Table 2.
Tissue-specific effects of TZDs and PPARγ in mouse models.
| Tissue | TZD effect in tissue or cell type |
Tissue-specific PPARγ knockout | Note | |
|---|---|---|---|---|
| Overall effect | TZD effect | |||
|
White Adipose |
-Increased adipogenesis -Increased lipid storage -Increased browning -Increased insulin sensitivity |
Severe lipoatrophy with marked insulin resistance (Wang et al, 2013) |
Not tested, but absent in another model of lipoatrophy (Chao et al, 2000) |
In another knockout model with milder lipodystrophy, the TZD effect was diminished but not lost. (He et al, 2003) |
| Liver | -Decreased hepatic steatosis -Increased insulin sensitivity |
Excess adiposity and whole body insulin resistance (Gavrilova et al, 2003) |
Normal response | Less steatosis is likely via “lipid steal” to adipose, as TZD effect on isolated hepatocytes is lipogenic. |
|
Skeletal Muscle |
-Increased insulin sensitivity -Decreased ectopic lipids (likely indirect effects via “lipid steal” to adipose) |
Excess adiposity and whole body insulin resistance (Norris et al, 2003) |
Normal response | Another knockout model had conflicting results, with no response to TZDs. (Hevener et al, 2003) |
|
Pancreatic beta cells |
-Increased insulin secretion | Altered islet mass but normal glucose homeostasis (Rosen et al, 2003) |
Normal response | Improved beta cell function on TZDs is also due to lower glucose and less insulin demand. |
| Macrophage | -Less M1 pro-inflammatory polarization -More M2 polarization |
Whole body insulin resistance (Hevener et al, 2007) |
Partial response | Macrophages reside in adipose tissue as well as atherosclerotic lesions. |
|
Regulatory T cell (Treg) |
-Increased number of Treg cells in obese visceral fat |
Decreased adipose Treg (Cippolletta et al, 2012) |
No longer significant response |
Effects of TZDs on isolated Treg cells have not yet been reported. |
| Brain | -Increased food intake | Less weight gain on high fat diet (Lu et al 2011) |
Normal but no longer increase food intake |
In brain knockout mice, TZDs restored whole body but not hepatic insulin sensitivity. |
| Kidney | -Fluid retention | No whole body effect reported (Guan et al, 2005) |
No longer retain fluid | Same result in a different knockout model. (Zhang et al, 2005) |
| Bone | -Increased osteoblasts -Decreased osteoclasts -Increased adipocytes |
Not known | Not known | FGF21 deletion eliminates TZDs effects on bone. (Wei et al, 2012) |
|
Cardiac Muscle |
-Cardiac hypertrophy (mice) -Increased lipid storage |
Hypertrophy with normal cardiac function (Duan et al 2005) |
Still induce further cardiac hypertrophy |
There is evidence for PPARγ-independent effects of TZDs on cardiomyocytes. |
|
Vascular Smooth Muscle |
-Reduced atherosclerotic lesions (may also be due to effects on macrophages or endothelial cells) |
Perivascular adipose tissue lost (Chang et al, 2012) |
No longer reduces atheromas (Hamblin et al, 2011) |
Both rosiglitazone and pioglitazone protect against atherosclerosis in mouse models. |
While PPARγ and TZD effects in adipose tissue are best validated, they have been investigated in other tissues and cell types. Many TZD effects are reported in isolated cells or in tissues of a whole organism, and gene targeted “knockout” mice have been generated and studied that lack PPARγ in various tissues.