The effect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats

Lv, Wenshan; Wen, Junping; Li, Li; Sun, Ruixia; Wang, Jing; Yang, Xian; Cao, Caixia; Wang, Yunlong; Gao, Yongxing

doi:10.1016/j.brainres.2012.01.028

Cited by 97 publications

(84 citation statements)

References 33 publications

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“…It has been observed that metformin can cross blood brain barrier and provokes effect in the central nervous system (CNS) and in the metabolism. 20,21 Changes in CNS during early phases is one the keys to change CNS structure and function, which induces a permanent changes in organism The data represent the mean § SEM obtained from each experimental group. * V P < 0.05, compared to control, by Student's t-test.…”

Section: Discussionmentioning

confidence: 99%

Early treatment with metformin induces resistance against tumor growth in adult rats

Trombini

Franco

Miranda

et al. 2015

Cancer Biology & Therapy

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These authors contributed equally to this work.Keywords: adolescence, antidiabetic, early treatment, metformin, prevention, tumor growth inhibition, Walker 256 tumor Abbreviations: AUC, area under the curve; HOMA-IR, homeostasis model assessment of insulin resistance; HOMA-b, homeostasis model assessment of b-cell function; LBW, body weight loss; MHC-I, major histocompatibility complex class I; NAL, nasal anal length; VEGF, vascular endothelial growth factor.It is known that antidiabetic drug metformin, which is used worldwide, has anti-cancer effects and can be used to prevent cancer growth. We tested the hypothesis that tumor cell growth can be inhibited by early treatment with metformin. For this purpose, adult rats chronically treated with metformin in adolescence or in adulthood were inoculated with Walker 256 carcinoma cells. Adult rats that were treated with metformin during adolescence presented inhibition of tumor growth, and animals that were treated during adult life did not demonstrate any changes in tumor growth. Although we do not have data to disclose a molecular mechanism to the preventive metformin effect, we present, for the first time, results showing that cancer growth in adult life is dependent on early life intervention, thus supporting a new therapeutic prevention for cancer.

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Section: Discussionmentioning

confidence: 99%

Early treatment with metformin induces resistance against tumor growth in adult rats

Trombini

Franco

Miranda

et al. 2015

Cancer Biology & Therapy

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“…The mechanisms by which metformin exerts body-lowering effects are still in a discussion. Some suggested that metformin can induce hypothalamic leptin receptor expression and increase central leptin sensitivity which then inhibits food intake [17]. Others suggested that changed gastrointestinal physiology and circadian rhythm by metformin could also affect food intake, fat oxidation and storage [18].…”

Section: Effects Of Metformin On Glucose Insulin and Lipid Profilesmentioning

confidence: 99%

The effects of metformin on fibroblast growth factor 19, 21 and fibroblast growth factor receptor 1 in high-fat diet and streptozotocin induced diabetic rats

et al. 2017

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TYPE 2 DIABETES MELLITUS (T2DM) is associated with obesity and insulin resistance and has severe complications. As an effective and safe oral drug, metformin has been used to treat T2DM for almost fifty years. Possible mechanisms of metformin in improving glucose homeostasis are partially depended on the activation of adenosine monophosphate-activated protein kinase (AMPK) which then inhibits glucose output and increases insulin sensitivity in peripheral tissues [1].Fibroblast growth factor-19 (FGF19) and FGF21 belong to beta-klotho family, and recent studies showedThe effects of metformin on fibroblast growth factor 19, 21 and fibroblast growth factor receptor 1 in high-fat diet and streptozotocin induced diabetic rats Yan Wang 1), 2) , Ningning Dang 3) , Pei Sun 2) , Jin Xia 2), 4) , Chunxue Zhang 2), 4) and Shuguang Pang 1), 2), 4) Abstract. To understand metformin's effects on fibroblast growth factors (FGFs) and fibroblast growth factor receptor 1 (FGFR1), we investigated circulating fibroblast growth factor-19 (FGF19), FGF21 levels, and FGFR1 in type 2 diabetes mellitus (T2DM). In addition, protein kinase B (Akt) signaling pathway was detected to explain the possible mechanisms. T2DM was induced by feeding rats with high-fat diet for 11 weeks, followed by a low dose of streptozotocin (STZ, 30-35 mg/kg, intraperitoneally). Control rats (Con) were fed on a normal chow; diabetic rats (DM) were fed on high-fat diet supplemented with or without metformin (METF) for 12 weeks (500 mg·kg -1 ·d -1 ). Biochemical parameters were detected at the end of 24th weeks. FGFR1 expression and protein kinase B (Akt) phosphorylation in the pancreas and visceral adipose tissues were detected using either Western blot (WB) or immunohistochemistry (IHC). Serum FGF19 and FGF21 were measured using enzyme-linked immune sorbent assay (ELISA). Metformin treated DM rats showed improved glucose, lipid and bile acid metabolism. Besides, significantly decreased FGF19 and increased FGF21 were observed in DM+METF rats. DM rats showed significantly increased FGFR1 both in the pancreas and visceral adipose tissues. While in DM+METF rats, FGFR1 was almost remained at a normal level in the pancreas and increased in the visceral adipose tissue compared to that in DM rats. Besides, metformin treatment restores Akt phosphorylation in both tissues. The altered glucose and lipid profiles by metformin treatment may be associated with the increased circulating FGF21 and tissue-specific expressions of FGFR1.Key words: Diabetes, FGF21, FGFR1, β cell, Visceral adipose that they were produced by the activation of Farnesoid X Receptor (FXR) in the ileum and liver, respectively [2,3]. FGF19 and FGF21 are emerging as endocrine hormones since they showed novel roles in bile acid, lipid, and glucose metabolism [4][5][6]. In obese or diabetic animal models, administration of FGF19 and FGF21 led to beneficial effects on metabolism through increasing insulin sensitivity, energy expenditure and white adipose browning [7][8][9][10].FGFs exert their roles by binding...

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“…The details of hypothalamic involvement in metformininduced anorexia have not been clarified by previous studies (16,19,27). Some reports have shown that metformin treatment affects the hypothalamic neuropeptide Y (NPY) system in obese rats and mice, although the effect of metformin on neuropeptide systems requires further investigation (19,27).…”

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confidence: 99%

“…The weight loss induced by metformin in humans and mice has mainly been attributed to a reduction in food intake (15,19,27,30). Despite the clear evidence for reduced food intake after metformin treatment, the underlying mechanism of its anorectic action remains unclear.…”

mentioning

confidence: 99%

“…Some reports have shown that metformin treatment affects the hypothalamic neuropeptide Y (NPY) system in obese rats and mice, although the effect of metformin on neuropeptide systems requires further investigation (19,27). A direct effect of metformin on hypothalamic AMPK was not observed in studies of food intake, despite the strong evidence for AMPK-mediated improvement of glucose regulation induced by metformin (16,19,29,35). In addition to the association between the hypothalamus and metformin-induced anorexia, we have shown that peripheral administration of metformin may reduce food intake via neuronal activation in the hindbrain regions that mediate satiety signals from peripheral tissues (15).…”

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confidence: 99%

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

Kim

Park

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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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

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The effect of metformin on food intake and its potential role in hypothalamic regulation in obese diabetic rats

Cited by 97 publications

References 33 publications

Early treatment with metformin induces resistance against tumor growth in adult rats

Early treatment with metformin induces resistance against tumor growth in adult rats

The effects of metformin on fibroblast growth factor 19, 21 and fibroblast growth factor receptor 1 in high-fat diet and streptozotocin induced diabetic rats

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

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