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 receptors work with other proteins to regulate the expression of speci ...

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 of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

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

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

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).

Gene expression

This gene encodes a member of the peroxisome proliferator-activated receptor (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 is likely to be the major e ...

s (RXRs) and these heterodimers regulate transcription of various genes. Three subtypes of PPARs are known:

PPAR-alpha Peroxisome proliferator-activated receptor alpha (PPAR-α), also known as NR1C1 (nuclear receptor subfamily 1, group C, member 1), is a nuclear receptor protein functioning as a transcription factor that in humans is encoded by the ''PPARA'' gene ...

, 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 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 adipogenesis. I ...

differentiation.

Alternatively spliced Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be in ...

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 or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

have been described. The activity 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 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), by enhancing adiponectin release from fat cells, by inducing FGF21, 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 bind ...

production through

upregulation In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proce ...

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 Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer cel ...

activation in mice. Adiponectin 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 is a multi-step process resulting in the net movement of cholesterol from peripheral tissues back to the liver first via entering the lymphatic system, then the bloodstream. Cholesterol from non-hepatic peripheral ti ...

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 Polyunsaturated fatty acids (PUFAs) are fatty acids that contain more than one double bond in their backbone. This class includes many important compounds, such as essential fatty acids and those that give drying oils their characteristic proper ...

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 structurally related to the saturated arachidic acid found in cupuaçu butter. Its name derives from the New Latin word ''arachi ...

and arachidonic acid metabolites such as certain members of the 5-hydroxyicosatetraenoicacid 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

tetrahydrocannabinol Tetrahydrocannabinol (THC) 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) describes multiple isomers, the term ''THC'' ...

(THC), its metabolite

THC-COOH 11-Nor-9-carboxy-Δ9-tetrahydrocannabinol (11-COOH-THC or THC-COOH), often referred to as 11-nor-9-carboxy-THC or THC-11-oic acid, is the main secondary metabolite of tetrahydrocannabinol (THC) which is formed in the body after cannabis is consu ...

, and its

synthetic Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to: Science * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic o ...

analog ajulemic acid (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 using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with: * Tetrahydrocannabivarin * Cannabidiol * Anandamide * CD36 *

EDF1 Endothelial differentiation-related factor 1 is a protein that in humans is encoded by the ''EDF1'' gene. Function This gene encodes a protein that may regulate endothelial cell differentiation. It has been postulated that the protein function ...

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 ...

* MED1 *

NCOA3 The nuclear receptor coactivator 3 also known as NCOA3 is a protein that, in humans, is encoded by the ''NCOA3'' gene. NCOA3 is also frequently called 'amplified in breast 1' (AIB1), steroid receptor coactivator-3 (SRC-3), or thyroid hormone recept ...

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 ...

NCOA2 NCOA may refer to: *National Change Of Address database (see United States Postal Service) *National Chamber Orchestra of Armenia *National Council on Aging * The Non-commissioned officer, Noncomissioned Officer Academy in the United States Air For ...

* NR0B2 * PPARGC1A * RB1. * miR3666

Research

PPAR-gamma

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

s have been used in the treatment of

hyperlipidaemia Hyperlipidemia is abnormally elevated levels of any or all lipids (fats, cholesterol, or triglycerides) or lipoproteins in the blood. citing: and The term ''hyperlipidemia'' refers to the laboratory finding itself and is also used as an umbre ...

and

hyperglycemia Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even ...

. 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 in ...

) used in the treatment of

diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...

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 condition in which cell (biology), cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...

than for insulin resistance of the liver.

References