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1.
Bioorg Med Chem ; 54: 116553, 2022 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-34953340

RESUMO

Retinol-binding protein 4 (RBP4) is a potential drug target for metabolic and ophthalmologic diseases. A high-throughput screening of our compound library has identified a small-molecule RBP4 reducer 7a, as a hit compound. Aiming to provide a suitable tool for investigating the pharmacological effects of RBP4 reducers, we conducted a structure-activity relationship study of 7a. Exploration of the aryl head, oxazole core, and propanoic acid tail of 7a resulted in the discovery of novel, potent, and orally available phenylpyrrolidine derivatives 43b and 43c. Compound 43b had a potent and long-lasting blood RBP4-level-reducing effect when orally administered to mice at a dose as low as 0.3 mg/kg.


Assuntos
Descoberta de Drogas , Pirrolidinas/farmacologia , Proteínas Plasmáticas de Ligação ao Retinol/antagonistas & inibidores , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Pirrolidinas/síntese química , Pirrolidinas/química , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Relação Estrutura-Atividade
2.
J Endocr Soc ; 1(7): 772-786, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29264529

RESUMO

Podocan, a member of the small leucine-rich repeat proteoglycans (SLRPs), is expressed in vascular endothelial cells with high levels of expression in the sclerotic glomerular lesions of experimental HIV-associated nephropathy. It is also found in vascular smooth muscle cells and is involved in atherosclerosis. Decorin, a protein similar to podocan, also belongs to the SLRP family and is highly expressed in adipose tissues. It is a secreted protein associated with obesity, type 2 diabetes, and diabetic nephropathy. Based on the similarity of podocan to decorin and its functions reported in the renal and cardiovascular systems, we hypothesized that podocan levels might correlate with the occurrence of metabolic syndromes such as obesity, diabetes, and diabetic nephropathy. We found that podocan was highly expressed in the adipose tissue of mice and humans and its expression was regulated by tumor necrosis factor-α in mouse 3T3-L1 adipocytes. In addition, podocan was detected in the plasma, and its levels tended to increase in diet-induced obese C57BL/6J mice and decrease in obese-diabetic KKAy and db/db mice. Podocan messenger RNA (mRNA) levels in the renal cortex correlated negatively with the urinary albumin-to-creatinine ratio, a surrogate marker of glomerular injury in uninephrectomized db/db mice used as a model of diabetic nephropathy. Our results suggest that podocan is involved in kidney function and could be a unique therapeutic target for diabetic nephropathy.

3.
Bioorg Med Chem Lett ; 22(14): 4769-72, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22677317

RESUMO

Spiro-pyrazolidinedione derivatives without quaternary chiral center were discovered by structure-based drug design and characterized as potent acetyl-CoA carboxylase (ACC) inhibitors. The high metabolic stability of the spiro-pyrazolo[1,2-a]pyridazine scaffold and enhancement of the activity by incorporation of a 7-methoxy group on the benzothiophene core successfully led to the identification of compound 4c as an orally bioavailable and highly potent ACC inhibitor. Oral administration of 4c significantly decreased the values of the respiratory quotient in rats, indicating the stimulation of fatty acid oxidation.


Assuntos
Acetil-CoA Carboxilase/antagonistas & inibidores , Inibidores Enzimáticos/química , Pirazóis/química , Compostos de Espiro/química , Animais , Inibidores Enzimáticos/farmacologia , Humanos , Microssomos/efeitos dos fármacos , Microssomos/enzimologia , Modelos Moleculares , Estrutura Molecular , Pirazóis/farmacologia , Ratos , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade
4.
Diabetes ; 51(10): 2915-21, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12351427

RESUMO

Plasma glycerol is a major substrate for hepatic gluconeogenesis. Aquaporin adipose (AQPap/7), an adipose-specific glycerol channel, provides fat-derived glycerol into plasma. In the present study, we cloned the coding and promoter regions of mouse aquaporin 9 (AQP9), a liver-specific glycerol channel. Fasting and refeeding of mice increased and decreased hepatic AQP9 mRNA levels, respectively. Insulin deficiency induced by streptozotocin resulted in increased hepatic AQP9 mRNA. These changes in hepatic AQP9 mRNA were accompanied by those of hepatic gluconeogenic mRNAs and plasma glycerol levels. In cultured hepatocytes, insulin downregulated AQP9 mRNA. The AQP9 promoter contained the negative insulin response element TGTTTTC at -496/-502, similar to the promoter of the AQPap/7 gene. In contrast, in insulin-resistant db+/db+ mice, AQPap/7 mRNA in fat and AQP9 mRNA in liver were increased, despite hyperinsulinemia, with high plasma glycerol and glucose levels. Glycerol infusion in the db+/db+ mice augmented hepatic glucose output. Our results indicate that coordinated regulations of fat-specific AQPap/7 and liver-specific AQP9 should be crucial to determine glucose metabolism in physiology and insulin resistance.


