Peroxisome proliferator-activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone reverse insulin resistance receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II

nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These intracellular receptors work with other proteins to regulate the ex ...

functioning as a

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...

that in humans is encoded by the ''PPARG''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

Tissue distribution

PPARG is mainly present in

adipose tissue Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, Blood vessel, vascular endothel ...

, 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).

Gene expression

This gene encodes a member of the

peroxisome proliferator-activated receptor In the field of molecular biology, the peroxisome proliferator–activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating gene expression. PPARs play essential roles in regulating cel ...

(PPAR) subfamily of nuclear receptors. PPARs form heterodimers with

retinoid X receptor The retinoid X receptor (RXR) is a type of nuclear receptor that is activated by 9-cis retinoic acid, which is discussed controversially to be of endogenous relevance, and 9-''cis''-13,14-dihydroretinoic acid, which may be an endogenous mamma ...

s (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 Adipocytes, also known as lipocytes and fat cells, are the cell (biology), cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through ...

differentiation.

Alternatively spliced Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

transcript variants that encode different

isoforms A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

have been described. The activity of PPARG can be regulated via phosphorylation through the MEK/ERK pathway. This modification decreases transcriptional activity of PPARG and leads to diabetic gene modifications, and results in insulin insensitivity. For example, the phosphorylation of serine 112 will inhibit PPARG function, and enhance adipogenic potential of fibroblasts.

Function

PPARG regulates fatty acid storage and glucose metabolism. The genes activated by PPARG stimulate lipid uptake and

adipogenesis Adipogenesis is the formation of adipocytes (fat cells) from stem cells. It involves 2 phases, determination, and terminal differentiation. Determination is mesenchymal stem cells committing to the adipocyte precursor cells, also known as lipoblast ...

by fat cells. PPARG

knockout mice A knockout mouse, or knock-out mouse, is a genetically modified mouse (''Mus musculus'') in which researchers have inactivated, or " knocked out", an existing gene by replacing it or disrupting it with an artificial piece of DNA. They are importan ...

are devoid of adipose tissue, establishing PPARG as a master regulator of

differentiation. PPARG increases insulin sensitivity by enhancing storage of fatty acids in fat cells (reducing

lipotoxicity Lipotoxicity is a metabolic syndrome that results from the accumulation of lipid intermediates in non-adipose tissue, leading to cellular dysfunction and death. The tissues normally affected include the kidneys, liver, heart and skeletal muscle. ...

), by enhancing

adiponectin Adiponectin (also referred to as GBP-28, apM1, AdipoQ and Acrp30) is a protein hormone and adipokine, which is involved in regulating glucose levels and fatty acid breakdown. In humans, it is encoded by the ''ADIPOQ'' gene and is produced prima ...

release from fat cells, by inducing

FGF21 Fibroblast growth factor 21 (FGF-21) is a protein that in mammals is encoded by the ''FGF21'' gene. The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family and specifically a member of the endocrine subfamily whi ...

, and by enhancing

nicotinic acid adenine dinucleotide phosphate Nicotinic acid adenine dinucleotide phosphate (NAADP) is a Ca2+-mobilizing second messenger synthesised in response to extracellular stimuli. Like its mechanistic cousins, IP3 and cyclic adenosine diphosphoribose (Cyclic ADP-ribose), NAADP binds ...

production through

upregulation In biochemistry, in the biological context of organisms' regulation of gene expression and production of gene products, downregulation is the process by which a cell decreases the production and quantities of its cellular components, such as R ...

of the

CD38 CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase, is a glycoprotein found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in ...

enzyme. PPARG promotes anti-inflammatory M2 macrophage activation in mice.

Adiponectin Adiponectin (also referred to as GBP-28, apM1, AdipoQ and Acrp30) is a protein hormone and adipokine, which is involved in regulating glucose levels and fatty acid breakdown. In humans, it is encoded by the ''ADIPOQ'' gene and is produced prima ...

induces

ABCA1 ATP-binding cassette transporter ABCA1 (member 1 of human transporter sub-family ABCA), also known as the ''cholesterol efflux regulatory protein'' (CERP) is a protein which in humans is encoded by the ''ABCA1'' gene. This transporter is a major ...

-mediated

reverse cholesterol transport Reverse cholesterol transport (RCT) is a multistep process comprising removal of excess cholesterol from cells in the body and delivery to the liver for excretion into the small intestine. Enhancing reverse cholesterol transport is considered a po ...

by activation of PPAR-γ and LXRα/β. Many naturally occurring agents directly bind with and activate PPAR gamma. These agents include various

polyunsaturated fatty acids In biochemistry and nutrition, a polyunsaturated fat is a fat that contains a polyunsaturated fatty acid (abbreviated PUFA), which is a subclass of fatty acid characterized by a backbone with two or more carbon–carbon double bonds. Some polyunsa ...

arachidonic acid Arachidonic acid (AA, sometimes ARA) is a polyunsaturated omega−6 fatty acid 20:4(ω−6), or 20:4(5,8,11,14). It is a precursor in the formation of leukotrienes, prostaglandins, and thromboxanes. Together with omega−3 fatty acids an ...

and arachidonic acid metabolites such as certain members of the

5-hydroxyicosatetraenoic acid 5-Hydroxyeicosatetraenoic acid (5-HETE, 5(''S'')-HETE, or 5''S''-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. It is produced by diverse cell types in humans and other animal species. These cells may then metabolize the formed 5(' ...

and 5-oxo-eicosatetraenoic acid family, e.g., 5-oxo-15(''S'')-HETE and 5-oxo-ETE or

