Peroxisome proliferator-activated receptor gamma

The peroxisome-proliferator-activated-receptor-gamma (short: PPARgamma; PPARƴ) is a receptor protein, which together with PPARα [NR1C1] and PPARß [NR1C2] belongs to the superfamily of cytosolic steroid receptors. PPARƴ acts as a ligand-activated transcription factor and is ubiquitously expressed. Both saturated and unsaturated fatty acids, eicosanoids and prostaglandins have been identified as natural ligands of the receptor protein. Saturated fatty acids such as stearic and palmitic acid predominantly bind to PPARα. However, these are rather weak ligands compared to unsaturated fatty acids (e.g. linoleic acid, arachidonic acid, eicosapentaenoic acid).

PPARƴ is localized both in the cytosol and the nucleus of adipocytes and is involved in the differentiation of these cells. PPARs can be activated by physiological as well as pharmacological ligands. After their activation, they bind to a likewise activated retinoid X receptor (RXR) (Mukherjee R et al. 1997). This complex binds to a specific DNA sequence, the so-called DNA response element (PPAR response element short: PPRE) and induces specific gene transcription patterns. The activation of gene transcription causes an increased formation of peroxisomes in the cells.

The activation of PPARγ primarily causes an improvement in glucose metabolism and insulin sensitivity. and macrophages (Deeb S et al. 1998). PPARγ is also a central regulator in adipocyte differentiation and the maintenance of specific adipocyte functions, such as fat storage in white adipose tissue and energy expenditure in brown adipose tissue. The highest expression levels of these receptors are also found in adipose tissue.
Furthermore, insulin resistance mediating adipocytokines (e.g. TNFα, leptin, resistin) are released in a decreased manner (in contrast to the increased release of the antiatherogenic and antidiabetic adiponectin). These changes lead to improvement in insulin sensitivity and glucose tolerance, and improvement in diabetic dyslipidemia with reduction in triglyceride levels and an increase in HDL cholesterol.

Differentiation from preadipocytes to adipocytes proceeds via a transcriptional cascade involving transcription factors of the CAAT/enhancer binding protein (C/EBP) family in addition to PPARγ (Fajas L et al. 2002). As part of this activation, free fatty acid uptake and triglyceride synthesis are promoted. In addition, there is a redistribution from visceral to subcutaneous fat.

Evidence suggests a role for PPARƴ in the pathogenesis of acne (Melnik B et al. 2018).

Furthermore, PPARγ is expressed in cardiovascular tissues (heart, vessels) and mediates protective effects there. Furthermore, the activation of PPARγ leads to anti-inflammatory effects.

Further results identify PPARδ as a key regulator in fat burning in adipose and muscle tissue, making it a hopeful target for the future of drug development. Insulin sensitizers, such as rosiglitazone or pioglitazone, which are used to treat type 2 diabetes mellitus, bind to the PPARγ.

Because the PPARs play an important role in normalizing metabolic dysfunction and reducing cardiovascular risk factors, they have become a "drug target" in modern drug development. Glitazones used in the therapy of insulin-resistant diabetes mellitus target the PPARγ. In current research, PPARs are considered lipid sensors that translate dietary lipid or fatty acid levels into metabolic activity. This can lead to fatty acid depletion on a low-energy diet and fat storage in the body on a high-energy diet.

Prostaglandins represent an important group of PPAR agonists. PGD2 gives rise to 15-deoxy-∆12,14-prostaglandin J2 , which binds to PPARγ and PPARα.

Mutations and polymorphisms of the PPAR gamma protein are known to be associated with various diseases:

• Carotid intimal medial thickness 1 OMIM: 609338
• Insulin resistance, severe, digenic OMIM: 604367
• Partial familial lipodystrophy type 3 OIMI:604367
• Obesity, severe OMIM 601665

1. Deeb S et al (1998) A pro12ala substitution in PPAR-gamma-2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nature Genet 20: 284-287.
2. Fajas L et al (2002) The retinoblastoma-histone deacetylase 3 complex inhibits PPAR-gamma and adipocyte differentiation. Dev. cell 3: 903-910.
3. Fajas L et al (2002) E2Fs regulate adipocyte differentiation. Dev. Cell 3: 39-49.
4. Ludtke A et al (2007) Peroxisomes proliferator-activated receptor-gamma C190S mutation causes partial lipodystrophy. J. Clin. Endocr. Metab. 92: 2248-2255.
5. Melnik B et al (2018) in: Plewig G et al (ed.) Braun-Flaco`s Dermatology, Veneroloy and Allergology. Springer Reference Medicine p.1305.
6. Mukherjee R et al (1997) Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPAR-gamma-2 versus PPAR-gamma-1 and activation with retinoid X receptor agonists and antagonists. J Biol Chem 272: 8071-8076.
7. Savage DB et al(2002) Digenic inheritance of severe insulin resistance in a human pedigree. Nature Genet 31: 379-384.
8. Wang X L et al (1999) Peroxisomes proliferator-activated receptor gamma C161-T polymorphism and coronary artery disease. Cardiovasc. Res. 44: 588-594