NO-1886 (ibrolipim), a lipoprotein lipase activator, increases the expression of uncoupling protein 3 in skeletal muscle and suppresses fat accumulation in high-fat diet-induced obesity in rats

Although the lipoprotein lipase (LPL) activator NO-1886 shows antiobesity effects in high-fat-induced obese animals, the mechanism remains unclear. To clarify the mechanism, we studied the effects of NO-1886 on the expression of uncoupling protein (UCP) 1, UCP2, and UCP3 in rats. NO-1886 was mixed with a high-fat chow to supply a dose of 100 mg/kg to 8-month-old male Sprague-Dawley rats. The animals were fed the high-fat chow for 8 weeks. At the end of the administration period, brown adipose tissue (BAT), mesenteric fat, and soleus muscle were collected and levels of UCP1, UCP2, and UCP3 messenger RNA (mRNA) were determined. NO-1886 suppressed the body weight increase seen in the high-fat control group after the 8-week administration (585 39 vs 657 66 g, P < .05). NO-1886 also suppressed fat accumulation in visceral (46.9 +/- 10.4 vs 73.7 +/- 14.5 g, P < .01) and subcutaneous (43.1 +/- 18.1 vs 68.9 +/- 18.8 g, P < .05) tissues and increased the levels of plasma total cholesterol and high-density lipoprotein cholesterol in comparison to the high-fat control group. In contrast, NO-1886 decreased the levels of plasma triglycerides, nonesterified free fatty acid, glucose, and insulin. NO-1886 increased LPL activity in soleus muscle (0.082 +/- 0.013 vs 0.061 +/- 0.016 mu mol of free fatty, acid per minute per gram of tissue, P < .05). NO-1886 increased the expression of UCP3 mRNA in soleus muscle 3,.14-fold (P < .01), compared with the high-fat control group without affecting the levels of UCP3 in mesenteric adipose tissue and BAT. In. addition, NO-1886 did not affect the expression of UCP1 and UCP2 in BAT, mesenteric, adipose tissue, and soleus muscle., in conclusion,, NO-1886 increased (he expression of UCP3 mRNA and LPL activity only in skeletal muscle. Therefore, a possible mechanism for NO-1886's antiobesity effects in rats may be the enhancement of LPL activity in skeletal muscle and the accompanying increase in UCP3 expression. (c) 2005 Elsevier Inc. All rights reserved.