Resistin
Encyclopedia
Resistin also known as adipose tissue-specific secretory factor (ADSF) or C/EBP-epsilon-regulated myeloid-specific secreted cysteine-rich protein (XCP1) is a cysteine
-rich protein
that in humans is encoded by the RETN gene
.
In primates, pigs, and dogs, resistin is secreted by immune and epithelial cells, while, in rodents, it is secreted by adipose tissue
. The length of the resistin pre-peptide
in human is 108 amino acid
residues and in the mouse and rat it is 114 aa; the molecular weight is ~12.5 kDa
. Resistin is a cytokine
whose physiologic role has been the subject of much controversy regarding its involvement with obesity
and type II diabetes mellitus (T2DM
).
from the University of Pennsylvania
School of Medicine. It was called "resistin" because of the observed insulin
resistance in mice injected with resistin. Resistin was found to be produced and released from adipose tissue to serve endocrine functions likely involved in insulin resistance
. This idea primarily stems from studies demonstrating that serum
resistin levels increase with obesity in several model systems (humans, rats
, and mice
). Since these observations, further research has linked resistin to other physiological systems such as inflammation
and energy homeostasis
.
This article discusses the current research proposing to link resistin to inflammation and energy homeostasis, including its alleged role in insulin resistance in obese subjects.
or irritation
resulting from leukocyte (neutrophils, mast cells, etc.) accumulation and their secretion of inflammatory, biogenic chemicals such as histamine
, prostaglandin
, and pro-inflammatory cytokines. As cited, it has recently been found that resistin also participates in the inflammatory response.
In further support of its inflammatory profile, resistin has been shown to increase transcriptional events, leading to an increased expression of several pro-inflammatory cytokines including (but not limited to) interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-12 (IL-12), and tumor necrosis factor-α (TNF-α) in an NF-κB-mediated fashion. It has also been demonstrated that resistin upregulates intercellular adhesion
molecule-1 (ICAM1) vascular
cell-adhesion molecule-1 (VCAM1) and CCL2
, all of which are occupied in chemotactic pathways involved in leukocyte recruitment to sites of infection. Resistin itself can be upregulated by interleukins and also by microbial antigens such as lipopolysaccharide
, which are recognized by leukocytes. Taken together, because resistin is reputed to contribute to insulin resistance, results such as those mentioned suggest that resistin may be a link in the well-known association between inflammation and insulin resistance.
In accordance, it is expected that, if resistin does indeed serve as a link between obesity and T2DM while at the same time contributing to the inflammatory response, then we should also observe proportional increases in chronic inflammation in association with obesity and insulin resistance. In fact, recent data have shown that this possibility is indeed the case by demonstrating positive correlations between obesity, insulin resistance, and chronic inflammation, which is believed to be directed in part by resistin signaling. This idea has recently been challenged by a study showing that increased levels of resistin in people with chronic kidney disease are associated with declined renal function and inflammation, but not with insulin resistance. Notwithstanding, regarding resistin and the inflammatory response, we can conclude that resistin does indeed bear features of a pro-inflammatory cytokine, and could act as a key node in inflammatory diseases with or without associated insulin resistance.
and T2DM can be derived from studies showing strong correlations between resistin and obesity. The underlying belief among those in support of this theory is that serum
resistin levels will increase with increased adiposity. Conversely, serum resistin levels have been found to decline with decreased adiposity following medical treatment. Specifically, central obesity
(waistline adipose tissue) seems to be the foremost region of adipose tissue contributing to rising levels of serum resistin. This fact takes on significant implications considering the well understood link between central obesity and insulin resistance; marked peculiarities of T2DM.
Although it seems that resistin levels increase with obesity, can we conclude then that such serum resistin increases are accountable for the insulin resistance
that appears to be associated with increased adiposity? Many researchers in their respective studies have shown that this is indeed the case by finding positive correlations between resistin levels and insulin resistance
. This discovery is further authenticated by studies that confirm a direct correlation between resistin levels and subjects with T2DM. Provided that resistin is at least in part due to the insulin resistance coupled to T2DM, fabricating drugs that specifically target cascades leading to decreased serum resistin in T2DM subjects will deliver immense therapeutic benefits.
supporting the resistin link theory between obesity and T2DM is vast and will most likely continue to grow. Nevertheless, this theory
lacks support from the entire scientific community
at large, as an increasingly greater number of studies presenting contradictory evidences continue to emerge. Such studies found significantly decreased serum concentrations of resistin with increased adiposity suggesting that not only is resistin downregulated in obese subjects but that it also presents itself as an unlikely candidate for linking obesity
to T2DM. Data contradicting the idea that weight loss coincides with decreased serum resistin concentrations have also been presented, finding that it instead matches up with marked increases in serum resistin. In reality, almost all findings (many times elucidated under the same experimental conditions) reported by groups opposing the resistin link theory
are the exact opposite from what those groups that support the theory
have observed. The idea that resistin links obesity
to T2DM is now under even more scrutiny, as recent investigations have confirmed a rather vast expression of resistin in many tissues rather than those only characteristic of obesity such as adipocytes.
