Physiological Role and Physiological Role and Molecular Mechanism of Molecular Mechanism of

AdiponectinAdiponectin Yumi AndoYumi Ando

Pomona CollegePomona College

Advanced BiochemistryAdvanced Biochemistry

What is Adiponectin??What is Adiponectin??

A signaling molecule that is secreted A signaling molecule that is secreted from white and brown adipose tissue.from white and brown adipose tissue.

Composed of 247 amino acids.Composed of 247 amino acids. Accounts for 0.05 % of total serum Accounts for 0.05 % of total serum

protein.protein. Concentration: 2~20 μg/mL in the blood Concentration: 2~20 μg/mL in the blood

Aside: Adipose TissueAside: Adipose Tissue

Adipose tissue stores & releases energy in the Adipose tissue stores & releases energy in the form of TAG and free fatty acids, respectively.form of TAG and free fatty acids, respectively.

HOWEVER, it is also gaining recognition as an HOWEVER, it is also gaining recognition as an endocrine organ that secretes proteins w/ pro-endocrine organ that secretes proteins w/ pro-inflammatory effects, as well as metabolic inflammatory effects, as well as metabolic effects. effects.

These proteins are called “adipocytokines” or These proteins are called “adipocytokines” or “adipokines”“adipokines”

Examples: adiponectin, leptin, resistin. Examples: adiponectin, leptin, resistin.

Structure of adiponectinStructure of adiponectin

3 domains: Collagen-like domain, globular 3 domains: Collagen-like domain, globular domain, and a signal sequence.domain, and a signal sequence.

Taken from Kadowaki and Yamauchi, 2004

Form homomultimersForm homomultimers 3 main oligomeric 3 main oligomeric

forms: LMW, MMW, forms: LMW, MMW, and HMWand HMW

Oligomerization of Oligomerization of adiponectin depends adiponectin depends on disulphide bonds on disulphide bonds formed by Cys39 formed by Cys39

Taken from Kadowaki and Yamauchi, 2005

Two forms, two different Two forms, two different functions?functions?

Adiponectin can exist as a Adiponectin can exist as a full-lengthfull-length protein or as a protein or as a globularglobular form by form by undergoing proteolytic cleavage, which undergoing proteolytic cleavage, which leaves only the globular head domain leaves only the globular head domain intact.intact.

The globular form of adiponectin appears The globular form of adiponectin appears to stimulate β oxidation in muscle, while to stimulate β oxidation in muscle, while the full-length form appears to decrease the full-length form appears to decrease glucose output by the liver glucose output by the liver

Genetic FactorsGenetic Factors

The gene for adiponectin is located on The gene for adiponectin is located on chromosome 3q27.chromosome 3q27.

This region of the chromosome has also been This region of the chromosome has also been linked to type 2 diabetes.linked to type 2 diabetes.

A SNP located 276 base pairs downstream of A SNP located 276 base pairs downstream of the start site of the adiponectin gene was the start site of the adiponectin gene was associated with increased insulin resistance associated with increased insulin resistance and risk of developing type 2 diabetes. and risk of developing type 2 diabetes.

Why is it important to Why is it important to study adiponectin?study adiponectin?

Evidence strongly suggests that adiponectin Evidence strongly suggests that adiponectin plays a role in the pathophysiology of type 2 plays a role in the pathophysiology of type 2 diabetes and other metabolic syndrome diabetes and other metabolic syndrome diseases!!diseases!!

Correlation between Correlation between adiponectin and insulin adiponectin and insulin

resistanceresistance Obesity and type 2 diabetes are Obesity and type 2 diabetes are

associated with decreased adiponectin associated with decreased adiponectin levels levels

Reduced plasma adiponectin is also Reduced plasma adiponectin is also seen in people with conditions such as seen in people with conditions such as cardiovascular disease and hypertension, cardiovascular disease and hypertension, diseases that are often associated with diseases that are often associated with insulin resistance.insulin resistance.

In a study conducted by Hotta et al., In a study conducted by Hotta et al., (2001), plasma adiponectin levels (2001), plasma adiponectin levels dropped in parallel to the observation of dropped in parallel to the observation of decreased insulin sensitivity in rhesus decreased insulin sensitivity in rhesus monkeys. monkeys.

Monkeys w/ decreased insulin sensitivity Monkeys w/ decreased insulin sensitivity developed type 2 diabetes. developed type 2 diabetes.

Molecular Mechanism of Molecular Mechanism of AdiponectinAdiponectin

A study conducted A study conducted by Yamauchi et al. by Yamauchi et al. (2001) showed that (2001) showed that adiponectin adiponectin stimulates glucose stimulates glucose utilization and fatty utilization and fatty acid oxidation by acid oxidation by activating AMP-activating AMP-activated protein activated protein kinase. kinase.

Adiponectin ReceptorsAdiponectin Receptors

There are two known ones: AdipoR1 and AdipoR2. There are two known ones: AdipoR1 and AdipoR2. They are integral membrane proteins that have seven They are integral membrane proteins that have seven

transmembrane domains where the N terminus is transmembrane domains where the N terminus is located within the cell, and the C terminus is external. located within the cell, and the C terminus is external.

AdipoR1 is a receptor that mainly binds globular AdipoR1 is a receptor that mainly binds globular adiponectin, while AdipoR2 binds to full-length adiponectin, while AdipoR2 binds to full-length adiponectin adiponectin

AdipoR1 is abundant in skeletal muscle. On the other AdipoR1 is abundant in skeletal muscle. On the other hand, AdipoR2 is most expressed in the liver. hand, AdipoR2 is most expressed in the liver.

Possible therapeutic Possible therapeutic strategies…strategies…

3 methods have been studied.3 methods have been studied.

Upregulation of adiponectinUpregulation of adiponectin Upregulation of adiponectin receptorsUpregulation of adiponectin receptors Development of adiponectin receptor Development of adiponectin receptor

agonistsagonists

OsmotinOsmotin

potential agonist for adiponectin!!potential agonist for adiponectin!! It is a plant protein that is implicated in It is a plant protein that is implicated in

the plant defense system. Causes the plant defense system. Causes apoptosis in yeast. apoptosis in yeast.

adiponectin and osmotin were able to adiponectin and osmotin were able to induce phosphorylation of AMP kinase in induce phosphorylation of AMP kinase in C2C12 myocytes. C2C12 myocytes.

5 things to remember…5 things to remember…

adiponectin is a potent insulin sensitizing molecule.adiponectin is a potent insulin sensitizing molecule. The two forms (globular and full-length) bind to The two forms (globular and full-length) bind to

different receptors and have different effects.different receptors and have different effects. Decreased levels of adiponectin induced by genetic Decreased levels of adiponectin induced by genetic

mutations, obesity, and high fat diets lead to insulin mutations, obesity, and high fat diets lead to insulin resistance and pathological conditions such as type 2 resistance and pathological conditions such as type 2 diabetes.diabetes.

Adiponectin activates signaling cascades that Adiponectin activates signaling cascades that eventually increase glucose uptake by muslce, eventually increase glucose uptake by muslce, increase fatty acid oxidation by muscle and liver, and increase fatty acid oxidation by muscle and liver, and decrease gluconeogenesis in the liver.decrease gluconeogenesis in the liver.

In the future, Osmotin could be used as a novel In the future, Osmotin could be used as a novel therapeutic method for hypoadiponectinemia. therapeutic method for hypoadiponectinemia.

ReferencesReferences

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