Assuntos
Aquaporinas/genética , Gorduras/metabolismo , Glicerol/metabolismo , Fígado/metabolismo , Sequência de Aminoácidos , Animais , Aquaporinas/metabolismo , Sequência de Bases , Carcinoma Hepatocelular , Clonagem Molecular , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Ingestão de Alimentos/fisiologia , Jejum/fisiologia , Regulação da Expressão Gênica/fisiologia , Glicerol Quinase/genética , Resistência à Insulina , Neoplasias Hepáticas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Dados de Sequência Molecular , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , RNA Mensageiro/análise , Ratos , Células Tumorais Cultivadas
5.
Diabetes ; 51(9): 2734-41, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12196466

RESUMO

Adiponectin, an adipose-specific secretory protein, exhibits antidiabetic and antiatherogenic properties. In the present study, we examined the effects of sex hormones on the regulation of adiponectin production. Plasma adiponectin concentrations were significantly lower in 442 men (age, 52.6 +/- 11.9 years [mean +/- SD]) than in 137 women (53.2 +/- 12.0 years) but not different between pre- and postmenopausal women. In mice, ovariectomy did not alter plasma adiponectin levels. In contrast, high levels of plasma adiponectin were found in castrated mice. Testosterone treatment reduced plasma adiponectin concentration in both sham-operated and castrated mice. In 3T3-L1 adipocytes, testosterone reduced adiponectin secretion into the culture media, using pulse-chase study. Castration-induced increase in plasma adiponectin was associated with a significant improvement of insulin sensitivity. Our results indicate that androgens decrease plasma adiponectin and that androgen-induced hypoadiponectinemia may be related to the high risks of insulin resistance and atherosclerosis in men.


Assuntos
Androgênios/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular , Proteínas/antagonistas & inibidores , Proteínas/análise , Células 3T3 , Adipócitos/metabolismo , Adiponectina , Adulto , Animais , Feminino , Humanos , Insulina/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Pessoa de Meia-Idade , Ovariectomia , Pós-Menopausa/metabolismo , Proteínas/metabolismo , Caracteres Sexuais , Testosterona/farmacologia
6.
Nat Med ; 8(7): 731-7, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12068289

RESUMO

Here we investigated the biological functions of adiponectin/ACRP30, a fat-derived hormone, by disrupting the gene that encodes it in mice. Adiponectin/ACRP30-knockout (KO) mice showed delayed clearance of free fatty acid in plasma, low levels of fatty-acid transport protein 1 (FATP-1) mRNA in muscle, high levels of tumor necrosis factor-alpha (TNF-alpha) mRNA in adipose tissue and high plasma TNF-alpha concentrations. The KO mice exhibited severe diet-induced insulin resistance with reduced insulin-receptor substrate 1 (IRS-1)-associated phosphatidylinositol 3 kinase (PI3-kinase) activity in muscle. Viral mediated adiponectin/ACRP30 expression in KO mice reversed the reduction of FATP-1 mRNA, the increase of adipose TNF-alpha mRNA and the diet-induced insulin resistance. In cultured myocytes, TNF-alpha decreased FATP-1 mRNA, IRS-1-associated PI3-kinase activity and glucose uptake, whereas adiponectin increased these parameters. Our results indicate that adiponectin/ACRP30 deficiency and high TNF-alpha levels in KO mice reduced muscle FATP-1 mRNA and IRS-1-mediated insulin signaling, resulting in severe diet-induced insulin resistance.


Assuntos
Dieta , Ácidos Graxos não Esterificados/sangue , Proteínas de Peixes , Resistência à Insulina/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular , Metabolismo dos Lipídeos , Proteínas/fisiologia , Fator de Necrose Tumoral alfa/genética , Adiponectina , Tecido Adiposo/metabolismo , Animais , Proteínas de Transporte/metabolismo , Células Cultivadas , Proteínas de Ligação a Ácido Graxo , Proteínas Substratos do Receptor de Insulina , Camundongos , Camundongos Knockout , Miocárdio/citologia , Miocárdio/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfoproteínas/metabolismo , Proteínas/genética , RNA Mensageiro/genética , Transcrição Gênica
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