

• Allelic Composition: Aqp9^tm1Nlsn/Aqp9^tm1Nlsn; Lepr^db/Lepr^db
• Genetic Background: involves: 129S1/Sv * C57BL/6 * C57BLKS/J

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

Genotype
MGI:3803207

cx29

• Allelic Composition: Lepr^db/Lepr^db; Serpine1^tm1Mlg/Serpine1^tm1Mlg
• Genetic Background: involves: 129S2/SvPas * C57BL/6 * C57BLKS/J

mortality/aging

premature death ( J:127478 )

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

growth/size/body

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

Genotype
MGI:5316083

cx30

• Allelic Composition: Lepr^db/Lepr^db; Rock1^tm1Leiw/Rock1^tm1Leiw
• Genetic Background: involves: 129S7/SvEvBrd * C57BLKS/J * FVB/N

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

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

enlarged kidney ( J:182287 )

• in mice treated with streptozotocin to induce diabetes as in similarly treated Lepr^db homozygotes

increased kidney weight ( J:182287 )

• in mice treated with streptozotocin to induce diabetes 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 )

• in mice treated with streptozotocin to induce diabetes as in similarly treated Lepr^db homozygotes

homeostasis/metabolism

hyperglycemia ( J:182287 )

• in mice treated with streptozotocin to induce diabetes 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

growth/size/body

increased body size ( J:182287 )

• in mice treated with streptozotocin to induce diabetes as in similarly treated Lepr^db homozygotes

increased body weight ( J:182287 )

• in mice treated with streptozotocin to induce diabetes as in similarly treated Lepr^db homozygotes

enlarged kidney ( J:182287 )

• in mice treated with streptozotocin to induce diabetes as in similarly treated Lepr^db homozygotes

increased kidney weight ( J:182287 )

• in mice treated with streptozotocin to induce diabetes as in similarly treated Lepr^db homozygotes

cellular

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

abnormal mitochondrial physiology ( J:182287 )

• mice treated with streptozotocin to induce diabetes exhibit mitochondrial reactive oxygen species production but not as much as in similarly treated Lepr^db homozygotes

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

oxidative stress ( J:182287 )

• mice treated with streptozotocin to induce diabetes exhibit mitochondrial reactive oxygen species production but not as much as in similarly treated Lepr^db homozygotes

Genotype
MGI:5903475

cx31

• Allelic Composition: Lepr^db/Lepr^db; Repin1^tm1.2Arte/Repin1^tm1.2Arte
• Genetic Background: involves: BALB/c * C57BL/6 * C57BLKS/J

growth/size/body

decreased body fat mass ( J:238672 )

• at 20 weeks compared with Lepr^db homozygotes

decreased body weight ( J:238672 )

• at 8 to 20 weeks compared with Lepr^db homozygotes

• however, body length is normal

adipose tissue

decreased body fat mass ( J:238672 )

• at 20 weeks compared with Lepr^db homozygotes

abnormal adipose tissue physiology ( J:238672 )

• reduced inflammatory infiltrate compared with Lepr^db homozygotes

homeostasis/metabolism

decreased circulating glucose level ( J:238672 )

• compared with Lepr^db homozygotes

increased insulin sensitivity ( J:238672 )

• compared with Lepr^db homozygotes

Genotype
MGI:5435319

cx32

• Allelic Composition: Lepr^db/Lepr⁺; Tg(APPswe,PSEN1dE9)85Dbo/0
• Genetic Background: involves: C3H * C57BL/6 * C57BLKS/J

homeostasis/metabolism

amyloidosis ( J:186924 )

• mutants exhibit an increase in expression of amyloid beta protein in plasma compared to Lepr^db heterozygotes, however they do not show amyloid beta plaques yet at 5-7 weeks of age

increased circulating glucose level ( J:186924 )

• nonfasting blood glucose levels are elevated compared to control Lepr^db heterozygotes

• however, fasting blood glucose is normal at 5-7 weeks of age

increased circulating insulin level ( J:186924 )

• nonfasting and fasting hyperinsulinemia

abnormal circulating cholesterol level ( J:186924 )

• elevation in nonfasting plasma cholesterol levels

• however, fasting cholesterol levels are normal

impaired glucose tolerance ( J:186924 )

insulin resistance ( J:186924 )

• mutants exhibit decreased insulin sensitivity

endocrine/exocrine glands

increased pancreatic beta cell mass ( J:186924 )