With nearly as many scientists against this theory
as those scientists that seem to support it, the likelihood that resistin will ever be viewed as the key node linking obesity
to T2DM in the near-future is very low. The very extent to which these two views oppose each other raises questions about the synchrony of methodology
used in these respective groups, which resulted in polar opposite results. It is unsurprising, however, that a “discovery
” linking T2DM to obesity
via resistin-mediated pathways would not go unchallenged in a highly competitive scientific world. Nevertheless, we can conclude that among this giant debate
lies sufficient evidence
to support the idea that resistin does have some incompletely-defined role in energy homeostasis
while also demonstrating properties that help to incite inflammatory responses
to sites of infection
.
The interchain disulfide bonds of resistin and RELMß are novel in that they are highly solvent when exposed, ranging from 84.6% to 89.5%. An average solvent exposure for all disulfide bonds of 9.9%, and of 16.7% for 1,209 interchain disulfide bonds. Therefore, the most highly uncovered disulfide bonds found for intact proteins are resistin’s disulfides in high-resolution.
The crystal structure shows a multimeric assembly consisting of hexamer-forming disulfide bonds. A Cys6Ser resistin mutant was substantially more potent at the low concentration and had a greater effect than the wild-type resistin at the high concentration. This result suggests that processing of the intertrimer disulfide bonds may reflect a mandatory step toward activation. The results also suggest that both the Cys6Ser-mutant and wild-type resistin target mainly the liver.
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
-rich protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the RETN gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
In primates, pigs, and dogs, resistin is secreted by immune and epithelial cells, while, in rodents, it is secreted by adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
. The length of the resistin pre-peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...
in human is 108 amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues and in the mouse and rat it is 114 aa; the molecular weight is ~12.5 kDa
KDA
KDA may refer to:* Karachi Development Authority* Kongsberg Defence & Aerospace* Kotelawala Defence Academy* Kramer Design Associates* Lithium diisopropylamide, KDA is the potassium analogue of lithium diisopropylamideOr kDa may refer to:...
. Resistin is a cytokine
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
whose physiologic role has been the subject of much controversy regarding its involvement with obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
and type II diabetes mellitus (T2DM
Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...
).
Discovery
Resistin was discovered in 2001 by the group of Dr Mitchell A. LazarMitchell Lazar
Mitchell Lazar is an endocrinologist and physician-scientist widely known for his discovery of the hormone resistin and his contributions to the transcriptional regulation of metabolism.Dr...
from the University of Pennsylvania
University of Pennsylvania
The University of Pennsylvania is a private, Ivy League university located in Philadelphia, Pennsylvania, United States. Penn is the fourth-oldest institution of higher education in the United States,Penn is the fourth-oldest using the founding dates claimed by each institution...
School of Medicine. It was called "resistin" because of the observed insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
resistance in mice injected with resistin. Resistin was found to be produced and released from adipose tissue to serve endocrine functions likely involved in insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
. This idea primarily stems from studies demonstrating that serum
Blood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...
resistin levels increase with obesity in several model systems (humans, rats
RATS
RATS may refer to:* RATS , Regression Analysis of Time Series, a statistical package* Rough Auditing Tool for Security, a computer program...
, and mice
MICE
-Fiction:*Mice , alien species in The Hitchhiker's Guide to the Galaxy*The Mice -Acronyms:* "Meetings, Incentives, Conferencing, Exhibitions", facilities terminology for events...
). Since these observations, further research has linked resistin to other physiological systems such as inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
and energy homeostasis
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
.
This article discusses the current research proposing to link resistin to inflammation and energy homeostasis, including its alleged role in insulin resistance in obese subjects.
Inflammation
Inflammation is the first innate immune response to infectionInfection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
or irritation
Irritation
Irritation or exacerbation, in biology and physiology, is a state of inflammation or painful reaction to allergy or cell-lining damage. A stimulus or agent which induces the state of irritation is an irritant...
resulting from leukocyte (neutrophils, mast cells, etc.) accumulation and their secretion of inflammatory, biogenic chemicals such as histamine
Histamine
Histamine is an organic nitrogen compound involved in local immune responses as well as regulating physiological function in the gut and acting as a neurotransmitter. Histamine triggers the inflammatory response. As part of an immune response to foreign pathogens, histamine is produced by...
, prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
, and pro-inflammatory cytokines. As cited, it has recently been found that resistin also participates in the inflammatory response.
In further support of its inflammatory profile, resistin has been shown to increase transcriptional events, leading to an increased expression of several pro-inflammatory cytokines including (but not limited to) interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-12 (IL-12), and tumor necrosis factor-α (TNF-α) in an NF-κB-mediated fashion. It has also been demonstrated that resistin upregulates intercellular adhesion
Adhesion
Adhesion is any attraction process between dissimilar molecular species that can potentially bring them in close contact. By contrast, cohesion takes place between similar molecules....
molecule-1 (ICAM1) vascular
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
cell-adhesion molecule-1 (VCAM1) and CCL2
CCL2
For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene.Chemokine ligand 2 also known as monocyte chemotactic protein-1 or small inducible cytokine A2 is a protein that in humans is encoded by the CCL2 gene. CCL2 is a small cytokine belonging to the CC...
, all of which are occupied in chemotactic pathways involved in leukocyte recruitment to sites of infection. Resistin itself can be upregulated by interleukins and also by microbial antigens such as lipopolysaccharide
Lipopolysaccharide
Lipopolysaccharides , also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals.-Functions:LPS is the major...
, which are recognized by leukocytes. Taken together, because resistin is reputed to contribute to insulin resistance, results such as those mentioned suggest that resistin may be a link in the well-known association between inflammation and insulin resistance.
In accordance, it is expected that, if resistin does indeed serve as a link between obesity and T2DM while at the same time contributing to the inflammatory response, then we should also observe proportional increases in chronic inflammation in association with obesity and insulin resistance. In fact, recent data have shown that this possibility is indeed the case by demonstrating positive correlations between obesity, insulin resistance, and chronic inflammation, which is believed to be directed in part by resistin signaling. This idea has recently been challenged by a study showing that increased levels of resistin in people with chronic kidney disease are associated with declined renal function and inflammation, but not with insulin resistance. Notwithstanding, regarding resistin and the inflammatory response, we can conclude that resistin does indeed bear features of a pro-inflammatory cytokine, and could act as a key node in inflammatory diseases with or without associated insulin resistance.
Arguments for
Much of what is hypothesized about a resistin role in energy metabolismMetabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
and T2DM can be derived from studies showing strong correlations between resistin and obesity. The underlying belief among those in support of this theory is that serum
Blood serum
In blood, the serum is the component that is neither a blood cell nor a clotting factor; it is the blood plasma with the fibrinogens removed...
resistin levels will increase with increased adiposity. Conversely, serum resistin levels have been found to decline with decreased adiposity following medical treatment. Specifically, central obesity
Central obesity
Abdominal obesity, colloquially known as belly fat or clinically as central obesity, is the accumulation of abdominal fat resulting in an increase in waist size...
(waistline adipose tissue) seems to be the foremost region of adipose tissue contributing to rising levels of serum resistin. This fact takes on significant implications considering the well understood link between central obesity and insulin resistance; marked peculiarities of T2DM.
Although it seems that resistin levels increase with obesity, can we conclude then that such serum resistin increases are accountable for the insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
that appears to be associated with increased adiposity? Many researchers in their respective studies have shown that this is indeed the case by finding positive correlations between resistin levels and insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
. This discovery is further authenticated by studies that confirm a direct correlation between resistin levels and subjects with T2DM. Provided that resistin is at least in part due to the insulin resistance coupled to T2DM, fabricating drugs that specifically target cascades leading to decreased serum resistin in T2DM subjects will deliver immense therapeutic benefits.
Arguments against
The amount of evidenceEvidence
Evidence in its broadest sense includes everything that is used to determine or demonstrate the truth of an assertion. Giving or procuring evidence is the process of using those things that are either presumed to be true, or were themselves proven via evidence, to demonstrate an assertion's truth...
supporting the resistin link theory between obesity and T2DM is vast and will most likely continue to grow. Nevertheless, this theory
Theory
The English word theory was derived from a technical term in Ancient Greek philosophy. The word theoria, , meant "a looking at, viewing, beholding", and referring to contemplation or speculation, as opposed to action...
lacks support from the entire scientific community
Scientific community
The scientific community consists of the total body of scientists, its relationships and interactions. It is normally divided into "sub-communities" each working on a particular field within science. Objectivity is expected to be achieved by the scientific method...
