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 ADIPOQ gene and is produced primarily in adipose tissue, but also in muscle and even in the brain. [7] [8]
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]
Adiponectin is a protein hormone that modulates a number of metabolic processes, including glucose regulation and fatty acid oxidation. [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]
Transgenic mice with increased adiponectin show reduced adipocyte differentiation and increased energy expenditure associated with mitochondrial uncoupling. [19] The hormone plays a role in the suppression of the metabolic derangements that may result in type 2 diabetes, [16] obesity, atherosclerosis, [12] non-alcoholic fatty liver disease (NAFLD) and an independent risk factor for metabolic syndrome. [20] Adiponectin in combination with leptin has been shown to completely reverse insulin resistance in mice. [21] Adiponectin enhances insulin sensitivity primarily though regulation of fatty acid oxidation and suppression of hepatic glucose production . [22]
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]
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]
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]
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 acids eicosapentaenoic 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]
Adiponectin effects:
Regulation of adiponectin
A low level of adiponectin is an independent risk factor for developing:
Lower levels of adiponectin are associated with ADHD in adults. [48]
Adiponectin levels were found to be increased in rheumatoid arthritis patients responding to DMARDs or TNF inhibitor therapy. [49]
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]
Circulating levels of adiponectin can indirectly be increased through lifestyle modifications and certain medications such as statins. [53]
A small molecule adiponectin receptor AdipoR1 and AdipoR2 agonist, AdipoRon, has been reported. [54] 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. [32]
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]
Leptin is a protein hormone predominantly made by adipocytes. Its primary role is likely to regulate long-term energy balance.
Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important regulatory hormone in lipolysis is insulin; lipolysis can only occur when insulin action falls to low levels, as occurs during fasting. Other hormones that affect lipolysis include leptin, glucagon, epinephrine, norepinephrine, growth hormone, atrial natriuretic peptide, brain natriuretic peptide, and cortisol.
Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue. Brown adipose tissue is found in almost all mammals.
Adipose tissue is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and a variety of immune cells such as adipose tissue macrophages. Its main role is to store energy in the form of lipids, although it also cushions and insulates the body.
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. In cell culture, adipocyte progenitors can also form osteoblasts, myocytes and other cell types.
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 peptide hormone derived from adipose tissue that in humans is encoded by the RETN gene.
Ghrelin is a hormone primarily produced by enteroendocrine cells of the gastrointestinal tract, especially the stomach, and is often called a "hunger hormone" because it increases the drive to eat. Blood levels of ghrelin are highest before meals when hungry, returning to lower levels after mealtimes. Ghrelin may help prepare for food intake by increasing gastric motility and stimulating the secretion of gastric acid.
The adipokines, or adipocytokines are cytokines secreted by adipose tissue. Some contribute to an obesity-related low-grade state of inflammation or to the development of metabolic syndrome, a constellation of diseases including, but not limited to, type 2 diabetes, cardiovascular disease and atherosclerosis. The first adipokine to be discovered was leptin in 1994. Since that time, hundreds of adipokines have been discovered.
Perilipin, also known as lipid droplet-associated protein, perilipin 1, or PLIN, is a protein that, in humans, is encoded by the PLIN gene. The perilipins are a family of proteins that associate with the surface of lipid droplets. Phosphorylation of perilipin is essential for the mobilization of fats in adipose tissue.
White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind is brown adipose tissue. White adipose tissue is composed of monolocular adipocytes.
The fatty-acid-binding proteins (FABPs) are a family of transport proteins for fatty acids and other lipophilic substances such as eicosanoids and retinoids. These proteins are thought to facilitate the transfer of fatty acids between extra- and intracellular membranes. Some family members are also believed to transport lipophilic molecules from outer cell membrane to certain intracellular receptors such as PPAR. The FABPs are intracellular carriers that “solubilize” the endocannabinoid anandamide (AEA), transporting AEA to the breakdown by FAAH, and compounds that bind to FABPs block AEA breakdown, raising its level. The cannabinoids are also discovered to bind human FABPs that function as intracellular carriers, as THC and CBD inhibit the cellular uptake and catabolism of AEA by targeting FABPs. Competition for FABPs may in part or wholly explain the increased circulating levels of endocannabinoids reported after consumption of cannabinoids. Levels of fatty-acid-binding protein have been shown to decline with ageing in the mouse brain, possibly contributing to age-associated decline in synaptic activity.
Obesogens are certain chemical compounds that are hypothesised to disrupt normal development and balance of lipid metabolism, which in some cases, can lead to obesity. Obesogens may be functionally defined as chemicals that inappropriately alter lipid homeostasis and fat storage, change metabolic setpoints, disrupt energy balance or modify the regulation of appetite and satiety to promote fat accumulation and obesity.
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.
Adipose triglyceride lipase, also known as patatin-like phospholipase domain-containing protein 2 and ATGL, is an enzyme that in humans is encoded by the PNPLA2 gene. ATGL catalyses the first reaction of lipolysis, where triacylglycerols are hydrolysed to diacylglycerols.
Adipose tissue is an endocrine organ that secretes numerous protein hormones, including leptin, adiponectin, and resistin. These hormones generally influence energy metabolism, which is of great interest to the understanding and treatment of type 2 diabetes and obesity.
Chemerin, also known as retinoic acid receptor responder protein 2 (RARRES2), tazarotene-induced gene 2 protein (TIG2), or RAR-responsive protein TIG2 is a protein that in humans is encoded by the RARRES2 gene.
Adipogenesis is the formation of adipocytes from stem cells. It involves 2 phases, determination, and terminal differentiation. Determination is mesenchymal stem cells committing to the adipocyte precursor cells, also known as lipoblasts or preadipocytes which lose the potential to differentiate to other types of cells such as chondrocytes, myocytes, and osteoblasts. Terminal differentiation is that preadipocytes differentiate into mature adipocytes. Adipocytes can arise either from preadipocytes resident in adipose tissue, or from bone-marrow derived progenitor cells that migrate to adipose tissue.
Lipotoxicity is a metabolic syndrome that results from the accumulation of lipid intermediates in non-adipose tissue, leading to cellular dysfunction and death. The tissues normally affected include the kidneys, liver, heart and skeletal muscle. Lipotoxicity is believed to have a role in heart failure, obesity, and diabetes, and is estimated to affect approximately 25% of the adult American population.
AdipoRon is a selective, orally active, synthetic small-molecule agonist of the adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2). It activates AMPK and PPARα signaling and ameliorates insulin resistance, dyslipidemia, and glucose intolerance in db/db mice. Moreover, AdipoRon has been found to extend the lifespans of db/db mice fed a high-fat diet, as well as improve exercise endurance. The compound was discovered by Japanese researchers in 2013 via screening of a compound library, and is the first orally active, small-molecule agonist of the adiponectin receptors to be identified.
Asprosin is a protein hormone produced by mammals in tissues that stimulates the liver to release glucose into the blood stream. Asprosin is encoded by the gene FBN1 as part of the protein profibrillin and is released from the C-terminus of the latter by specific proteolysis. In the liver, asprosin activates rapid glucose release via a cyclic adenosine monophosphate (cAMP)-dependent pathway.
