Intracerebroventricular Injection of Metformin Induces Anorexia in Rats

Abstract

BackgroundMetformin, an oral biguanide insulin-sensitizing agent, is well known to decrease appetite. Although there is evidence that metformin could affect the brain directly, the exact mechanism is not yet known.MethodsTo evaluate whether metformin induces anorexia via the hypothalamus, various concentrations of metformin were injected into the lateral ventricle of rats through a chronically implanted catheter and food intake was measured for 24 hours. The hypothalamic neuropeptides associated with regulation of food intake were also analyzed following 1 hour of intracerebroventricular (ICV) injections of metformin.ResultsAn ICV injection of metformin decreased food intake in a dose-dependent manner in unrestrained conscious rats. Hypothalamic phosphorylated AMP-activated protein kinase (pAMPK) increased by 3 µg with metformin treatment, but there was no further increase in pAMPK with increases in metformin dosage. The hypothalamic phosphorylated signal transducer and activator of transcription 3 (pSTAT3) increased by 3 µg with metformin treatment, but, there was no further increase in pSTAT3 level following increases of metformin dosage. Hypothalamic proopiomelanocortin was elevated with metformin treatment, while neuropeptide Y was not significantly changed.ConclusionOur results suggest that metformin induces anorexia via direct action in the hypothalamus and the increase in pSTAT3, at least in part, is involved in the process. However, hypothalamic pAMPK appears not to contribute to metformin-induced appetite reduction in normal rats. Further studies exploring new pathways connecting metformin and feeding regulation are needed.

Effects of metformin on weight loss

“…This apparent discrepancy between weight loss and elevated ghrelin is likely explained by the fact that centrally administered metformin in rodents blocks ghrelin-induced activation of AMPK [18]. Although these findings are consistent with the studies indicating that metformin blocks hypoglycemia-induced AMPK activation in rat primary hypothalamic neurons, others have not observed reduced AMPK activity with metformin under normal glucose concentrations, suggesting that metformin has unique effects on hypothalamic AMPK based on the metabolic milieu [19]. In either case, signal transducer and activator of transcription 3 (STAT3) was recently identified as a key mediator of feeding, and STAT3 activation is associated with the leptin receptor.…”

“…In either case, signal transducer and activator of transcription 3 (STAT3) was recently identified as a key mediator of feeding, and STAT3 activation is associated with the leptin receptor. Metformin increases STAT3 signaling in the hypothalamus and inhibits NPY and AgRP expression [17,19], highlighting that metformin regulates food intake by affecting multiple appetite regulatory pathways.…”

Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice

“…A recent study on human diabetic patients supports this finding by showing an increase in lean to fat ratio in diabetic patients on metformin treatment [32]). Metformin’s ability to affect food intake and hypothalamic activity regulating feeding behavior has been documented [25, 33–36]. However, the difference in the body fat content of mice in this study was not due to decreased feeding behavior, as caloric intake was equalized among the groups.…”

Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway

“…12,13 In this regard, lifestyle modification through CR and taking metformin are thought to induce autophagy; a promising approach for treating NAFLD. 8,14 Based on these reports, we used an animal model to implement CR as a lifestyle modification, and metformin as a drug therapy in both cellular and animal models.…”