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

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.

Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity

“…In addition, Metformin, a first-line treatment in type 2 diabetes (American Diabetes Association, 2016) with neutral effects on body weight, is supposed to exert its antidiabetic effects, at least in part, via inhibition of mitochondrial respiration (Owen et al, 2000; El-Mir et al, 2000). Consistent with this, direct application of metformin to the brain in rodents has been shown to decrease food intake and improve glucose metabolism (Portela et al, 2015). …”

Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity

“…Indeed, succinate in the absence of metformin appears to have no effect(20). The role that ROS and the electron transport chain play in the genesis of preeclampsia could be parsed both pharmacologically and genetically(216–219). The changes in the mitochondrial function in preeclampsia suggest there are perturbations in the cellular energy balance of patients with this syndrome that affect cell growth and division (especially in the placenta and the fetus); all are modified by metformin.…”

Hypothalamic Mitochondrial Dysfunction as a Target in Obesity and Metabolic Disease

“…Peripheral treatment with metformin improved peripheral insulin resistance, decreased plasma and brain oxidative stress, and restored brain mitochondrial function, that were all produced from high-fat diet ( 101 ). On the other hand, direct administration of metformin in the brain for up to 7 days in mice caused severe hypoglycemia and alterations in mitochondrial function/viability ( 102 ). Finally, using an experimental model of diet-induced obesity in rats, it was found that HFD caused brain mitochondrial dysfunction indicated by an increase of brain mitochondrial ROS and increase of the size of mitochondria in the brain ( 103 ).…”