Adiponectin (also referred to as GBP-28, apM1, AdipoQ and Acrp30) is a
protein hormone
Peptide hormones or protein hormones are hormones whose molecules are peptide, or proteins, respectively. The latter have longer amino acid chain lengths than the former. These hormones have an effect on the endocrine system of animals, including h ...
and
adipokine
The adipokines, or adipocytokines (Greek ', fat; ', cell; and ', movement) are cytokines (cell signaling proteins) secreted by adipose tissue. Some contribute to an obesity-related low-grade state of inflammation or to the development of metabolic ...
, which is involved in regulating
glucose levels as well as
fatty acid breakdown. In humans it is encoded by the ''ADIPOQ''
gene and it is produced in primarily in
adipose tissue
Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular e ...
, but also in muscle, and even in the brain.
Structure
Adiponectin is a 244-amino-acid-long polypeptide
(protein). There are four distinct regions of adiponectin. The first is a short signal sequence that targets the hormone for secretion outside the cell; next is a short region that varies between species; the third is a 65-amino acid region with similarity to collagenous proteins; the last is a globular domain. Overall this protein shows similarity to the complement 1Q factors (
C1Q
The complement component 1q (or simply C1q) is a protein complex involved in the complement system, which is part of the innate immune system. C1q together with C1r and C1s form the C1 complex.
Antibodies of the adaptive immune system can bin ...
). However, when the 3-dimensional structure of the globular region was determined, a striking similarity to
TNFα
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
was observed, despite unrelated protein sequences.
Function
Adiponectin is a protein
hormone that modulates a number of metabolic processes, including
glucose regulation and
fatty acid oxidation.
Adiponectin is secreted from
adipose tissue
Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular e ...
(and also from the
placenta in pregnancy
) into the
bloodstream and is very abundant in
plasma relative to many hormones. High adiponectin levels correlate with a lower risk of diabetes mellitus type 2. Plasma levels of adiponectin are lower in obese subjects than in lean subjects.
Many studies have found adiponectin to be inversely correlated with body mass index in patient populations.
However, a meta analysis was not able to confirm this association in healthy adults.
Circulating adiponectin concentrations increase during caloric restriction in animals and humans, such as in patients with
anorexia nervosa
Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gre ...
. Furthermore, a recent study suggests that adipose tissue within bone marrow, which increases during caloric restriction, contributes to elevated circulating adiponectin in this context.
Transgenic mice with increased adiponectin show reduced
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. ...
differentiation and increased energy expenditure associated with mitochondrial
uncoupling.
The hormone plays a role in the suppression of the metabolic derangements that may result in
type 2 diabetes,
obesity,
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no ...
,
non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD), also known as metabolic (dysfunction) associated fatty liver disease (MAFLD), is excessive fat build-up in the liver without another clear cause such as alcohol use. There are two types; non-alcoholic ...
(NAFLD) and an
independent risk factor for
metabolic syndrome.
Adiponectin in combination with
leptin has been shown to completely reverse
insulin resistance
Insulin resistance (IR) is a pathological condition in which 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 glucose (blood sugar ...
in mice.
Adiponectin enhances insulin sensitivity primarily though regulation of fatty acid oxidation and suppression of hepatic glucose production .
Adiponectin is secreted into the bloodstream where it accounts for approximately 0.01% of all plasma protein at around 5-10 μg/mL (mg/L). In adults, plasma concentrations are higher in females than males, and are reduced in diabetics compared to non-diabetics. Weight reduction significantly increases circulating concentrations.
Adiponectin automatically self-associates into larger structures. Initially, three adiponectin molecules bind together to form a homotrimer. The
trimers continue to self-associate and form hexamers or dodecamers. Like the plasma concentration, the relative levels of the higher-order structures are sexually dimorphic, where females have increased proportions of the high-molecular weight forms. Recent studies showed that the high-molecular weight form may be the most biologically active form regarding glucose homeostasis.
High-molecular-weight adiponectin was further found to be associated with a lower risk of diabetes with similar magnitude of association as total adiponectin.
