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Mechanism by which a novel non-thiazolidinedione peroxisome proliferator-activated receptor gamma agonist, FK614, ameliorates insulin resistance in Zucker fatty rats.
Diabetes Obes Metab. 2007 May; 9(3):369-78.DO

Abstract

AIM

The aim of this study was to examine the mechanism by which a novel non-thiazolidinedione (TZD) peroxisome proliferator-activated receptor (PPAR) gamma agonist, FK614, ameliorates insulin resistance in Zucker fatty rats.

METHODS

FK614 (1, 3.2 or 10 mg/kg) and a TZD PPARgamma agonist, pioglitazone (1, 3.2 or 10 mg/kg), were orally administered to Zucker fatty rats (genetically obese and insulin resistant) once a day for 14 days, and an oral glucose tolerance test was performed. The expression levels of various genes in the white adipose tissue (WAT) of Zucker fatty rats treated with FK614 (3.2 mg/kg), pioglitazone (10 mg/kg) and another TZD PPARgamma agonist, rosiglitazone (3.2 mg/kg), were determined using a real-time reverse transcription-polymerase chain reaction method. Morphometric analysis of the WAT of Zucker fatty rats treated with FK614 (3.2 mg/kg) and pioglitazone (10 mg/kg) was performed. Glucose transport activity in the isolated soleus muscle of FK614-treated Zucker fatty rats was also investigated.

RESULTS

FK614 and pioglitazone both improved glucose tolerance in Zucker fatty rats. FK614 significantly increased the expression levels of acyl CoA oxidase, a PPAR-responsive gene, and adipocyte fatty acid-binding protein (aP2), an adipocyte differentiation marker gene, in epididymal WAT. It also significantly decreased the level of gene expression of tumour necrosis factor-alpha, an insulin resistance-inducing factor in retroperitoneal WAT, as did pioglitazone and rosiglitazone. FK614 and pioglitazone both significantly increased the total number of adipocytes and decreased their average size in WAT, mainly by increasing the number of small adipocytes. Additionally, administration of FK614 to Zucker fatty rats enhanced insulin sensitivity for glucose uptake in the soleus muscle.

CONCLUSION

This study suggests the possibility that FK614 induces adipocyte differentiation in Zucker fatty rats by stimulating PPARgammain vivo, thereby changing the character of WAT and improving insulin sensitivity throughout the body.

Authors+Show Affiliations

Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, Osaka, Japan. hideaki.monoura@jp.astellas.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

17391165

Citation

Minoura, H, et al. "Mechanism By Which a Novel Non-thiazolidinedione Peroxisome Proliferator-activated Receptor Gamma Agonist, FK614, Ameliorates Insulin Resistance in Zucker Fatty Rats." Diabetes, Obesity & Metabolism, vol. 9, no. 3, 2007, pp. 369-78.
Minoura H, Takeshita S, Kimura C, et al. Mechanism by which a novel non-thiazolidinedione peroxisome proliferator-activated receptor gamma agonist, FK614, ameliorates insulin resistance in Zucker fatty rats. Diabetes Obes Metab. 2007;9(3):369-78.
Minoura, H., Takeshita, S., Kimura, C., Hirosumi, J., Takakura, S., Kawamura, I., Seki, J., Manda, T., & Mutoh, S. (2007). Mechanism by which a novel non-thiazolidinedione peroxisome proliferator-activated receptor gamma agonist, FK614, ameliorates insulin resistance in Zucker fatty rats. Diabetes, Obesity & Metabolism, 9(3), 369-78.
Minoura H, et al. Mechanism By Which a Novel Non-thiazolidinedione Peroxisome Proliferator-activated Receptor Gamma Agonist, FK614, Ameliorates Insulin Resistance in Zucker Fatty Rats. Diabetes Obes Metab. 2007;9(3):369-78. PubMed PMID: 17391165.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanism by which a novel non-thiazolidinedione peroxisome proliferator-activated receptor gamma agonist, FK614, ameliorates insulin resistance in Zucker fatty rats. AU - Minoura,H, AU - Takeshita,S, AU - Kimura,C, AU - Hirosumi,J, AU - Takakura,S, AU - Kawamura,I, AU - Seki,J, AU - Manda,T, AU - Mutoh,S, PY - 2007/3/30/pubmed PY - 2007/6/23/medline PY - 2007/3/30/entrez SP - 369 EP - 78 JF - Diabetes, obesity & metabolism JO - Diabetes Obes Metab VL - 9 IS - 3 N2 - AIM: The aim of this study was to examine the mechanism by which a novel non-thiazolidinedione (TZD) peroxisome proliferator-activated receptor (PPAR) gamma agonist, FK614, ameliorates insulin resistance in Zucker fatty rats. METHODS: FK614 (1, 3.2 or 10 mg/kg) and a TZD PPARgamma agonist, pioglitazone (1, 3.2 or 10 mg/kg), were orally administered to Zucker fatty rats (genetically obese and insulin resistant) once a day for 14 days, and an oral glucose tolerance test was performed. The expression levels of various genes in the white adipose tissue (WAT) of Zucker fatty rats treated with FK614 (3.2 mg/kg), pioglitazone (10 mg/kg) and another TZD PPARgamma agonist, rosiglitazone (3.2 mg/kg), were determined using a real-time reverse transcription-polymerase chain reaction method. Morphometric analysis of the WAT of Zucker fatty rats treated with FK614 (3.2 mg/kg) and pioglitazone (10 mg/kg) was performed. Glucose transport activity in the isolated soleus muscle of FK614-treated Zucker fatty rats was also investigated. RESULTS: FK614 and pioglitazone both improved glucose tolerance in Zucker fatty rats. FK614 significantly increased the expression levels of acyl CoA oxidase, a PPAR-responsive gene, and adipocyte fatty acid-binding protein (aP2), an adipocyte differentiation marker gene, in epididymal WAT. It also significantly decreased the level of gene expression of tumour necrosis factor-alpha, an insulin resistance-inducing factor in retroperitoneal WAT, as did pioglitazone and rosiglitazone. FK614 and pioglitazone both significantly increased the total number of adipocytes and decreased their average size in WAT, mainly by increasing the number of small adipocytes. Additionally, administration of FK614 to Zucker fatty rats enhanced insulin sensitivity for glucose uptake in the soleus muscle. CONCLUSION: This study suggests the possibility that FK614 induces adipocyte differentiation in Zucker fatty rats by stimulating PPARgammain vivo, thereby changing the character of WAT and improving insulin sensitivity throughout the body. SN - 1462-8902 UR - https://www.unboundmedicine.com/medline/citation/17391165/Mechanism_by_which_a_novel_non_thiazolidinedione_peroxisome_proliferator_activated_receptor_gamma_agonist_FK614_ameliorates_insulin_resistance_in_Zucker_fatty_rats_ L2 - https://doi.org/10.1111/j.1463-1326.2006.00619.x DB - PRIME DP - Unbound Medicine ER -