PPARg Knockout

1. lethal

a) PPARg deficient embryos die at E9.5-E10 (Rosen, Hsu et al. 2002)-(Barak 1999, Kubota 1999)

2. changes in tumor susceptibility

2.1 does 7,12-dimethylbenz[a]anthracene (DMBA) cause more tumors in the heterozygote?

a) DMBA causes tumors at multiple locations in normal animals

b) in PPARg heterozygotes, there were more tumors at all timepoints between 2-16 weeks (Gonzalez and Peters 2001)

1) hypothesis that PPARg is inhibiting DMBA cancers by causing the proliferating cells to differentiate (Gonzalez and Peters 2001)

3. PPARg heterozygote

a) high fat diet-induced fatty liver is not present in the heterozygote, as it is in the wild type (reviewed in (Lowell 1999))

1) higher levels of leptin mRNA and protein levels, due to decreased inhibition of PPARg expression

2) higher leptin decreases food intake and increases energy expenditure protecting the mice from high fat diet-induced obesity and insulin resistance

3) higher leptin may modify insulin sensitivity

b) generation of the mice (Bar-Tana 2001)-(Kubota 1999)

1) higher insulin sensitivity lower plasma insulin, better glucose lowering in response to insulin,

2) TZD treatment stopped the protection these mice had from insulin resistance induced by a high fat diet

c) protected from high fat-diet induced adipocyte hypertrophy, obesity, and insulin resistance (Yamauchi, Waki et al. 2001)-11,12

4. PPARg conditional knockout (Akiyama, Sakai et al. 2002)

a) CRE/lox knockout between the 1st and 2nd exons (Akiyama, Sakai et al. 2002)

b) lower PPARg-responsive genes in response to ligand treatment

1) LPL, CD36, LXRa, and ABCG1 were lower basally, and induction was lower as well (Akiyama, Sakai et al. 2002)

2) lower apoE mRNA in macrophages and apoE protein in total plasma and HDL were observed (Akiyama, Sakai et al. 2002)

5. macrophage knockouts

a) still differentiate from precursors and have normal phagocytosis and inflammatory cytokine production (Clark 2002)-101

b) have no basal CD36 expression, but SR-A is ok (Clark 2002)-101

1) required for IL-4-induced expression in macrophage CD36 (Clark 2002)-101

c) reduced uptake and degradation of OxLDL

d) normal surface markers

e) normal TNFa and IL-6 production after LPS stimulation (Clark 2002)-101

f) following PMA stimulation, PPARg ligands do not further induce IL-6 expresion, as it does in the wild-type cells (Clark 2002)-101

1) 15d-PGJ2 inhibits PMA_induced IL-6 production in wt macrophages just as well as in PPARg-deficient macrophages, showing this response is not dependent on PPARg (Clark 2002)-101

6. colon cancer

a) heterozygotes are more susceptible to tumor formation and death following treatment with azoxymethane (colon cancer carcinogen) in mice (Girnun, Smith et al. 2002)

1) tumors are larger and more morphologically different

2) functional APC gene is needed for the tumor suppressor effect of PPARg (Girnun, Smith et al. 2002)

a) higher b-catenin is present in PPARg heterozygotes

7. PPARg liver knockout and ob/ob whole mouse knockout

a) higher liver weight, higher % liver weight, lower serum FFA, TG, and total cholesterol (Matsusue, Haluzik et al. 2003)

b) ob/ob mice usually have severse obesity and fatty liver these are remedied by coknockout of PPARg (Matsusue, Haluzik et al. 2003)