# Metabolomics/Hormones/Adiponectin

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## Introduction

Adiponectin (Acrp30) is a protein hormone that is secreted adipocytes, also known as fat cells. The adipocytes are the only producers and secretors of this hormone. Two receptors for adiponectin are known to date, AdipoR1 and AdipoR2; which are expressed on the liver and skeletal muscle. The protein is produced as a monomer and it can then assemble into higher order complexes (trimers, hexamers, oligomers), the full length protein can also be cleaved to produce the globular head. The different forms of the hormone show different signaling affects. This hormone affects a range of metabolic processes such as glucose flux, lipid catabolism and response to insulin. Specifically, the release of adiponectin causes an increased tolerance to glucose as well as an increased sensitivity to insulin in peripheral tissues of the body. Low levels of adiponectin have been linked to increased risk of heart attack, obesity, and type 2 diabetes; while high levels of this hormone show decreased weight gain and risk of heart attack.

## Adiponectin and Mitochondrial Function

Mitochondrial function is crucial for adiponectin production in adipocytes. Rosiglitazone and mitochondrial biogenesis enhancement (Ad-NRF-1) treatments have been discovered to increase adiponectin synthesis. Chemicals that are detrimental to mitochondrial function and mitochondrial biogenesis reduction (mtTFA-specific siRNA) treatments lead to attenuated adiponectin synthesis. The impairment of mitochondrial function has also proven to place stress on the endoplasmic reticulum (ER), which results in overall decreased adiponectin transcription.
It is an established fact that adiponectin synthesis is elevated in small fat cells, as a result of enhanced mitochondrial function. By contrast, hypertrophied fat cells experience decreased adiponectin synthesis, as a result of impaired mitochondrial function. Obese individuals are proven to have a high number of hypertrophied fat cells, which provides an explanation for reduced levels of adiponectin. Researchers have assumed that adiponectin synthesis is regulated by the cellular energy-production system of mitochondria, because adipocytes are known to produce large quantities of adiponectin, when compared to other proteins.
Calcium-handling and protein-folding processes in the ER require large amounts of ATP, glucose deprivation and hypoxia – all of which are stimuli that elicit ER stress. Impaired mitochondrial function has also proven to place stress upon the ER. This stress was reversed in the event of enhanced mitochondrial biogenesis. By comparison, impaired mitochondrial function was discovered to activate c-Jun NH2-terminating kinase (JNK) and the activating transcription factor (ATF3), both of which are proven to be activated in the event of ER stress. JNK and ATF3 inhibition reverses mitochondrial function and reduces adiponectin transcription. This further demonstrates that reduced adiponectin transcription is a result of mitochondrial dysfunction.
Adiponectin expression is also impaired by elevated levels of reactive oxygen species (ROS) and increased CHOP10 expression. These factors inhibit adiponectin gene expression via CCAAT/enhancer-binding protein-binding region interference of the adiponectin gene promoter.
A number of hormones and transcription factors that are involved in adiponectin synthesis have been identified in previous studies. These include TNF- and interleukin-6, which are both known to reduce adiponectin synthesis. These adipocytokines are also believed to contribute to the reduced adiponectin levels in obesity. Researchers have also proven that TNF- reduces mitochondrial biogenesis, while increasing the potential for mitochondrial injury. The impact of rosiglitazone on adiponectin synthesis is believed to involve mechanisms that are independent of mitochondrial function. Specifically, PPAR /retinoid X receptors bind directly to functional PPAR-responsive elements in human adiponectin promoters, which increases the promoter activity.
It has been established that adiponectin levels increase mitochondrial number and function in skeletal muscle via 5-AMP-activated protein kinase activation. This activation has also been proven to stimulate skeletal muscle mitochondrial biogenesis. This presents the potential for mitochondrial or metabolic activity in adipocytes to regulate mitochondrial, metabolic, or insulin activity in skeletal muscle by way of adiponectin.
Researchers have surmised that mitochondrial function is directly linked to adiponectin synthesis in adipocytes. The impaired mitochondrial function in adipose tissue is also believed to contribute to decreased plasma adiponectin levels, during obesity. Adiponectin synthesis has been proven to be onset by the activation of mechanisms involving ER stress, JNK, and ATF3 that result from impaired mitochondrial function. Mitochondrial dysfunction and ER stress have been identified as determinants of insulin resistance, in tissue samples from obese subjects.
Link to article:
http://diabetes.diabetesjournals.org/cgi/content/full/56/12/2973#SEC3

