Endocrine Pharmacology
Pioglitazone-induced body weight gain is prevented by combined administration with the lipoprotein lipase activator NO-1886

https://doi.org/10.1016/j.ejphar.2011.07.030Get rights and content

Abstract

Pioglitazone improves insulin resistance in diabetics but often causes body weight gain. The lipoprotein lipase activator NO-1886 has been shown to exert both anti-obesity and anti-insulin-resistance effects. In this study, we investigated the effect of the combined administration of pioglitazone with NO-1886 (pioglitazone + NO-1886) in preventing body weight gain in insulin-resistant, high-fat fed rats. The rats were fed a standard or high-fat diet for 16 weeks. The high-fat fed rats were randomized at week 9 into 4 groups (i.e., control, pioglitazone (30 mg/kg/day), NO-1886 (100 mg/kg/day), and pioglitazone + NO-1886 (30 and 100 mg/kg/day, respectively)). The high-fat fed control rats developed obesity and insulin resistance. After 7 weeks of drug treatment, pioglitazone + NO-1886 was found to prevent the body weight gain caused by pioglitazone alone (pioglitazone + NO-1886: Δ76.0 ± 16.8 g vs. pioglitazone: Δ127.8 ± 39.5 g, P < 0.05) and to increase glucose infusion rate during insulin clamp, compared with the results in the high-fat fed control group. No differences in plasma nonesterified fatty acid, leptin, adiponectin, glucose, or insulin levels were observed between the pioglitazone + NO-1886 and the pioglitazone-alone groups. However, plasma total cholesterol and HDL-cholesterol levels were significantly increased and plasma triglyceride levels were slightly decreased in the pioglitazone + NO-1886 group, compared with the values in the pioglitazone-alone group. In summary, the combined administration of pioglitazone and NO-1886 prevented the pioglitazone-induced body weight gains and ameliorated insulin resistance observed in high-fat fed rats. These results indicate that combined therapy with pioglitazone and NO-1886 may be beneficial for the treatment of type 2 diabetes.

Introduction

The antidiabetic agent pioglitazone is thought to promote the differentiation of adipocytes, convert large-type hypertrophic adipocytes into small-type adipocytes, and to increase insulin activity through peroxisome proliferator-activated receptor-γ (PPARγ) activation (de Souza et al., 2001, Spiegelman, 1998). In addition, thiazolidinediones have also been shown to improve the serum levels of several adipocytokines, such as adiponectin and TNF-α, in type 2 diabetic patients (Miyazaki and DeFronzo, 2008, Oz et al., 2008). However, as a result of the enhanced adipocyte differentiation, pioglitazone treatment has been shown to be associated with body weight gain in obese animals and type 2 diabetic patients (Boden and Zhang, 2006, de Souza et al., 2001, Hermansen and Mortensen, 2007, Miyazaki and DeFronzo, 2008). As the mechanism underlying the body weight gain, Hallakou et al. (1997) explained that pioglitazone stimulated the expression of genes involved in lipid metabolism and induced a large increase in glucose utilization in the adipose tissue. Obesity aggravates diabetes and promotes cardiovascular diseases and atherosclerosis (Allison et al., 1999, Fontaine et al., 2003, Kadowaki and Yamauchi, 2005), and the body-weight-increasing action of pioglitazone is a disadvantage in diabetic patients. On the other hand, the lipoprotein lipase (LPL) activator NO-1886 (Kusunoki et al., 2002, Tsutsumi et al., 1993, Tsutsumi et al., 1995) is known to improve both obesity and insulin resistance in obese animals (Hara et al., 1998, Kusunoki et al., 2000).

In this study, we investigated the effect of the simultaneous administration of pioglitazone, which induces a body weight gain, and NO-1886, which has an anti-obesity action, on the body weight and insulin resistance of obese rats.

Section snippets

Materials

NO-1886 (4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl) benzamide; ibrolipim), was obtained from Otsuka Pharmaceutical Factory, Inc. (Naruto, Tokushima, Japan). Pioglitazone was obtained from Takeda Chemicals Industries, Ltd. (Osaka, Japan). All other chemicals used in this study were high-grade, commercially available products.

Animal experiments

Male SD rats aged 6–7 weeks old and weighing 180–200 g, were obtained from Japan SLC, Inc. (Shizuoka, Japan). The animals were maintained under a 12-h light–dark

Body weight, visceral fat weight, and food consumption

The body weight in the high-fat diet group was generally higher than that in the normal group. The body weight in the pioglitazone group was significantly higher than that in the normal diet group over a period of 7 weeks during the study period (week 9 to week 16). In contrast, the body weight in the NO-1886 group was significantly lower than that in the pioglitazone group during the last 4 weeks (week 12 to week 16). The body weight in the pioglitazone + NO-1886 group was significantly lower than

Discussion

Pioglitazone is a useful therapeutic agent for the treatment of type 2 diabetes and is widely used in clinical settings (Aronoff et al., 2000, Dormandy et al., 2005, Einhorn et al., 2000, Kawamori et al., 2007, Schernthaner et al., 2004). However, several studies have suggested that thiazolidinediones induce body weight gain (Boden and Zhang, 2006, Hermansen and Mortensen, 2007, Miyazaki and DeFronzo, 2008). In this context, the LPL activator NO-1886 improves obesity and insulin resistance (

Conclusions

The addition of NO-1886 counteracted the pioglitazone-induced body weight gain in obese rats fed a high-fat diet. The combined administration of pioglitazone and NO-1886 also ameliorated insulin resistance in obese animals more prominently than either compound alone. Thus, the combined administration of pioglitazone and NO-1886 may be of great benefit for the treatment of type 2 diabetic patients.

Acknowledgments

The authors thank the Takeda Pharmaceutical Co., Ltd. and the Otsuka Pharmaceutical Factory Inc. for providing the pioglitazone and NO-1886, respectively, without accepting compensation.

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