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ragaglitazar eliminates fatty liver and enhances
insulin action in fat-fed rats in the absence of hepatomegaly
1 Diabetes and Obesity Program, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia; 2 Rheoscience, DK-2100 Copenhagen; and 3 Novo Nordisk, DK-2760 Måløv, Denmark
Peroxisome proliferator-activated receptor
(PPAR)
and PPAR
agonists lower lipid accumulation in muscle and
liver by different mechanisms. We investigated whether benefits could
be achieved on insulin sensitivity and lipid metabolism by the dual
PPAR/ agonist ragaglitazar in high fat-fed rats. Ragaglitazar
completely eliminated high-fat feeding-induced liver triglyceride
accumulation and visceral adiposity, like the PPAR agonist
Wy-14643 but without causing hepatomegaly. In contrast, the
PPAR agonist rosiglitazone only slightly lessened liver triglyceride
without affecting visceral adiposity. Compared with rosiglitazone or
Wy-14643, ragaglitazar showed a much greater effect (79%, P
< 0.05) to enhance insulin's suppression of hepatic glucose
output. Whereas all three PPAR agonists lowered plasma triglyceride
levels and lessened muscle long-chain acyl-CoAs, ragaglitazar and
rosiglitazone had greater insulin-sensitizing action in muscle than
Wy-14643, associated with a threefold increase in plasma adiponectin
levels. There was a significant correlation of lipid content and
insulin action in liver and particularly muscle with adiponectin levels
(P < 0.01). We conclude that the PPAR/ agonist
ragaglitazar has a therapeutic potential for insulin-resistant states
as a PPAR ligand, with possible involvement of adiponectin.
Additionally, it can counteract fatty liver, hepatic insulin
resistance, and visceral adiposity generally associated with PPAR
activation, but without hepatomegaly.
peroxisome proliferator-activated receptor subtypes; adipokines; tissue lipids; insulin resistance
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