15-hydroxyicosatetraenoic acid 15-Hydroxyeicosatetraenoic acid (also termed 15-HETE, 15(''S'')-HETE, and 15''S''-HETE) is an eicosanoid, i.e. a metabolite of arachidonic acid. Various cell types metabolize arachidonic acid to 15(''S'')-hydroperoxyeicosatetraenoic acid (15(''S'' ...

family including 15(''S'')-HETE, 15(''R'')-HETE, and 15(''S'')-HpETE, the

phytocannabinoid Cannabinoids () are several structural classes of compounds found primarily in the ''Cannabis'' plant or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoac ...

tetrahydrocannabinol Tetrahydrocannabinol (THC) is a cannabinoid found in cannabis. It is the principal psychoactive constituent of ''Cannabis'' and one of at least 113 total cannabinoids identified on the plant. Although the chemical formula for THC (C21H30O2) de ...

(THC), its metabolite THC-COOH, and its

synthetic Synthetic may refer to: Science * Synthetic biology * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic elements, chemical elements that are not naturally found on Earth and therefore have to be created in ...

analog

ajulemic acid Lenabasum (also known as ajulemic acid, 1',1'-dimethylheptyl-delta-8-tetrahydrocannabinol-11-oic acid, DMH-D8-THC-11-OIC, AB-III-56, HU-239, IP-751, CPL 7075, CT-3, JBT-101, Anabasum, and Resunab) is a synthetic cannabinoid that shows anti-fibro ...

(AJA). 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. During embryogenesis, PPARG first substantially expresses in interscapular brown fat pad. The depletion of PPARG will result in embryonic lethality at E10.5, due to the vascular anomalies in placenta, with no permeation of fetal blood vessels and dilation and rupture of maternal blood sinuses. The expression PPARG can be detected in placenta as early as E8.5 and through the remainder of gestation, mainly located in the primary trophoblast cell in the human placenta. PPARG is required for epithelial differentiation of trophoblast tissue, which is critical for proper placenta vascularization. PPARG agonists inhibit extravillous cytotrophoblast invasion. PPARG is also required for the accumulation of lipid droplets by the placenta.

Interactions

Peroxisome proliferator-activated receptor gamma has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...

with: *

Tetrahydrocannabivarin Tetrahydrocannabivarin (THCV, THV, O-4394, GWP42004) is a Homologous series, homologue of tetrahydrocannabinol (THC) having a propyl (3-carbon) side chain instead of pentyl (5-carbon), making it non-psychoactive in lower doses. It has been shown ...

Cannabidiol Cannabidiol (CBD) is a phytocannabinoid, one of 113 identified cannabinoids in ''Cannabis'', along with tetrahydrocannabinol (THC), and accounts for up to 40% of the plant's extract. Medically, it is an anticonvulsant used to treat multiple f ...

Anandamide Anandamide (ANA), also referred to as ''N''-arachidonoylethanolamine (AEA) is a fatty acid neurotransmitter belonging to the fatty acid derivative group known as N-acylethanolamine (NAE). Anandamide takes its name from the Sanskrit word ''ananda ...

CD36 CD36 (cluster of differentiation 36), also known as platelet glycoprotein 4, fatty acid translocase (FAT), scavenger receptor class B member 3 (SCARB3), and glycoproteins 88 (GP88), IIIb (GPIIIB), or IV (GPIV) is a protein that in humans is enco ...

* EDF1 *

EP300 Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an enzyme that, in humans, is encoded by the ''EP300'' gene. It functions as histone ace ...

HDAC3 Histone deacetylase 3 is an enzyme encoded by the ''HDAC3'' gene in both humans and mice. Function Histones are highly alkaline proteins that package and order DNA into structural units called nucleosomes, which comprise the major protein comp ...

NCOA4 Nuclear receptor coactivator 4, also known as Androgen Receptor Activator (ARA70), is a protein that in humans is encoded by the ''NCOA4'' gene. It plays an important role in ferritinophagy, acting as a cargo receptor, binding to the ferritin hea ...

* NR0B2 * PPARGC1A *

RB1 RB1 may refer to: * Red Bull RB1, a Formula 1 car * Retinoblastoma protein Retinoblastoma (Rb) is a rare form of cancer that rapidly develops from the immature cells of a retina, the light-detecting tissue of the eye. It is the most common pr ...

. * miR3666

Research

PPAR-gamma

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

s have been used in the treatment of

hyperlipidaemia Hyperlipidemia is abnormally high levels of any or all lipids (e.g. fats, triglycerides, cholesterol, phospholipids) or lipoproteins in the blood. citing: and The term ''hyperlipidemia'' refers to the laboratory finding itself and is also use ...

and

hyperglycemia Hyperglycemia is a condition where unusually high amount of glucose is present in blood. It is defined as blood glucose level exceeding 6.9 mmol/L (125 mg/dL) after fasting for 8 hours or 10 mmol/L (180 mg/dL) 2 hours after eating. Blood gluc ...

. Many insulin sensitizing drugs (namely, the

thiazolidinediones The thiazolidinediones , abbreviated as TZD, also known as glitazones after the prototypical drug ciglitazone, are a class of heterocyclic compounds consisting of a five-membered C3NS ring. The term usually refers to a family of drugs used i ...

) used in the treatment of

diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

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 Insulin resistance (IR) is a pathological response in which cells in insulin-sensitive tissues in the body fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia. Insulin is a horm ...

than for insulin resistance of the liver.

References