Peroxisome proliferator-activated receptor gamma

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Peroxisome proliferator-activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor that in humans is encoded by the PPARG gene.[1][2][3]

Tissue distribution

PPARG is mainly present in adipose tissue, colon and macrophages. Two isoforms of PPARG are detected in the human and in the mouse: PPAR-γ1 (found in nearly all tissues except muscle) and PPAR-γ2 (mostly found in adipose tissue and the intestine).[4][5]


PPARG regulates fatty acid storage and glucose metabolism. The genes activated by PPARG stimulate lipid uptake and adipogenesis by fat cells. PPARG knockout mice fail to generate adipose tissue when fed a high-fat diet.[6]

This gene encodes a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors. PPARs form heterodimers with retinoid X receptors (RXRs) and these heterodimers regulate transcription of various genes. Three subtypes of PPARs are known: PPAR-alpha, PPAR-delta, and PPAR-gamma. The protein encoded by this gene is PPAR-gamma and is a regulator of adipocyte differentiation. Alternatively spliced transcript variants that encode different isoforms have been described.[7]

Many naturally occurring agents directly bind with and activate PPAR gamma. These agents include various polyunsaturated fatty acids like arachidonic acid and arachidonic acid metabolites such as certain members of the 5-Hydroxyicosatetraenoic acid and 5-oxo-eicosatetraenoic acid family, e.g. 5-oxo-15(S)-HETE and 5-oxo-ETE or 15-Hydroxyicosatetraenoic acid family including 15(S)-HETE, 15(R)-HETE, and 15(S)-HpETE.[8][9][10] The phytocannabinoid tetrahydrocannabinol (THC),[11] its metabolite THC-COOH, and its synthetic analog ajulemic acid (AJA).[12] The activation of PPAR gamma by these and other ligands may be responsible for inhibiting the growth of cultured human breast, gastric, lung, prostate and other cancer cell lines.[13]


Peroxisome proliferator-activated receptor gamma has been shown to interact with:

Clinical relevance

PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis, and cancer. PPAR-gamma agonists have been used in the treatment of hyperlipidaemia and hyperglycemia.[24][25] PPAR-gamma decreases the inflammatory response of many cardiovascular cells, particularly endothelial cells.[26] PPAR-gamma activates the PON1 gene, increasing synthesis and release of paraoxonase 1 from the liver, reducing atherosclerosis.[27]

Many insulin sensitizing drugs (namely, the thiazolidinediones) used in the treatment of diabetes activate PPARG as a means to lower serum glucose without increasing pancreatic insulin secretion. Activation of PPARG is more effective for skeletal muscle insulin resistance than for insulin resistance of the liver.[28] Different classes of compounds which activate PPARG weaker than thiazolidinediones (the so-called “partial agonists of PPARgamma”) are currently studied with the hope that such compounds would be still effective hypoglycemic agents but with fewer side effects.[29]

The medium-chain triglyceride decanoic acid has been shown to be a partially-activating PPAR-gamma ligand that does not increase adipogenesis.[30] Activation of PPAR-gamma by decanoic acid has been shown to increase mitochondrial number, increase the mitochondrial enzyme citrate synthase, increase complex I activity in mitochondria, and increase activity of the antioxidant enzyme catalase.[31]

A fusion protein of PPAR-γ1 and the thyroid transcription factor PAX8 is present in approximately one-third of follicular thyroid carcinomas, to be specific those cancers with a chromosomal translocation of t(2;3)(q13;p25), which permits juxtaposition of portions of both genes.[32][33]


