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.[5][6] In humans, it is encoded by the ADIPOQgene and is produced primarily in
adipose tissue, but also in muscle and even in the brain.[7][8]
Structure
Adiponectin is a 244-amino-acid-long polypeptide
(protein). It has four distinct regions: 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), but when the three-dimensional structure of the globular region was determined, a striking similarity to
TNFα was observed, despite unrelated protein sequences.[9]
Function
Adiponectin is a protein
hormone that modulates a number of metabolic processes, including
glucose regulation and
fatty acidoxidation.[10][11][12] Adiponectin is secreted from
adipose tissue (and also from the
placenta in pregnancy[13]) 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.[14] Plasma levels of adiponectin are lower in obese subjects than in lean subjects.[15] Many studies have found adiponectin to be inversely correlated with body mass index in patient populations.[16] However, a meta analysis was not able to confirm this association in healthy adults.[17] Circulating adiponectin concentrations increase during caloric restriction in animals and humans, such as in patients with
anorexia nervosa. Furthermore, a recent study suggests that adipose tissue within bone marrow, which increases during caloric restriction, contributes to elevated circulating adiponectin in this context.[18]
Adiponectin is secreted into the bloodstream, where it accounts for about 0.01% of all plasma protein at around 5-10 μg/mL. In adults, plasma concentrations are higher in females than males, and are reduced in diabetics compared to nondiabetics. Weight reduction significantly increases circulating concentrations.[23]
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.[15] High-molecular-weight adiponectin was further found to be associated with a lower risk of diabetes with similar magnitude of association as total adiponectin.[24] However,
coronary artery disease has been found to be positively associated with high molecular weight adiponectin, but not with low molecular weight adiponectin.[25]
Adiponectin exerts some of its weight-reduction effects via the
brain. This is similar to the action of
leptin;[26] adiponectin and leptin can act synergistically.
Adiponectin promoted
synaptic and memory function in the brain.[27] Humans with lower levels of adiponectin have reduced cognitive function.[27]
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.[8] Six months of exercise has been shown in rats to double muscle AdipoR1.[8]
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.[30][31]
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.[32]
Discovery
Adiponectin was first characterised in 1995 in differentiating 3T3-L1 adipocytes (Scherer PE et al.).[33] In 1996 it was characterised in mice as the mRNA transcript most highly expressed in adipocytes.[7] In 2007, adiponectin was identified as a
transcript highly expressed in preadipocytes[34] (precursors of fat cells) differentiating into
adipocytes.[34][35]
The human homologue was identified as the most abundant transcript in adipose tissue. Contrary to expectations, despite being produced in
adipose tissue, adiponectin was found to be decreased in
obesity.[12][16][26][11] 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.[26][34][36][37][38][39] 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, an isoquinoline alkaloid, has been shown to increase adiponectin expression,[40] which partly explains its beneficial effects on metabolic disturbances. Mice fed the
omega-3 fatty acidseicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA) have shown increased plasma adiponectin.[41]Curcumin,
capsaicin,
gingerol, and
catechins have also been found to increase adiponectin expression.[42]
Phylogenetic distribution includes expression in birds[43] and fish.[44]
A low adiponectin to
leptin ratio has been found in patients with
COVID-19 pneumonia compared to healthy controls.[50]
Exercise induced release of adiponectin increased hippocampal growth and led to antidepressive symptoms in mice.[51]
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.[52]
As a medication target
Circulating levels of adiponectin can indirectly be increased through
lifestyle modifications and certain medications such as
statins.[53]
Extracts of sweet potatoes have been reported to increase levels of adiponectin and thereby improve
glycemic control in humans.[55] However, a
systematic review concluded there is insufficient evidence to support the consumption of sweet potatoes to treat
type 2 diabetes mellitus.[56]
Adiponectin is apparently able to cross the
blood-brain-barrier.[51] However, conflicting data on this issue exist.[57] Adiponectin has a
half-life of 2.5 hours in humans.[58]
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