# Resources

1) Mechanisms regulating energy metabolism by adiponectin in obesity and diabetes http://www.biochemsoctrans.org/bst/034/0798/0340798.pdf
This, fairly short, journal article, gives a broad overview of the interaction of the hormone adiponectin on metabolism by looking at its structure, function, and regulation. Adiponectin is a protein hormone that is secreted from fat cells. The authors show that adiponectin’s structure relates to function, adiponectin can exist in multiple forms (monomers, trimers, hexamers, oligomers, and as the globular C-terminal domain) and that each form produces a different affect on different tissues. The article also explains that adiponectin acts by binding to two receptors (AdipoR1 and AdipoR2) and that the expression of the receptors can be changed to regulate the action of adiponectin; also liver and skeletal muscle show different profiles of expression for AdipoR1 and AdipoR2. The authors point out the downstream molecules that adiponectin signaling affects, some of them include: AMP-activated protein kinase (AMPK), p38, and cAMP. The author demonstrated the insulin sensitizing effects of adiponectin by injecting mice with it and by creating knockout mice. Injection of adiponectin increased blood glucose uptake in normal mice and prevented insulin-resistance in obese mice. Expression of globular adiponectin in transgenic ob/ob mice showed decreased insulin resistance and diabetes compared with transgenic ob/ob mice not expressing globular adiponectin. From their research the authors concluded that regulation of adiponectin is complicated; that it plays a role in obesity and diabetes type 2 by affects on glucose uptake and insulin sensitivity.
New Terms:
Adipokines – a group of cytokines secreted by adipose tissue
Hyperinsulinaemia – excessively high levels of insulin in blood
Metabolic syndrome – a combination of disorders that increase risk of cardiovascular disease and diabetes
Pathophysiology – functional changes due to disease
Ameliorating – to make better or improve
2) Adiponectin: A Fat Cell Hormone That Promotes Insulin Sensitivity
http://www.medscape.com/viewarticle/438373 (need to google address to see page: http://www.google.com/search?client=safari&rls=en&q=http://www.medscape.com/viewarticle/438373&ie=UTF-8&oe=UTF-8)
This web resource summarizes speeches and articles about the function of adiponectin. It states that adiponectin increases insulin sensitivity, decreases gluconeogenesis, and activates AMP-activated protein kinase and protein kinase B. It says that research suggests that adiponectin regulation may relate to the distribution, as opposed to amount, of body fat (shown in rats). The article says that regulation of adiponectin secretion is affected by glucocorticoids, proliferators-activated receptor gamma (PPAR) agonists, testosterone, estrogen, and prolactin. The article also explores research looking at defects in adiponectin and insulin resistance; adiponectin gene polymorphisms are shown to be linked to type 2 diabetes. It then goes on to say that further research is being done on adiponectin for potential therapeutic use.
New Terms:
Hyperinsulinemic euglycemic clamp – a test to quantify insulin resistance
Thiazolidinediones – a type of drug used to treat type 2 diabetes
Metformin – a type of drug used to treat type 2 diabetes
Glucocorticoids – a group of hormones produced by the adrenal cortex and involved in carbohydrate, protein, and fat metabolism
Adiposity – synonym for obesity
3) Adiponectin Receptor-1 &-2 (AdipoR1 & AdipoR2) two recently identified receptors
http://www.phoenixbiotech.net/Catalog%20Files/Adiponectin/adiponectin-receptor.htm