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Further reading

  • Qi C, Zhu Y, Reddy JK (2001). "Peroxisome proliferator-activated receptors, coactivators, and downstream targets". Cell Biochemistry and Biophysics. 32 Spring: 187–204. PMID 11330046.
  • Kadowaki T, Hara K, Kubota N, Tobe K, Terauchi Y, Yamauchi T, Eto K, Kadowaki H, Noda M, Hagura R, Akanuma Y (2002). "The role of PPARgamma in high-fat diet-induced obesity and insulin resistance". Journal of Diabetes and Its Complications. 16 (1): 41–5. doi:10.1016/S1056-8727(01)00206-9. PMID 11872365.
  • Wakino S, Law RE, Hsueh WA (2002). "Vascular protective effects by activation of nuclear receptor PPARgamma". Journal of Diabetes and Its Complications. 16 (1): 46–9. doi:10.1016/S1056-8727(01)00197-0. PMID 11872366.
  • Takano H, Komuro I (2002). "Roles of peroxisome proliferator-activated receptor gamma in cardiovascular disease". Journal of Diabetes and Its Complications. 16 (1): 108–14. doi:10.1016/S1056-8727(01)00203-3. PMID 11872377.
  • Stumvoll M, Häring H (August 2002). "The peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism". Diabetes. 51 (8): 2341–7. doi:10.2337/diabetes.51.8.2341. PMID 12145143.
  • Koeffler HP (January 2003). "Peroxisome proliferator-activated receptor gamma and cancers". Clinical Cancer Research. 9 (1): 1–9. PMID 12538445.
  • Puigserver P, Spiegelman BM (February 2003). "Peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1 alpha): transcriptional coactivator and metabolic regulator". Endocrine Reviews. 24 (1): 78–90. doi:10.1210/er.2002-0012. PMID 12588810.
  • Takano H, Hasegawa H, Nagai T, Komuro I (May 2003). "The role of PPARgamma-dependent pathway in the development of cardiac hypertrophy". Drugs of Today. 39 (5): 347–57. doi:10.1358/dot.2003.39.5.799458. PMID 12861348.
  • Rangwala SM, Lazar MA (June 2004). "Peroxisome proliferator-activated receptor gamma in diabetes and metabolism". Trends in Pharmacological Sciences. 25 (6): 331–6. doi:10.1016/ PMID 15165749.
  • Cuzzocrea S (July 2004). "Peroxisome proliferator-activated receptors gamma ligands and ischemia and reperfusion injury". Vascular Pharmacology. 41 (6): 187–95. doi:10.1016/j.vph.2004.10.004. PMID 15653094.
  • Savage DB (January 2005). "PPAR gamma as a metabolic regulator: insights from genomics and pharmacology". Expert Reviews in Molecular Medicine. 7 (1): 1–16. doi:10.1017/S1462399405008793. PMID 15673477.
  • Pégorier JP (April 2005). "[PPAR receptors and insulin sensitivity: new agonists in development]". Annales d'Endocrinologie. 66 (2 Pt 2): 1S10–7. PMID 15959400.
  • Tsai YS, Maeda N (April 2005). "PPARgamma: a critical determinant of body fat distribution in humans and mice". Trends in Cardiovascular Medicine. 15 (3): 81–5. doi:10.1016/j.tcm.2005.04.002. PMID 16039966.
  • Gurnell M (December 2005). "Peroxisome proliferator-activated receptor gamma and the regulation of adipocyte function: lessons from human genetic studies". Best Practice & Research. Clinical Endocrinology & Metabolism. 19 (4): 501–23. doi:10.1016/j.beem.2005.10.001. PMID 16311214.
  • Cecil JE, Watt P, Palmer CN, Hetherington M (June 2006). "Energy balance and food intake: the role of PPARgamma gene polymorphisms". Physiology & Behavior. 88 (3): 227–33. doi:10.1016/j.physbeh.2006.05.028. PMID 16777151.
  • Rousseaux C, Desreumaux P (2007). "[The peroxisome-proliferator-activated gamma receptor and chronic inflammatory bowel disease (PPARgamma and IBD)]". Journal De La Societe De Biologie. 200 (2): 121–31. doi:10.1051/jbio:2006015. PMID 17151549.
  • Eriksson JG (April 2007). "Gene polymorphisms, size at birth, and the development of hypertension and type 2 diabetes". The Journal of Nutrition. 137 (4): 1063–5. doi:10.1093/jn/137.4.1063. PMID 17374678.
  • Tönjes A, Stumvoll M (July 2007). "The role of the Pro12Ala polymorphism in peroxisome proliferator-activated receptor gamma in diabetes risk". Current Opinion in Clinical Nutrition and Metabolic Care. 10 (4): 410–4. doi:10.1097/MCO.0b013e3281e389d9. PMID 17563457.
  • Burgermeister E, Seger R (July 2007). "MAPK kinases as nucleo-cytoplasmic shuttles for PPARgamma". Cell Cycle. 6 (13): 1539–48. doi:10.4161/cc.6.13.4453. PMID 17611413.
  • Papageorgiou E, Pitulis N, Msaouel P, Lembessis P, Koutsilieris M (August 2007). "The non-genomic crosstalk between PPAR-gamma ligands and ERK1/2 in cancer cell lines". Expert Opinion on Therapeutic Targets. 11 (8): 1071–85. doi:10.1517/14728222.11.8.1071. PMID 17665979.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.