The aim of the present study was to evaluate the effects of monotherapies and combinations of drugs on insulin sensitivity, adipose tissue morphology, and pancreatic and hepatic remodelling in C57BL/6 mice fed on a very HF (high-fat) diet. Male C57BL/6 mice were fed on an HF (60% lipids) diet or SC (standard chow; 10% lipids) diet for 10 weeks, after which time the following drug treatments began: HF-T (HF diet treated with telmisartan; 5.2 mg·kg−1 of body weight·day−1), HF-S (HF diet treated with sitagliptin; 1.08 g·kg−1 of body weight·day−1), HF-M (HF diet treated with metformin; 310.0 mg·kg−1 of body weight·day−1), HF-TM (HF diet treated with telmisartan+metformin), HF-TS (HF diet treated with telmisartan+sitagliptin) and HF-SM (HF diet treated with sitagliptin+metformin). Treated groups also had free access to the HF diet, and treatments lasted for 6 weeks. Morphometry, stereological tools, immunostaining, ELISA, Western blot analysis and electron microscopy were used. The HF diet yielded an overweight phenotype, an increase in oral glucose intolerance, hyperinsulinaemia, hypertrophied islets and adipocytes, stage 2 steatosis (>33%), and reduced liver PPAR-α (peroxisome-proliferator-activated receptor-α) and GLUT-2 (glucose transporter-2) levels, concomitant with enhanced SREBP-1 (sterol-regulatory-element-binding protein-1) expression (P<0.0001). Conversely, all drug treatments resulted in significant weight loss, a reversal of insulin resistance, islet and adipocyte hypertrophy, and alleviated hepatic steatosis. Only the HF-T and HF-TS groups had body weights similar to the SC group at the end of the experiment, and the latter treatment reversed hepatic steatosis. Increased PPAR-α immunostaining in parallel with higher GLUT-2 and reduced SREBP-1 expression may explain the favourable hepatic outcomes. Restoration of adipocyte size was consistent with higher adiponectin levels and lower TNF-α (tumour necrosis factor-α) levels (P<0.0001) in the drug-treated groups. In conclusion, all of the drug treatments were effective in controlling the metabolic syndrome. The best results were achieved using telmisartan and sitagliptin as monotherapies or as a dual treatment, combining partial PPAR-γ agonism and PPAR-α activation in the liver with extended incretin action.
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Research Article|
June 08 2010
Comparative effects of telmisartan, sitagliptin and metformin alone or in combination on obesity, insulin resistance, and liver and pancreas remodelling in C57BL/6 mice fed on a very high-fat diet
Vanessa Souza-Mello;
Vanessa Souza-Mello
1Laboratory of Morphometry, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, 20551-030 Rio de Janeiro, RJ, Brazil
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Bianca M. Gregório;
Bianca M. Gregório
1Laboratory of Morphometry, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, 20551-030 Rio de Janeiro, RJ, Brazil
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Fernando S. Cardoso-de-Lemos;
Fernando S. Cardoso-de-Lemos
1Laboratory of Morphometry, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, 20551-030 Rio de Janeiro, RJ, Brazil
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Laís de Carvalho;
Laís de Carvalho
1Laboratory of Morphometry, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, 20551-030 Rio de Janeiro, RJ, Brazil
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Márcia B. Aguila;
Márcia B. Aguila
1Laboratory of Morphometry, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, 20551-030 Rio de Janeiro, RJ, Brazil
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Carlos A. Mandarim-de-Lacerda
1Laboratory of Morphometry, Biomedical Center, Institute of Biology, State University of Rio de Janeiro, 20551-030 Rio de Janeiro, RJ, Brazil
Correspondence: Professor Carlos A. Mandarim-de-Lacerda (email [email protected]).
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Publisher: Portland Press Ltd
Received:
January 25 2010
Revision Received:
March 23 2010
Accepted:
April 23 2010
Accepted Manuscript online:
April 23 2010
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2010 Biochemical Society
2010
Clin Sci (Lond) (2010) 119 (6): 239–250.
Article history
Received:
January 25 2010
Revision Received:
March 23 2010
Accepted:
April 23 2010
Accepted Manuscript online:
April 23 2010
Citation
Vanessa Souza-Mello, Bianca M. Gregório, Fernando S. Cardoso-de-Lemos, Laís de Carvalho, Márcia B. Aguila, Carlos A. Mandarim-de-Lacerda; Comparative effects of telmisartan, sitagliptin and metformin alone or in combination on obesity, insulin resistance, and liver and pancreas remodelling in C57BL/6 mice fed on a very high-fat diet. Clin Sci (Lond) 1 September 2010; 119 (6): 239–250. doi: https://doi.org/10.1042/CS20100061
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