This web resource gives an overview of the adiponectin receptors one and two, also known as AdipoR1 and AdipoR2. The article focuses on how the two receptors were discovered and provides summaries for three experiments that were based around adiponectin receptors. This article goes into depth on the different analyses for the receptors including western blot analysis and immuno-staining. Five new words I encountered while reading this resource include: Immunohistochemistry, atherosclerotic lesions, leptin, LXR ligands, and lipolysis. Immunohistochemistry is the microscopic localization of specific antigens in tissues by staining with antibodies labeled with fluorescent or pigmented material. Atherosclerotic lesions are characterized by foam cells derived from cholesterol-loaded macrophages. Leptin is a peptide hormone neurotransmitter produced by fat cells and involved in the regulation of appetite. LXR ligands are metabolites of cholesterol, such as 22(R)-hydroxycholesterol, 24(S),25-epoxycholesterol and 27-hydroxycholesterol, and are known to activate both LXR and LXRβ. Lipolysis is the hydrolysis of fats into fatty acids and glycerol, by lipase. Adiponectin effects gluconeogenesis and glucose uptake via increased tolerance to glucose and increased sensitivity to insulin in peripheral tissues. The receptors for Adiponectin allow it to help regulate these pathways through concentration levels of these receptors and the adiponectin itself.
New Terms:
Immunohistochemistry - A type of assay in which specific antigens are made visible by the use of fluorescent dye or enzyme markers.
Atherosclerotic lesions - Formed via inflammation leading to formation of atheromatous plaques in the arterial tunica intima which then rupture to form lesions.
Leptin - A peptide hormone that is produced by fat cells. It plays a role in body weight regulation by acting on the hypothalamus to suppress appetite and burn fat stored in adipose tissue.
LXR ligands - ligand-activated transcription factors that regulate the expression of genes controlling lipid metabolism.
Lipolysis - The hydrolysis of triglycerides into free fatty acids and glycerol.
4) Reduced response to adiponectin and lower abundance of adiponectin receptor proteins in type 2 diabetic monocytes
http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T36-4SCTWNX-4&_user=47004&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000005018&_version=1&_urlVersion=0&_userid=47004&md5=bac23b7223919347d2bf3f392c20ee6e
This journal resource focuses mainly on the abundance of the adiponectin receptors and the effects of the antidiabetic adipokine adiponectin in monocytes of normal-weight, overweight controls, and type two diabetic patients. The journal goes into specific detail regarding adiponectin resistance in monocytes as well as it’s upregulation of interleukin. The new definition terms I have found while viewing this journal are as follows: antiatherosclerotic, metformin, p38 MAPK, statins, and fibrates. Metformin is an oral antidiabetic agent, C4H11N5, that decreases glucose production by the liver and lowers plasma glucose levels. P38 MAPK is the archetypal member of the third MAPK-related pathway in mammalian cells. Statins are any of a class of lipid-lowering drugs that reduce serum cholesterol levels by inhibiting a key enzyme involved in the biosynthesis of cholesterol. Fibrates are a class of amphipathic carboxylic acids. They are used for a range of metabolic disorders, mainly hypercholesterolemia (high cholesterol), and are therefore hypolipidemic agents. This journal resource reviews adiponectin’s effect as an upregulator for IL-6 and IL-8 through the p38 MAPK pathway. It also touches upon the effect the concentration of adiponectin receptors one and two have on the activity of adiponectin.
New Terms:
Antiatherosclerotic - formation of multiple plaques within the arteries which cause a range of effects to the individual.
Metformin - an antidiabetic drug (trade name Glucophage) prescribed to treat type II diabetes.
p38 MAPK - protein kinase activated by environmental stress such as ultraviolet radiation and osmotic shock and by pro-inflammatory cytokines such as tumor necrosis factor (TNF)
Statins - a class of hypolipidemic agents, used as pharmaceutical agents to lower cholesterol levels in people with or at risk for cardiovascular disease.
Fibrates - a group of cholesterol-moderating drugs in use since the early 1960s that includes bezafibrate, gemfibrozil, and fenofibrate. Fibrates are used primarily to treat high triglyceride levels. They can also help to increase HDL levels.