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Intracerebroventricular Metformin Decreases Body Weight But Has Pro-oxidant Effects and Decreases Survival

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Abstract

Metformin (Met), which is an insulin-sensitizer, decreases insulin resistance and fasting insulin levels. The precise molecular target of Met is unknown; however, several reports have shown an inhibitory effect on mitochondrial complex I of the electron transport chain (ETC), which is a related site for reactive oxygen species production. In addition to peripheral effects, Met is capable of crossing the blood–brain barrier, thus regulating the central mechanism involved in appetite control. The present study explores the effects of intracerebroventricular (i.c.v.) infusion of Met on ROS production on brain, insulin sensitivity and metabolic and oxidative stress outcomes in CF1 mice. Metformin (Met 50 and 100 µg) was injected i.c.v. in mice daily for 7 days; the brain mitochondrial H2O2 production, food intake, body weight and fat pads were evaluated. The basal production of H2O2 of isolated mitochondria from the hippocampus and hypothalamus was significantly increased by Met (100 µg). There was increased peripheral sensitivity to insulin (Met 100 µg) and glucose tolerance tests (Met 50 and 100 µg). Moreover, Met decreased food intake, body weight, body temperature, fat pads and survival rates. Additionally, Met (1, 4 or 10 mM) decreased mitochondrial viability and increased the production of H2O2 in neuronal cell cultures. In summary, our data indicate that a high dose of Met injected directly into the brain has remarkable neurotoxic effects, as evidenced by hypothermia, hypoglycemia, disrupted mitochondrial ETC flux and decreased survival rate.

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Acknowledgments

This work was supported by Brazilian agencies and grants: CNPq, CAPES 02/2102, FAPERGS0543/12-4-PPSUS, Brazil-Swiss 590011/2010-3, Brazilian Institute of Neuroscience-IBN Net FINEP, INCT-Excitotoxicity and Neuroprotection.

Conflict of interest

The authors declare that they have no financial conflicts of interest.

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Authors and Affiliations

  1. Departamento de Bioquímica, Programa de Pós Graduação em Ciências Biológicas-Bioquímica, ICBS, UFRGS, Rua: Ramiro Barcelos, 2600 anexo, Porto Alegre, Rio Grande do Sul, CEP 90035-003, Brazil

    Luis Valmor Portela, Jussania Gnoatto, Andressa Wigner Brochier, Clarissa Branco Haas, Adriano Martimbianco de Assis, Afonso Kopczynski de Carvalho, Gisele Hansel & Eduardo Rigon Zimmer

  2. Programa de Pós-Graduação em Saúde and Comportamento Centro de Ciências da Vida e da Saúde, Universidade Católica de Pelotas, Rua Almirante Barroso, 1202 sala G109, Pelotas, Rio Grande do Sul, CEP 96010-280, Brazil

    Jean Pierre Oses

  3. Unidade de Ciências da Saúde, Laboratório de Bioquímica e Fisiologia do Exercício-LAFIBE, Universidade do Extremo Sul Catarinense-UNESC, Av. Universitária, 1105-Bairro Universitário, Criciúma, Santa Catarina, CEP 88806-000, Brazil

    Alexandre Pastoris Muller

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  1. Luis Valmor Portela
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  2. Jussania Gnoatto
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  3. Andressa Wigner Brochier
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  4. Clarissa Branco Haas
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  10. Alexandre Pastoris Muller
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Correspondence to Alexandre Pastoris Muller.

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Portela, L.V., Gnoatto, J., Wigner Brochier, A. et al. Intracerebroventricular Metformin Decreases Body Weight But Has Pro-oxidant Effects and Decreases Survival. Neurochem Res 40, 514–523 (2015). https://doi.org/10.1007/s11064-014-1496-7

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  • DOI: https://doi.org/10.1007/s11064-014-1496-7

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