However,
coronary artery disease has been found to be positively associated with high molecular weight adiponectin, but not with low molecular weight adiponectin.
Adiponectin exerts some of its weight reduction effects via the
brain. This is similar to the action of
leptin;
adiponectin and leptin can act synergistically.
Adiponectin promoted
synaptic and memory function in the brain.
Humans with lower levels of adiponectin have reduced cognitive function.
Receptors
Adiponectin binds to a number of receptors. So far, two
receptors
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
have been identified with
homology to
G protein-coupled receptors, and one receptor similar to the cadherin family:
*
Adiponectin receptor 1
Adiponectin receptor 1 (AdipoR1) is a protein which in humans is encoded by the ''ADIPOR1'' gene. It is a member of the progestin and adipoQ receptor (PAQR) family, and is also known as PAQR1.
Structure
Similar to G protein-coupled receptors ( ...
(AdipoR1)
*
Adiponectin receptor 2 (AdipoR2)
*
T-cadherin - CDH13
These have distinct tissue specificities within the body and have different affinities to the various forms of adiponectin. AdipoR1 is enriched in skeletal muscle, whereas AdipoR2 is enriched in liver.
Six months of exercise has been shown in rats to double muscle AdipoR1.
The receptors affect the downstream target
AMP kinase, an important cellular metabolic rate control point. Expression of the receptors is correlated with insulin levels, as well as reduced in mouse models of diabetes, particularly in
skeletal muscle and adipose tissue.
In 2016, the University of Tokyo announced that it would launch an investigation into claims of fabrication of AdipoR1 and AdipoR2 identification data, as accused by an anonymous person/group called
Ordinary_researchers.
[University of Tokyo to investigate data manipulation charges against six prominent research groups](_blank)
ScienceInsider, Dennis Normile, Sep 20, 2016
Discovery
Adiponectin was first characterised in 1995 in differentiating 3T3-L1 adipocytes (Scherer PE et al.). In 1996 it was characterised in mice as the mRNA transcript most highly expressed in adipocytes.
In 2007, adiponectin was identified as a
transcript highly expressed in preadipocytes
(precursors of fat cells) differentiating into
adipocytes
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 ...
.
The human homologue was identified as the most abundant transcript in adipose tissue. Contrary to expectations, despite being produced in
adipose tissue
Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular e ...
, adiponectin was found to be decreased in
obesity.
This downregulation has not been fully explained. The gene was localised to chromosome 3q27, a region highlighted as affecting genetic susceptibility to type 2 diabetes and obesity. Supplementation by differing forms of adiponectin was able to improve
insulin control, blood glucose and triglyceride levels in mouse models.
The gene was investigated for variants that predispose to type 2 diabetes.
Several
single nucleotide polymorphisms in the coding region and surrounding sequence were identified from several different populations, with varying prevalences, degrees of association and strength of effect on type 2 diabetes.
Berberine
Berberine is a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids found in such plants as ''Berberis vulgaris'' (barberry), ''Berberis aristata'' (tree turmeric), ''Mahonia aquifolium'' (Oregon grape), ''Hydras ...
, an isoquinoline alkaloid, has been shown to increase adiponectin expression,
which partly explains its beneficial effects on metabolic disturbances. Mice fed the
omega-3 fatty acids
eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA) have shown increased plasma adiponectin.
Curcumin
Curcumin is a bright yellow chemical produced by plants of the ''Curcuma longa'' species. It is the principal curcuminoid of turmeric (''Curcuma longa''), a member of the ginger family, Zingiberaceae. It is sold as a herbal supplement, cosme ...
,
capsaicin
Capsaicin (8-methyl-''N''-vanillyl-6-nonenamide) ( or ) is an active component of chili peppers, which are plants belonging to the genus '' Capsicum''. It is a chemical irritant for mammals, including humans, and produces a sensation of burni ...
,
gingerol
Gingerol ( gingerol) is a phenolic phytochemical compound found in fresh ginger that activates spice receptors on the tongue. It is normally found as a pungent yellow oil in the ginger rhizome, but can also form a low-melting crystalline solid. T ...
