Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases?
Abstract
:1. Introduction
2. Human Aspects of PPARγ in Metabolic Syndrome
2.1. PPARg Polymorphisms Related to Metabolic Traits without Lipodystrophy
2.2. PPARg Mutations Associated with Lipodystrophy
3. Mouse Models for Study the Role of PPARγ in Metabolic Diseases
3.1. PPARγ Full Body Knockout Mice
3.2. Heterozygous PPARγ Mice
3.3. Hypomorph Mouse Model
3.4. Ablation of PPARγ2 Isoform
3.5. PPARγ Mutant Mice
3.6. Tissue Specific Ablation of PPARγ
3.6.1. Adipose-Specific PPARγ Knockout
3.6.2. Muscle-Specific Ablation of PPARγ
3.6.3. Liver-Specific Disruption of PPARγ
3.6.4. PPARγ Ablation in Pancreatic Beta Cells
3.6.5. Disruption of PPARγ in Macrophages and Dendritic cells
4. Testing of Novel PPARγ Modulators in Mice
5. Comparison of Human and Mouse Findings
6. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Polymorphism | Metabolic Traits Involved | References |
---|---|---|
Pro12Ala | T2D | [20,32] |
Monogenic diabetes | [21] | |
Higher BMI | [24,32] | |
Altered insulin levels | [30] | |
Insulin sensitivity | [36] | |
BMI and insulin sensitivity in PCOS | [37] | |
P467L V290M | Insulin resistance, liver steatosis, T2D and hypertension | [43] |
Promoter variants polymorphism rs29722164 rs11128598 rs17793951 rs1151996 rs1175541 rs3856806 | Deterioration of B-cell function | [44] |
V162 | Increase total cholesterol and LDL-cholesterol levels | [45] |
C161T | CHD in patients with T2D | [46] |
C1431T | Altered fasting serum lipids and risk factor for CHD | [47] |
S289C | Dyslipidemia, obesity and hypertension | [48] |
H449L | Hypertriglyceridemia, insulin resistance and hepatic steatosis, FPLD3 | [49] |
R165T L339X | FPLD3 and severe hypertension | [50] |
c.1040A > C | FPLD3, Diabetes Mellitus, hypertension and dyslipidemia | [51] |
Biallelic mutation E138V and R164W | CGL, hypertriglyceridemia, diabetes mellitus, pancreatitis and renal failure | [52] |
Features | Mouse Models | ||||||||
---|---|---|---|---|---|---|---|---|---|
MORE- PG KO [69] | HET-PPARγ [72,75] | HYPO- PPARγ [76] | PPARγ2 KO [78] | Adipo PPARγ KO [88,89] | Sc.M. PPARγ KO [94,95] | Liver PPARγ KO [98] | β-cell PPARγ KO [103] | MΦ PPARγ KO [112] | |
Obesity | No | ↓ | ↓ | No | ↓ (HFD) | ↑ (HFD) | No | No | ↑ (HFD) |
Insuline resistance | Yes | IS | Yes | Yes (male) | unclear | Yes | Yes | No | Yes |
Glucose tolerance | ↓ (male) | ND | ↓ | ↓ | ND | ↓ | ND | NC | ↓ (HFD) |
Type 2 diabetes | Yes (male) | No | ND | ND | Yes | Yes | ND | No | ND |
Lipodystrophy | Yes | No | Yes | Yes | Yes | No | No | ND | ND |
Liver steatosis | No | No | No | No | Yes | ND | No | ND | No |
Hypertension | hypoten. | ND | ND | ND | ND | ND | ND | ND | ND |
Organomegaly | Yes | No | No | No | ND | Yes | No | ND | No |
Food intake | NC | ↓ | NC | NC | ↑ (HFD) | ↓ | NC | ND | ND |
Triglicerides | ↑ | ↓ | ↓ | NC | ↑ | ↑ | ↑ * | ND | NC |
Free fatty acids | ↑ | ↓ | ↑ (fed) | ND | ↑ | ↑ | NC | ND | ND |
Cholesterol | ND | ND | ND | ND | ND | ND | NC | ND | LDL ↓ |
Glucose | ↑ | ND | ↑ (fed) | NC | NC | ↑ | ↑ * | NC | ↑ (HFD) |
Insulin | ↑ | ↓ | ↑ | ND | ↑ | ↑ | ↑ * | NC | ↑ (HFD) |
Leptin | ↓ | ↑ | ↓ | ↓ | ↓ | ↑ | ↑ * | ND | ↑ |
Adiponectin | ↓ | ↑ | ↓ | ↓ | ↓ | ND | ↓ * | ND | ↓ |
TZD effectiveness | ND | Yes | ND | Yes | partial | partial | Yes | Yes | Yes |
Features | Human Mutants | Mouse Mutants | ||||
---|---|---|---|---|---|---|
P12A Mutant [20] | P467L Mutant [43,65] | F388L Mutant [64] | Biallelic E138V R164W [52] | P12A Mutant [85] | P465L Mutant [81] | |
Obesity | Yes | No | No | No | No | No |
Insuline resistance | Yes | Yes | Yes | Yes | IS | No |
Glucose tolerance | ND | ↓ | ND | ND | ↑ | ↑ |
Type 2 diabetes | Yes | Yes | Yes | Yes | No | No |
Lipodystrophy | No | No | FPLD3 | CGL | No | redistr. |
Liver steatosis | ND | ND | No | ND | ND | ND |
Hypertension | ND | Yes | Yes | No | ND | Yes |
Organomegaly | No | ND | No | Yes | No | ND |
Food intake | ND | ND | ND | ND | NC | NC |
Triglicerides | ↑ | ↑ | ↑ | ↑ | ↓ | NC |
Free fatty acids | ND | ND | ND | ND | NC | NC |
Cholesterol | ↑ | HDL ↓ | HDL ↓ | NC | ↓ | NC |
Glucose | ↑ | ND | ↑ | ↑ | NC | NC |
Insulin | ND | ↑ | ↑ | ↑ | NC | ↑ (HFD) |
Leptin | ND | ND | ND | ↓ | NC | ND |
Adiponectin | ND | ND | ND | ↓ | NC | ND |
TZD effectiveness | ND | ND | partial | ND | partial | ND |
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Pap, A.; Cuaranta-Monroy, I.; Peloquin, M.; Nagy, L. Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases? Int. J. Mol. Sci. 2016, 17, 1236. https://doi.org/10.3390/ijms17081236
Pap A, Cuaranta-Monroy I, Peloquin M, Nagy L. Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases? International Journal of Molecular Sciences. 2016; 17(8):1236. https://doi.org/10.3390/ijms17081236
Chicago/Turabian StylePap, Attila, Ixchelt Cuaranta-Monroy, Matthew Peloquin, and Laszlo Nagy. 2016. "Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases?" International Journal of Molecular Sciences 17, no. 8: 1236. https://doi.org/10.3390/ijms17081236