• increase in beta cell mass and beta cell area compared to control Lepr^db heterozygotes

growth/size/body

growth/size/body region phenotype ( J:186924 )

N • body weight is normal at 5-7 weeks of age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Alzheimer's disease		DOID:10652		J:186924
type 2 diabetes mellitus		DOID:9352	OMIM:125853 OMIM:601283 OMIM:601407 OMIM:603694 OMIM:608036	J:186924

Genotype
MGI:3693608

cx33

• Allelic Composition: Dbsq3^C57BLKS/J/Dbsq3^C3H/HeJ; Lepr^db/Lepr⁺
• Genetic Background: involves: C3H/HeJ * C57BLKS

homeostasis/metabolism

increased circulating glucose level ( J:116038 )

• increased blood glucose concentration in males at 30, 60, and 120 minutes during the intraperitoneal glucose tolerance test

Genotype
MGI:3693605

cx34

• Allelic Composition: Dbsq2^C3H/HeJ/Dbsq2^C3H/HeJ; Lepr^db/Lepr⁺
• Genetic Background: involves: C3H/HeJ * C57BLKS

growth/size/body

increased body weight ( J:116038 )

• increased body weight in males at 7, 8, 9, 10 weeks of age and at sacrifice

Genotype
MGI:3693603

cx35

• Allelic Composition: Dbsq1^C57BLKS/J/Dbsq1^C57BLKS/J; Lepr^db/Lepr^db
• Genetic Background: involves: C3H/HeJ * C57BLKS

adipose tissue

abnormal fat pad morphology ( J:116038 )

• increased fat pad weight in males

Genotype
MGI:3693604

cx36

• Allelic Composition: Dbsq1^C57BLKS/J/Dbsq1^C3H/HeJ; Lepr^db/Lepr^db
• Genetic Background: involves: C3H/HeJ * C57BLKS

adipose tissue

abnormal fat pad morphology ( J:116038 )

• increased fat pad weight in males

Genotype
MGI:3693607

cx37

• Allelic Composition: Dbsq3^C3H/HeJ/Dbsq3^C3H/HeJ; Lepr^db/Lepr⁺
• Genetic Background: involves: C3H/HeJ * C57BLKS

homeostasis/metabolism

increased circulating glucose level ( J:116038 )

• increased blood glucose concentration in males at 30, 60, and 120 minutes during the intraperitoneal glucose tolerance test

Genotype
MGI:3693606

cx38

• Allelic Composition: Dbsq2^C57BLKS/J/Dbsq2^C3H/HeJ; Lepr^db/Lepr⁺
• Genetic Background: involves: C3H/HeJ * C57BLKS

growth/size/body

increased body weight ( J:116038 )

• increased body weight in males at 7, 8, 9, 10 weeks of age and at sacrifice

Genotype
MGI:5552736

cx39

• Allelic Composition: Ccr2^{tm1.1(CCR2)Rodb}/Ccr2^{tm1.1(CCR2)Rodb}; Lepr^db/Lepr^db
• Genetic Background: involves: C57BL/6 * C57BLKS/J

homeostasis/metabolism

abnormal urine protein level ( J:203000 )

• CCX140-B treatment improves albuminuria

renal/urinary system

abnormal urine protein level ( J:203000 )

• CCX140-B treatment improves albuminuria

Genotype
MGI:5707502

cx40

• Allelic Composition: Helz2^tm1Tesa/Helz2^tm1Tesa; Lepr^db/Lepr^db
• Genetic Background: involves: C57BL/6 * C57BLKS/J

growth/size/body

growth/size/body region phenotype ( J:218127 )

N • mice have no protection against obesity on a high fat diet

Genotype
MGI:5828524

cx41

• Allelic Composition: Lepr^db/Lepr^db; Tg(SHBG)4-aGlha/0
• Genetic Background: involves: C57BL/6 * C57BLKS/J * CBA

growth/size/body

obese ( J:232827 )

• progressive increase in body weight from 6 to 12 weeks of age, however a 15-20% reduction in body weight is seen compared to single Lepr^db homozygotes

increased kidney weight ( J:232827 )

increased liver weight ( J:232827 )

• increase in liver weight in both males and females compared to either single heterozygous mice, however liver weight in males is reduced compared to single Lepr^db homozygotes

adipose tissue

abnormal adipose tissue morphology ( J:232827 )

