The adiponectin is one of the most abundant secretory proteins produced by a special type of cells known as adipocyte, adipose tissue characteristics. It is responsible for increasing sensitivity to insulin and is involved in energy homeostasis and obesity.
The human adiponectin gene was cloned from adipose tissue in 1996, during experiments carried out by Matsuzawa, who named it the most abundant adipose gene transcript-1 (apM1, from the English adipose most abundant gene transcript 1).
Three-dimensional structure of mouse hexameric adiponectin (Source: own work via Wikimedia Commons)
The protein, on the other hand, was identified in blood plasma that same year by Nakano et al.
This hormone contributes to the integration of endocrine and metabolic signals that are related to the control of energy homeostasis. Its expression is induced during adipocyte differentiation and circulates in serum at relatively high concentrations.
Structure
Adiponectin belongs to the complement 1q (C1q) family and can be found in blood plasma in a wide variety of multimeric complexes (of several subunits): trimers, hexamers, and high molecular weight multimers (of more than 18 subunits).
The gene that codes for adiponectin (ADIPOQ) is located on the long arm of chromosome 3 in humans, has 16 kilo bases and has 3 exons. Its expression yields a water-soluble protein, composed of 247 amino acid residues and a molecular weight of just under 30 kDa, with an isoelectric point of 5.42.
Ideogram of the human chromosome. Chromosome 3 highlighted. Source: National Center for Biotechnology Information, US National Library of Medicine
It is made up of four domains: a signal sequence at the N-terminal end, a variable region, a collagen domain (cAd) and a globular C-terminal domain.
In the amino terminal portion, a collagen-like sequence known as the collagen domain is distinguished, which is a region of great importance for the formation of multimers and is highly conserved between species.
The hydroxylation and concomitant glycosylation of lysine residues in the collagen domain of this protein is what enables the formation of trimers, which at the same time can associate with each other to form hexamers and other high molecular weight complexes.
These complexes appear to have specificity for "target" tissues, for example high molecular weight complexes are more active in the liver, while trimers and hexamers act without much distinction in a wide variety of tissues.
The globular region at the C-terminus, called the globular domain or gAd, is homologous to proteins such as collagen VIII and collagen X, as well as complement factor C1q.
Function
In general, it is thought that the hormone adiponectin acts in a relevant way in the regulation of the metabolism of lipids and carbohydrates in various insulin-sensitive tissues.
This acts on different body tissues, since its receptors are expressed in several places. Produced exclusively by adipocytes, adiponectin promotes the biosynthesis of fatty acids and the inhibition of gluconeogenesis in the liver, one of the tissues where its AdipoR2 receptor is found.
Diagram and histological section of adipose tissue (Source: OpenStax College via Wikimedia Commons)
In skeletal muscle, where the AdipoR1 and AdipoR2 receptors are found, it promotes the oxidation of fatty acids and the entry of glucose into the muscle cells.
Adiponectin also improves insulin resistance in some patients, since it reduces the amount of intracellular fat by activating fatty acid oxidation in both muscle and liver.
Certain authors suggest that this hormone also acts as an antioxidant, as an anti-inflammatory agent, and as an anti-arteriosclerotic factor.
Receivers
The different adiponectin complexes appear to have some preference over specific tissues. These tissue-specific interactions occur in response to the differential expression of different types of adiponectin receptors.
Adiponectin receptors (AdipoR) are G-protein coupled receptors belonging to the family of receptors known as PAQR. Two types are known: AdipoR1 and AdipoR2. Both maintain their N-terminal domains in the intracellular space, while their C-terminal domains are exposed to the extracellular space.
Receptors of the AdipoR1 type have 375 amino acids and 42 kDa molecular weight, while receptors of the AdipoR2 type have 311 amino acids and a weight of 35 kDa. Both have 7 transmembrane domains, that is, their structure crosses 7 times the plasma membrane of the cells where they are found.
There is about 70% sequence homology between both receptors, with the exception of their N-terminal ends, which are specific to each one.
Both AdipoR1 and AdipoR2 are expressed in all tissues, although their abundance varies from one to the other. AdipoR1 is primarily in skeletal muscle and AdipoR2 is in both skeletal muscle and liver.
T-cadherin
There is also a “putative” receptor for adiponectin known as T-cadherin, which consists of a single molecule of cadherin that has lost its cytosolic and transmembrane domains, and is bound to the cell surface via glycosylphosphatidylinositol anchors (GPI anchors).
This adiponectin "receptor" is expressed in all tissues, but has been reported most abundantly in the heart, the aortic, carotid, and iliac arteries, and the renal arteries.
Mechanism of action
Although the mechanisms of production and release of adiponectin into the bloodstream are not fully elucidated, it is thought that the signal transduction pathway begins with adiponectin binding to membrane receptors on its target cells.
This hormone induces the activation of AMP-activated protein kinase (AMPK), which occurs through an “adapter” protein that contains a domain of homology to pleckstrin (typical of proteins involved in cell signaling processes) and a domain of phosphotyrosine binding (PTB), plus a leucine 1 closure motif (APPL).
The APPL domain is the one that binds to the intracellular portion of either of the two AdipoR receptors. A small GTPase protein known as Rab5 binds to one of the sites in the leucine closing domain and promotes the membrane translocation of GLUT4, an insulin-regulated glucose transporter.
Furthermore, adiponectin acts on a nuclear transcription factor known as PPARα, which is important from the point of view of protein, lipid, and carbohydrate metabolism, as well as cell differentiation and development.
Normal values
The normal values reported for adiponectin in blood plasma correspond to the multimeric complexes of this protein, whose concentration range is between 5 and 20 micrograms per milliliter, although concentrations of up to 30 micrograms per milliliter have also been documented.
With the above in mind, it is worth mentioning that adiponectin concentrations in plasma vary significantly; women, for example, tend to have higher values than men.
The values of this hormone depend greatly on the nutritional status, the presence or absence of any pathology, etc., but are generally inversely correlated with adiposity and with conditions such as cardiovascular diseases, hypertension and metabolic syndromes.
There are reports that ensure that the plasma concentrations of adiponectin decrease in those patients who suffer from pathological conditions such as insulin resistance and obesity.
References
- Chandran, M., Phillips, SA, Ciaraldi, T., & Henry, RR (2003). Adiponectin: more than just another fat cell hormone? Diabetes care, 26 (8), 2442-2450.
- Hirako, S. (2016). Adiponectin. In Handbook of Hormones (pp. 308-e34B). Academic Press.
- Kadowaki, T., & Yamauchi, T. (2005). Adiponectin and adiponectin receptors. Endocrine reviews, 26 (3), 439-451.
- Kadowaki, T., Yamauchi, T., Kubota, N., Hara, K., Ueki, K., & Tobe, K. (2006). Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. The Journal of clinical investigation, 116 (7), 1784-1792.
- Klein, S., & Romijn, JA (2007). Chapter 35-Obesity. Williams Textbook of Endocrinology, 11, 1568-1569.
- Steyn, FJ, & Chen, C. (2013). Adiponectin.