Sketch of Adiponectin Receptors

Hongkui YuHongqiang Ye

Jie NieXiangyu Sun

These authors contributed equally to this work.

introductionAdipose tissue endocrine organ

hypertention

AS

diabetes

Metabolic syndrome

infarction Heart failure

Adiponectin

Adiponectin

introduction

• Adipose tissue endocrine organ secretes adipokines

– plasminogen activator inhibitor-1,– leptin,– resistin– TNF-alpha. –

Adipose tissue endocrine organ

introductionAdipose tissue endocrine organ

Adiponectin is one such adipokine

that has recently attracted much attention.

Adiponectin

Adiponectin

• Reduced adiponectin levels are seen in patients with

Adiponectin and disease

•cardiovascular diseases• hypertension,• metabolic syndrome

•cardiovascular diseases• hypertension,• metabolic syndrome

Adiponectin

• overexpression of adiponectin resulted in marked reduction of atherosclerotic lesion formation

Adiponectin and AS

Adiponectin

Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis.[J]. J Biol Chem.,2003,278(4):2461-2468.

Adiponectin and AS

reduction of atherosclerotic lesion formation

overexpression of adiponectin

Adiponectin

• Adiponectin deficinet– Incresed myocardial infarct size– Myocardial apoptosis– TNF-alpha expression

• Administration of adiponectin– Diminish infarct size– Myocardial apoptosis– TNF-alpha expression

Adiponectin and HF

Adiponectin

• Adiponectin protects against myocardial ischemia-reperfusion injury through

AMPK- and COX-2-dependent mechanisms.

Adiponectin and HF

Nature medicine. 2005.11(10):1096-1103

Adiponectin

Adiponectin and Adiponectin Receptors[J]. Endocr. Rev.Endocrine Reviews,2005,26(3):439-451.

Adiponectin and structure•high molecular weight multimers (HMW)dodecamers and 18 mers

•Homomultimertrimers and hexamers

•full-length or globular fragment

Adiponectin Receptors

Adiponectin Receptors

AdipoR1 and AdipoR2

• integral membrane proteins; • N internal, C external;not GPCR• conserved from yeast to man

Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome[J]. J. Clin. Invest.,2006,116(7):1784-1792.

AdipoR and structure

• C Adiponectin; • N interacts with an adaptor protein, APPL (Adapt

or protein containing Pleckstrin homology domain, Phosphotyrosine-binding domain and a Leucine zipper motif).

AdipoR and structure

AdipoR and structure

•highly expressed in insulin-sensitive tissue

•mediateds

•lipid oxidation,

•glucose uptake

•GLUT4 translocation

•crosstalk

•adiponectin & insulin signalling pathways APPLied mechanics: Uncovering how adiponectin modulates insulin action[J]. Cell Metabolism,2006,4(1):5-6.

lanes: 1, brain; 2, heart; 3, kidney; 4, liver; 5, lung; 6, skeletal muscle; 7, spleen; 8, testis

AdipoR1 and AdipoR2

Cloning of adiponectin receptors that mediate antidiabetic metabolic effects[J]. Nature,2003,423:762-769.

AdipoR and distribution

• AdipoR1 – ubiquitously,

– globular adiponectin

• AdipoR2 – abundantly in the live

– full-length adiponectin

AdipoR1 and AdipoR2

Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome[J]. J. Clin. Invest.,2006,116(7):1784-1792.

Brief summary

Biological function

• AdipoR1 or R2 over-expression • AdipoR1-KO, AdipoR2-KO • AdipoR1/R2-KO

function and AdipoR

AdipoR1 over-expression

• Via AMPK

• Reduce gluconeogenesis – glucose-6-phosphatase– phosphoenolpyruvate carboxykinase 1

• Reduce lipogenesis– sterol regulatory element-binding protein 1

(Srebf1) ↓

function and AdipoR

AdipoR1-KO

• normal and fertile

• impaired glucose tolerance

• insulin resistance

• gluconeogenic enzymes ↑

• Lipogenesis ↑– Srebf-1↑

function and AdipoR

AdipoR1/R2-KO

• abolished adiponectin binding – although T-cadherin express in liver

• tissue triglyceride content↑

• inflammation and oxidative stress ↑

• insulin resistance

• glucose intolerance.

function and AdipoR

Cardiovascular diseasevs

AdipoR1/R2

Cardiovascular vs AdipoR1/R2

• Adiponectin and receptors are expressed in adult ventricular cardiomyocyte

• AdipoR1 /2 non-diseased carotid artery areas– SMC and endothelial cell

• slightly induced atherosclerotic lesions– lipid-enriched macrophages lipid core

