Topiramate treatment improves hypothalamic insulin and leptin signaling and action and reduces obesity in mice

Abstract

Topiramate (TPM) treatment has been shown to reduce adiposity in humans and rodents. The reduction in adiposity is related to decreased food intake and increased energy expenditure. However, the molecular mechanisms through which TPM induces weight loss are contradictory and remain to be clarified. Whether TPM treatment alters hypothalamic insulin, or leptin signaling and action, is not well established. Thus, we investigate herein whether short-term TPM treatment alters energy balance by affecting insulin and leptin signaling, action or neuropeptide expression in the hypothalamus of mice fed with a high fat diet. As expected, short-term treatment with TPM diminished adiposity in obese mice mainly due to reduced food intake. TPM increased anorexigenic signaling by enhanced leptin induced OBR/JAK2/STAT3 pathway and insulin induced IRS/Akt/FoxO1 pathway in parallel to reduced phosphatases protein expression in the hypothalamus of obese mice. These effects were independently of body weight. TPM also raised anorexigenic neuropeptides as POMC, TRH and CRH mRNA levels in obese mice. In addition, TPM increased the activation of the hypothalamic MAPK/ERK pathway induced by leptin, accompanied by an increase in PGCa and UCP-1 protein levels in BAT. Further, TPM increased AMPK and ACC phosphorylation in peripheral tissues which may help to improve energy metabolism in these tissues. Together, these results provide novel insights into the molecular mechanisms through which TPM treatment reduces adiposity. (AU)