• increase in adipose tissue weight compared to either single heterozygous mice, however visceral adipose tissue weight is reduced compared to single Lepr^db homozygotes

homeostasis/metabolism

abnormal blood homeostasis ( J:232827 )

♂ • plasma levels of SHBG in obese males do not increase from week 4 to week 6 and remain lower at 8 weeks of age unlike in controls and this is due to altered hepatic HNF-4alpha and PPAR-gamma mRNA and protein levels

hyperglycemia ( J:232827 )

• obese mice develop hyperglycemia after 6 weeks of age to a similar extent as single Lepr^db homozygotes

increased circulating testosterone level ( J:232827 )

♂ • total testosterone plasma levels are reduced in obese males

increased circulating insulin level ( J:232827 )

• higher plasma insulin levels in obese males and females comparable to single Lepr^db homozygotes

increased circulating leptin level ( J:232827 )

• higher plasma leptin levels in obese males and females comparable to single Lepr^db homozygotes

increased circulating cholesterol level ( J:232827 )

• obese males and females exhibit higher plasma cholesterol levels comparable to single Lepr^db homozygotes

increased circulating free fatty acids level ( J:232827 )

• higher plasma nonsterified fatty acids level in obese males and females comparable to single Lepr^db homozygotes

increased circulating triglyceride level ( J:232827 )

• obese males and females exhibit higher plasma triglycerides with levels comparable to single Lepr^db homozygotes

increased liver triglyceride level ( J:232827 )

liver/biliary system

increased liver weight ( J:232827 )

• increase in liver weight in both males and females compared to either single heterozygous mice, however liver weight in males is reduced compared to single Lepr^db homozygotes

increased liver triglyceride level ( J:232827 )

hepatic steatosis ( J:232827 )

• mice develop fatty liver

renal/urinary system

increased kidney weight ( J:232827 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
obesity		DOID:9970	OMIM:601665	J:232827

Genotype
MGI:5427610

cx42

• Allelic Composition: Lepr^db/Lepr^db; Tg(Fabp4-Fcor)1Jnak/0
• Genetic Background: involves: C57BL/6 * C57BLKS/J * DBA/2

homeostasis/metabolism

increased oxygen consumption ( J:184684 )

• compared with Lepr^db homozygotes

improved glucose tolerance ( J:184684 )

• compared with Lepr^db homozygotes

increased insulin sensitivity ( J:184684 )

• compared with Lepr^db homozygotes

adipose tissue

decreased abdominal adipose tissue amount ( J:184684 )

• decreased visceral fat compared with Lepr^db homozygotes

• however, subcutaneous and total adipose mass are normal

decreased white fat cell size ( J:184684 )

• compared with Lepr^db homozygotes

growth/size/body

decreased body weight ( J:184684 )

• compared with Lepr^db homozygotes

Genotype
MGI:3529778

cx43

• Allelic Composition: Cdkn1b^tm1Kin/Cdkn1b⁺; Lepr^db/Lepr^db
• Genetic Background: involves: C57BL/6J * C57BLKS/J

behavior/neurological

polyphagia ( J:96047 )

endocrine/exocrine glands

abnormal pancreatic islet morphology ( J:96047 )

• islet mass, but not islet density, is significantly increased compared to Lepr single homozygotes

increased pancreatic beta cell number ( J:96047 )

• 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/body

obese ( J:96047 )

homeostasis/metabolism

hyperglycemia ( J:96047 )

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

increased circulating insulin level ( J:96047 )

hyperlipidemia ( J:96047 )

decreased body temperature ( J:96047 )

Genotype
MGI:3529774

cx44

• Allelic Composition: Cdkn1b^tm1Kin/Cdkn1b^tm1Kin; Lepr^db/Lepr^db
• Genetic Background: involves: C57BL/6J * C57BLKS/J

behavior/neurological

polyphagia ( J:96047 )

endocrine/exocrine glands

abnormal pancreatic islet morphology ( J:96047 )

• islet mass, but not islet density, is significantly increased compared to Lepr single homozygotes

increased pancreatic beta cell number ( J:96047 )

• 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/body

obese ( J:96047 )

homeostasis/metabolism

increased circulating insulin level ( J:96047 )

hyperlipidemia ( J:96047 )

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

decreased body temperature ( J:96047 )