Regulation and AdipoR

Cardiovascular vs AdipoR1/R2Regulation and AdipoR

AdipoR1 /2 mediate the effects of adiponectin in the subendothelial space and cardiomyocyte in a

autocrine &paracrine way

Mechanism

• cardiac energy β-oxidation of fatty acids• AMPK phosphorylate acetyl coenzyme A carboxyl

ase (ACC)• malonyl-CoA↓• Carnitine palmitoyltransferase-1 (CPT-1)

Regulation and AdipoR

Lehninger 4th, FIGURE 17–6

MechanismRegulation and AdipoR

Carnitine palmitoyltransferase-1

AMPK ACC-Pimalonyl-

CoA↓CPT-1↑

AdipoR

Lehninger 4th, FIGURE 17–6

MechanismRegulation and AdipoR

Adiponectin modulates carnitine palmitoyltransferase-1 through AMPK signaling cascade in rat cardiomyocytes[J]. Regulatory Peptides,2007,139(1-3):72-79.

Phospho-AMPK

Phospho-ACC

Adiponectin and AdipoRs as Therapeutic Targets

• Up-regulation of plasma adiponectin – PPAR gamma agonists have been shown to incr

ease adiponectin levels

Therapeutic and AdipoR

Adiponectin and AdipoRs as Therapeutic Targets

• Cardiomyocytes Up-regulation of adiponectin receptors

• Rosiglitazone elevate expression of adipone-ctin and adipoR1/2 cultured cardiomyocytes

Therapeutic and AdipoR

Cardiomyocytes

Adiponectin and AdipoRs as Therapeutic Targets

• Macrophages Up-regulation of adiponectin receptors

• LXR (liver X receptors) agonist ↑AdipoR1/2

• PPAR alpha and PPAR gamma activators ↑AdipoR2

Therapeutic and AdipoR

macrophages

OsmotinOsmotin

Adiponectin and AdipoRs as Therapeutic Targets

• development of AdipoRs agonists

Therapeutic and AdipoR

• Osmotin pathogenesis-related (PR)-5 family• Plant defense protein in tobacco

• activate AMP kinase in C2C12myocytes. • Stable remain active in contact with the digestive

or respiratory systems.

Therapeutic and AdipoR

Summary

hypertention

AS

diabetes

Metabolic syndrome

Heart failure

Adiponectin

AdipoRs

Osmotin

References

• [1] Yamauchi T, Kamon J, Waki H, et al. Globular adiponectin protected ob/ob mice from diabetes and ApoE-deficient mice from atherosclerosis.[J]. J Biol Chem.,2003,278(4):2461-2468.

• [2] Kadowaki T, Yamauchi T. Adiponectin and Adiponectin Receptors[J]. Endocr. Rev.Endocrine Reviews,2005,26(3):439-451.

• [3] Kadowaki T, Yamauchi T, Kubota N, et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome[J]. J. Clin. Invest.,2006,116(7):1784-1792.

• [4] Toshimasa Yamauchi, Junji Kamon, Yusuke Ito, et al. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects[J]. Nature,2003,423:762-769.

• [5] Hug C, Wang J, Ahmad N S, et al. T-cadherin is a receptor for hexameric and high-molecular-weight forms of Acrp30/adiponectin[J]. PNAS,2004,101(28):10308-10313.

• [6] Yamauchi T, Nio Y, Maki T, et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions.[J]. Nat Med,2007,13:332–339.

• [7] Atsushi Tsuchida, Toshimasa Yamauchi, Yusuke Ito, et al. Insulin/Foxo1 Pathway Regulates Expression Levels of Adiponectin Receptors and Adiponectin Sensitivity[J]. J. Biol. Chem.,2004,279(29):30817-30822.

• [8] Hosch S E, Olefsky J M, Kim J J. APPLied mechanics: Uncovering how adiponectin modulates insulin action[J]. Cell Metabolism,2006,4(1):5-6.

• [9] Ding Gl, Qin Qh, He N E A. Adiponectin and its receptors are expressed in adult ventricular cardiomyocytes and upregulated by activation of peroxisome proliferator-activated receptor gamma[J]. J. molecular AND cellular cardiology,2007,43(1):73-84.

• [10] Li L, Wu L, Wang C, et al. Adiponectin modulates carnitine palmitoyltransferase-1 through AMPK signaling cascade in rat cardiomyocytes[J]. Regulatory Peptides,2007,139(1-3):72-79.

• [11] Chinetti G, Zawadski C, Fruchart J C, et al. Expression of adiponectin receptors in human macrophages and regulation by agonists of the nuclear receptors PPAR[alpha], PPAR[gamma], and LXR[J]. Biochemical and Biophysical Research Communications,2004,314(1):151-158.