at large, as an increasingly greater number of studies presenting contradictory evidences continue to emerge. Such studies found significantly decreased serum concentrations of resistin with increased adiposity suggesting that not only is resistin downregulated in obese subjects but that it also presents itself as an unlikely candidate for linking obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
to T2DM. Data contradicting the idea that weight loss coincides with decreased serum resistin concentrations have also been presented, finding that it instead matches up with marked increases in serum resistin. In reality, almost all findings (many times elucidated under the same experimental conditions) reported by groups opposing the resistin link theory
Theory
The English word theory was derived from a technical term in Ancient Greek philosophy. The word theoria, , meant "a looking at, viewing, beholding", and referring to contemplation or speculation, as opposed to action...
are the exact opposite from what those groups that support the theory
Theory
The English word theory was derived from a technical term in Ancient Greek philosophy. The word theoria, , meant "a looking at, viewing, beholding", and referring to contemplation or speculation, as opposed to action...
have observed. The idea that resistin links obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
to T2DM is now under even more scrutiny, as recent investigations have confirmed a rather vast expression of resistin in many tissues rather than those only characteristic of obesity such as adipocytes.
With nearly as many scientists against this theory
Theory
The English word theory was derived from a technical term in Ancient Greek philosophy. The word theoria, , meant "a looking at, viewing, beholding", and referring to contemplation or speculation, as opposed to action...
as those scientists that seem to support it, the likelihood that resistin will ever be viewed as the key node linking obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
to T2DM in the near-future is very low. The very extent to which these two views oppose each other raises questions about the synchrony of methodology
Methodology
Methodology is generally a guideline for solving a problem, with specificcomponents such as phases, tasks, methods, techniques and tools . It can be defined also as follows:...
used in these respective groups, which resulted in polar opposite results. It is unsurprising, however, that a “discovery
Discovery (observation)
Discovery is the act of detecting something new, or something "old" that had been unknown. With reference to science and academic disciplines, discovery is the observation of new phenomena, new actions, or new events and providing new reasoning to explain the knowledge gathered through such...
” linking T2DM to obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
via resistin-mediated pathways would not go unchallenged in a highly competitive scientific world. Nevertheless, we can conclude that among this giant debate
Debate
Debate or debating is a method of interactive and representational argument. Debate is a broader form of argument than logical argument, which only examines consistency from axiom, and factual argument, which only examines what is or isn't the case or rhetoric which is a technique of persuasion...
lies sufficient evidence
Evidence
Evidence in its broadest sense includes everything that is used to determine or demonstrate the truth of an assertion. Giving or procuring evidence is the process of using those things that are either presumed to be true, or were themselves proven via evidence, to demonstrate an assertion's truth...
to support the idea that resistin does have some incompletely-defined role in energy homeostasis
Energy balance (biology)
In biology, energy balance is the biological homeostasis of energy in living systems. It is measured with the following equation: Energy intake = internal heat produced + external work + storage. It is also an aspect of bioenergetics, concerning energy flow through living systems.It generally uses...
while also demonstrating properties that help to incite inflammatory responses
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
to sites of infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
.
Structure
Resistin has a high sequence identity (43% in a mature protein). Crystal structures of resistin reveal an unusual composition of several subunits that are held together by non-covalent interactions that make up its structure. Each protein subunit comprises a carboxy-terminal disulfide-rich beta-sandwich "head" domain and an amino-terminal alpha-helical "tail" segment. The alpha-helical segments associate to form three-stranded coiled coils, and surface-exposed interchain disulfide linkages mediate the formation of tail-to-tail hexamers. The globular domain from resistin contains five disulfide bonds (Cys35-Cys88, Cys47-Cys87, Cys56-Cys73, Cys58-Cys75, and Cys62-Cys77). This suggests that the disulfide pattern with be conserved.The interchain disulfide bonds of resistin and RELMß are novel in that they are highly solvent when exposed, ranging from 84.6% to 89.5%. An average solvent exposure for all disulfide bonds of 9.9%, and of 16.7% for 1,209 interchain disulfide bonds. Therefore, the most highly uncovered disulfide bonds found for intact proteins are resistin’s disulfides in high-resolution.
The crystal structure shows a multimeric assembly consisting of hexamer-forming disulfide bonds. A Cys6Ser resistin mutant was substantially more potent at the low concentration and had a greater effect than the wild-type resistin at the high concentration. This result suggests that processing of the intertrimer disulfide bonds may reflect a mandatory step toward activation. The results also suggest that both the Cys6Ser-mutant and wild-type resistin target mainly the liver.