2007 Fiscal Year Final Research Report Summary
Molecular Interaction between Adipose Function and Metabolic Syndrome
| Project/Area Number |
15081207
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | Kyoto University |
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Principal Investigator |
MASUZAKI Hiroaki Kyoto University, Graduate School of Medicine, Assistant Professor (00291899)
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| Project Period (FY) |
2003 – 2007
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| Keywords | dyslipidemia / interal medicine / hypertension / diabetes / metabolic syndrome / translational research / therapy / adipomics |
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| Research Abstract |
The prevalence of the metabolic syndrome is increasing worldwide, bringing about a parallel rise in the incidence of fatal cardiovascular events. In the ADIPOMICS project, we have focused my attention on molecular mechanism of adipose dysfunction, a central pathophysiology of the metabolic syndrome. The first branch of the study is to elucidate regulatory mechanism of intracellular glucocortiocoid reactivating enzyme, 11β-HSD1 in obese adipose tissue. Glucocorticoid plays a pivotal role in regulating adipose tissue metabolism, function and distribution, and its action on target tissue depends not only on circulating level but on intracellular concentration. Evidence has accumulated that locally-enhanced action of glucocorticoid in adipose tissue via 11β-HSD1 contributes to adipose dysfunction in obesity. In the present study, we revealed that (1) inflammatory cytokine, ceramide signaling pathway and NADPH provided by enzymes involved in pentose phosphate pathway augment the enzyme acti
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vity of 11β-HSD1 in adipose tissue, (2) elevated expression and activity of 11β-HSD1 in obese adipose tissue is reproduced in humans (approved by the ethical committee of Kyoto University, No.553, since 2004), (3) 11β-HSD1 activity is also exaggerated in infiltrated macrophages in obese adipose tissue, and thus (4) inhibition of 11β-HSD1 in obese adipose tissue may be crucial in multifaceted effects of PPARγ agonists. The second branch of the study is to explore the molecular basis of leptin resistance commonly seen in the metabolic syndrome and obesity. Little is known about a role of central melanocortin system in the control of fuel metabolism in the peripheral tissue. Skeletal muscle AMP-activated protein kinase (AMPK) is activated by leptin and serves as a master regulator of fatty acid β-oxidation, thereby improving lipotoxicity and fuel dyshomeostasis. To explore an unidentified role of central melanocortin in muscular AMPK regulation, we treated conscious mice intracerebroventricularly with melanocortin agonist (MT-II) or antagonist (SHU9119). MT-II augmented phosphorylation of AMPK and its target acetyl-CoA carboxylase (ACC) independent of caloric intake. Conversely, AMPK/ACC phosphorylation by leptin was abrogated by co-administration of SHU9119 or in KKA^y mice which centrally express endogenous melanocortin antagonist High-fat diet-induced attenuation in AMPK/ACC phosphorylation in leptin transgenic mice was not reversed by leptin, whereas markedly recovered by MT-II. Our data provide the first evidence for critical role of central melanocortin in leptin-skeletal muscle AMPK axis and highlight the system as a promising therapeutic target in leptin resistance in obesity and the metabolic syndrome. Less
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