, and
catechin
Catechin is a flavan-3-ol, a type of secondary metabolite providing antioxidant roles in plants. It belongs to the subgroup of polyphenols called flavonoids.
The name of the catechin chemical family derives from '' catechu'', which is the tanni ...
s have also been found to increase adiponectin expression.
Phylogenetic distribution includes expression in birds
and fish.
Metabolic
Adiponectin effects:
* glucose flux
** decreased
gluconeogenesis
** increased
glucose uptake
* lipid catabolism
**
β-oxidation
In biochemistry and metabolism, beta-oxidation is the catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric acid cyc ...
**
triglyceride clearance
*
protection from endothelial dysfunction (important facet of atherosclerotic formation)
*
insulin sensitivity
Insulin resistance (IR) is a pathological condition in which 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 glucose (blood sugar) ...
* weight loss
* control of energy metabolism.
* upregulation of
uncoupling protein
An uncoupling protein (UCP) is a mitochondrial inner membrane protein that is a regulated proton channel or transporter. An uncoupling protein is thus capable of dissipating the proton gradient generated by NADH-powered pumping of protons from th ...
s
* reduction of TNF-alpha
* promotion of
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 t ...
Regulation of adiponectin
* Obesity is associated with decreased adiponectin.
**The exact mechanism of regulation is unknown, but adiponectin could be regulated by post-translational mechanisms in cells.
Hypoadiponectinemia
A low level of adiponectin is an
independent risk factor for developing:
*
Metabolic syndrome
*
Diabetes mellitus
*
Dyslipidemia
Dyslipidemia is an abnormal amount of lipids (e.g. triglycerides, cholesterol and/or fat phospholipids) in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular disease ( ASCVD). ASCVD includes coronary ar ...
*
Obesity
Other
Lower levels of adiponectin are associated with
ADHD
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...
in adults.
Adiponectin levels were found to be increased in
rheumatoid arthritis patients responding to
DMARD
Disease-modifying antirheumatic drugs (DMARDs) comprise a category of otherwise unrelated disease-modifying drugs defined by their use in rheumatoid arthritis to slow down disease progression. The term is often used in contrast to nonsteroidal ...
s or
TNF inhibitor
A TNF inhibitor is a pharmaceutical drug that suppresses the physiologic response to tumor necrosis factor (TNF), which is part of the inflammatory response. TNF is involved in autoimmune and immune-mediated disorders such as rheumatoid arthrit ...
therapy.
A low adiponectin to
leptin ratio has been found in patients with
COVID-19 pneumonia compared to healthy controls.
Exercise induced release of adiponectin increased hippocampal growth and led to antidepressive symptoms in mice.
Several studies have found a positive correlation in caffeine consumption and increased adiponectin levels, although the mechanism for this is unknown and requires more research.
As a medication target
Circulating levels of adiponectin can indirectly be increased through
lifestyle modifications and certain medications such as
statins.
A
small molecule adiponectin receptor AdipoR1 and
AdipoR2 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 ...
,
AdipoRon, has been reported. In 2016, the University of Tokyo announced it was launching an investigation into anonymously made claims of fabricated and falsified data on AdipoR1, AdipoR2, and AdipoRon.
Extracts of sweet potatoes have been reported to increase levels of adiponectin and thereby improve
glycemic control
The term ''diabetes'' includes several different metabolic disorders that all, if left untreated, result in abnormally high concentration of a sugar called glucose in the blood. Diabetes mellitus type 1 results when the pancreas no longer produces ...
in humans. However, a
systematic review concluded there is insufficient evidence to support the consumption of sweet potatoes to treat
type 2 diabetes mellitus
Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urination, ...
.
Adiponectin is apparently able to cross the
blood-brain-barrier.
However, conflicting data on this issue exist.
Adiponectin has a
half-life
Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable ato ...
of 2.5 hours in humans.
References
External links
*
*
*
{{Hormones
Adiponectin receptor agonists
Peptide hormones
Proteins
Obesity