Adiponectin

Adiponectin (also referred to as GBP-28, apM1, AdipoQ and Acrp30) is a

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]

Receptors

Adiponectin binds to a number of receptors. So far, two receptors have been identified with homology to G protein-coupled receptors, and one receptor similar to the cadherin family:^[28][29]

• Adiponectin receptor 1 (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.^[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

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.

Phylogenetic distribution includes expression in birds[43] and fish.^[44]

Metabolic

Adiponectin effects:

• glucose flux
  • decreased gluconeogenesis
  • increased glucose uptake^[12][26][37]
• lipid catabolism^[37]
  • β-oxidation^[26]
  • triglyceride clearance^[26]
• protection from endothelial dysfunction (important facet of atherosclerotic formation)
• insulin sensitivity
• weight loss
• control of energy metabolism.^[37]
• upregulation of uncoupling proteins^[19]
• reduction of TNF-alpha
• promotion of reverse cholesterol transport^[45]

Regulation of adiponectin

• Obesity is associated with decreased adiponectin.^[11]
  • The exact mechanism of regulation is unknown, but adiponectin could be regulated by post-translational mechanisms in cells.^[46]

Hypoadiponectinemia

A low level of adiponectin is an

• Metabolic syndrome^[20]
• Diabetes mellitus^{[10][26][34][36][38][39]}
• Dyslipidemia^[10]
• Obesity^[11]
• Hypertension^[47]

Other

Lower levels of adiponectin are associated with

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