PRDM16
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PR domain containing 16, also known as PRDM16, is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
which in humans is encoded by the ''PRDM16''
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 ...
. PRDM16 acts as a transcription coregulator that controls the development of brown adipocytes in
brown adipose tissue Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue (or white fat). Brown adipose tissue is found in almost all mammals. Classification of brown fat refers to two distinct cell populations with si ...
. Previously, this coregulator was believed to be present only in brown adipose tissue, but more recent studies have shown that PRDM16 is highly expressed in subcutaneous
white adipose tissue White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind is brown adipose tissue. White adipose tissue is composed of monolocular Adipocyte, adipocytes. In humans, the healthy body fat percent ...
as well.


Function

The protein encoded by this gene is a
zinc finger A zinc finger is a small protein structural motif that is characterized by the coordination of one or more zinc ions (Zn2+) which stabilizes the fold. The term ''zinc finger'' was originally coined to describe the finger-like appearance of 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 ...
. PRDM16 controls the cell fate between muscle and
brown fat Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue (or white fat). Brown adipose tissue is found in almost all mammals. Classification of brown fat refers to two distinct cell populations with si ...
cells. Loss of PRDM16 from brown fat precursors causes a loss of brown fat characteristics and promotes muscle differentiation.


Clinical significance

The reciprocal translocation t(1;3)(p36;q21) occurs in a subset of
myelodysplastic syndrome A myelodysplastic syndrome (MDS) is one of a group of cancers in which blood cells in the bone marrow do not mature, and as a result, do not develop into healthy blood cells. Early on, no symptoms typically are seen. Later, symptoms may includ ...
(MDS) and
acute myeloid leukemia Acute myeloid leukemia (AML) is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal cells that build up in the bone marrow and blood and interfere with haematopoiesis, normal blood cell production. Sympt ...
(AML). This gene is located near the 1p36.3 breakpoint and has been shown to be specifically expressed in the t(1:3)(p36;q21)-positive MDS/AML. The protein encoded by this gene contains an
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
PR domain. The translocation results in the overexpression of a truncated version of this protein that lacks the PR domain, which may play an important role in the pathogenesis of MDS and AML. Alternatively spliced transcript variants encoding distinct isoforms have been reported.


PRDM16 in BAT

Brown adipose tissue (BAT) oxidizes chemical energy to produce heat. This heat energy can act as a defense against hypothermia and obesity. PRDM16 is highly enriched in brown adipose cells as compared to white adipose cells, and plays a role in these
thermogenic Thermogenic means tending to produce heat, and the term is commonly applied to drugs which increase heat through metabolic stimulation, or to microorganisms which create heat within organic waste. Approximately all enzymatic reaction in the human ...
processes in brown adipose tissue. PRDM16 activates brown fat cell identity and can control the determination of brown adipose fate. A knock-out of PRDM16 in mice shows a loss of brown cell characteristics, showing that PRDM16 activity is important in determining brown adipose fate. Brown adipocytes consist of densely packed mitochondria that contain uncoupling protein 1 (UCP-1). UCP-1 plays a key role in brown adipocyte thermogenesis. The presence of PRDM16 in adipose tissue causes a significant up-regulation of thermogenic genes, such as UCP-1 and CIDEA, resulting in thermogenic heat production. Understanding and stimulating the thermogenic processes in brown adipocytes provides possible therapeutic options for treating
obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...
.


PRDM16 in WAT

White adipose tissue (WAT) primarily stores excess energy in the form of triglycerides. Recent research has shown that PRDM16 is present in subcutaneous white adipose tissue. The activity of PRDM16 in white adipose tissue leads to the production of brown fat-like adipocytes within white adipose tissue, called beige cells (also called brite cells). These beige cells have a brown adipose tissue-like phenotype and actions, including thermogenic processes seen in BAT. In mice, the levels of PRDM16 within WAT, specifically anterior subcutaneous WAT and inguinal subcutaneous WAT, is about 50% that of interscapular BAT, both in protein expression and in mRNA quantity. This expression takes place primarily within mature adipocytes.
Transgenic A transgene is a gene that has been transferred naturally, or by any of a number of genetic engineering techniques, from one organism to another. The introduction of a transgene, in a process known as transgenesis, has the potential to change the ...
aP2-PRDM16 mice were used in a study to observe the effects of PRDM16 expression in WAT. The study found that the presence of PRDM16 in subcutaneous WAT leads to a significant up-regulation of brown-fat selective genes UCP-1, CIDEA, and PPARGC1A. This up-regulation lead to the development of a BAT-like phenotype within the white adipose tissue. Expression of PRDM16 has also been shown to protect against high-fat diet induced weight gain. Seale et al.’s experiment with aP2-PRDM16 transgenic mice and wild type mice showed that transgenic mice eating a 60% high-fat diet had significantly less weight gain than wild type mice on the same diet. Seale et al. determined the weight difference was not due to differences in food intake, as both transgenic and wild type mice were consuming the same amount of food on a daily basis. Rather, the weight difference stemmed from higher energy expenditure in the transgenic mice. Another of Seale et al.’s experiments showed the transgenic mice consumed a greater volume of oxygen over a 72-hour period than the wild type mice, showing a greater amount of energy expenditure in the transgenic mice. This energy expenditure in turn is attributed to PRDM16’s ability to up-regulate UCP-1 and CIDEA gene expression, resulting in thermogenesis. If human WAT expresses PRDM16 as in mice, this WAT could be a potential target for stimulating energy expenditure and combating obesity.


Notes


References

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Further reading

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External links

* {{Transcription factors Transcription factors