Central administration of metformin into the third ventricle of C57BL/6 mice decreases meal size and number and activates hypothalamic S6 kinase

Abstract

Kim HJ, Park EY, Oh MJ, Park SS, Shin KH, Choi SH, Chun BG, Kim DH. Central administration of metformin into the third ventricle of C57BL/6 mice decreases meal size and number and activates hypothalamic S6 kinase. Am J Physiol Regul Integr Comp Physiol 305: R499 -R505, 2013. First published July 3, 2013 doi:10.1152/ajpregu.00099.2013.-Administration of metformin is known to reduce both body weight and food intake. Although the hypothalamus is recognized as a critical regulator of energy balance and body weight, there is currently no evidence for an effect of metformin in the hypothalamus. Therefore, we sought to determine the central action of metformin on energy balance and body weight, as well as its potential involvement with key hypothalamic energy sensors, including adenosine monophosphate-activated protein kinase (AMPK) and S6 kinase (S6K). We used meal pattern analysis and a conditioned taste aversion (CTA) test and measured energy expenditure in C56BL/6 mice administered metformin (0, 7.5, 15, or 30 g) into the third ventricle (I3V). Furthermore, we I3V-administered either control or metformin (30 g) and compared the phosphorylation of AMPK and S6K in the mouse mediobasal hypothalamus. Compared with the control, I3V administration of metformin decreased body weight and food intake in a dose-dependent manner and did not result in CTA. Furthermore, the reduction in food intake induced by I3V administration of metformin was accomplished by decreases in both nocturnal meal size and number. Compared with the control, I3V administration of metformin significantly increased phosphorylation of S6K at Thr 389 and AMPK at Ser 485/491 in the mediobasal hypothalamus, while AMPK phosphorylation at Thr 172 was not significantly altered. Moreover, I3V rapamycin pretreatment restored the metformin-induced anorexia and weight loss. These results suggest that the reduction in food intake induced by the central administration of metformin in the mice may be mediated by activation of S6K pathway. metformin; energy homeostasis; hypothalamus; S6 kinase; AMPactivated protein kinase; meal pattern

Exposure of mouse embryonic pancreas to metformin enhances the number of pancreatic progenitors

“…In these experiments we present surprising evidence suggesting that metformin increases mTORC1 signaling in embryonic pancreata. This positive effect of metformin has been recently demonstrated in hypothalamic tissue and suggests that the responses to metformin could be tissue and developmental stage specific [49]. The effect on PDX1 + proliferation induced by metformin was reproduced after treatment with AICAR in vitro , providing strong evidence that this is an AMPK-dependent effect.…”

Acute oral metformin enhances satiation and activates brainstem nesfatinergic neurons

“…They concluded that if glucosuria reduction per se could explain the increase in body weight induced by sulfonylureas in diabetic patients, additional mechanisms, such as reduction in food intake and/or increase in EE, might account for the reduction in body weight induced by metformin. Previous studies failed to detect any enhancing effect of metformin on EE . On the contrary, and in accordance with previous studies , we show that metformin transiently reduces EE in WT mice.…”

“…Previous studies failed to detect any enhancing effect of metformin on EE . On the contrary, and in accordance with previous studies , we show that metformin transiently reduces EE in WT mice. In our hands, this EE reduction was equivalent to the caloric content of 300 mg of food, which led to a net effect of metformin‐induced anorexia on energy balance, consistent with the body weight reduction observed in patients under chronic metformin treatment.…”

“…However, along the 7 days of their daily oral metformin treatment paradigm, Kim and collaborators noticed that the meal number remained unaffected the first 2 days and was reduced thereafter. It is striking that acute metformin treatment does not reduce meal number when orally delivered (5; the present study), whereas it readily reduces it when centrally delivered . Interestingly, acute icv administration of metformin was shown to inhibit ghrelin‐induced food intake .…”

The effect of Korean Red Ginseng extract on rosiglitazone-induced improvement of glucose regulation in diet-induced obese mice

“…The phosphorylation of AMPK and Akt was measured as previously described [20]. The liver and skeletal muscle were quickly dissected and the tissue was homogenized and lysed with radioimmunoprecipitation assay buffer (1.25% Triton X-100, 0.1% sodium dodecyl sulfate, 50mM Tris-HCl, 150mM sodium chloride, 5mM EDTA, pH 7.6) containing a mixture of phosphatase inhibitors, sodium fluoride (Sigma-Aldrich, St. Louis, MO, USA), and sodium pyrophosphate decahydrate (Sigma-Aldrich).…”