AJP - Endo AJP: Regulatory, Integrative and Comparative Physiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Endocrinol Metab 294: E833-E840, 2008. First published January 22, 2008; doi:10.1152/ajpendo.00627.2007
0193-1849/08 $8.00
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
294/5/E833    most recent
00627.2007v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Tsunoda, M.
Right arrow Articles by Murakami, K.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tsunoda, M.
Right arrow Articles by Murakami, K.

A novel PPAR{alpha} agonist ameliorates insulin resistance in dogs fed a high-fat diet

Masaki Tsunoda, Naoki Kobayashi, Tomohiro Ide, Mari Utsumi, Michiaki Nagasawa, and Koji Murakami

Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., Tochigi, Japan

Submitted 28 September 2007 ; accepted in final form 18 January 2008

Agonism of peroxisome proliferator-activated receptor (PPAR) {alpha}, a key regulator of lipid metabolism, leads to amelioration of lipid abnormalities in dyslipidemic patients. However, whether PPAR{alpha} agonism is an effective form of therapy for obesity-related insulin resistance associated with lipid abnormalities is unclear. The present study investigated the effects of a potent and subtype-selective PPAR{alpha} agonist, KRP-101, in a nonrodent insulin-resistant animal model under pair-fed conditions. Beagle dogs were fed a high-fat diet for 24 wk to induce insulin resistance. During the final 12 wk, 0.03 mg·kg–1·day–1 KRP-101 (n = 5) or vehicle (n = 5) was administered orally once a day. KRP-101 administration resulted in a significantly lower weight of overall visceral fat, which is associated with increased adiponectin and decreased leptin in serum. KRP-101 administration improved hyperglycemia and hyperinsulinemia as well as dyslipidemia in dogs fed a high-fat diet. Oral glucose tolerance test showed that KRP-101 administration improved glucose intolerance. The KRP-101 group showed a markedly lower hepatic triglyceride concentration. Lipid oxidation was increased in the liver and skeletal muscles of the KRP-101 group. These findings in the dog model suggest that the use of potent and subtype-selective PPAR{alpha} agonists as a potentially relevant therapeutic approach to treat human insulin resistance associated with visceral obesity.

KRP-101; obesity; insulin resistance; muscle lipid oxidation


Address for reprint requests and other correspondence: K. Murakami, Discovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd., 2399–1 Nogi-Machi, Shimotsuga-Gun, Tochigi 329-0114, Japan (e-mail: kouji.murakami{at}mb.kyorin-pharm.co.jp)






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2008 by the American Physiological Society.