Metformin-induced inhibition of the mitochondrial respiratory chain increases FGF21 expression via ATF4 activation

Kim, Kook Hwan; Jeong, Yeon Taek; Kim, Seong Hun; Jung, Hye Seung; Park, Kyong Soo; Lee, Hae Youn; Lee, Myung-Shik

doi:10.1016/j.bbrc.2013.09.026

Cited by 97 publications

(108 citation statements)

References 23 publications

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“…There are several mechanisms responsible for the increased FGF21 by metformin treatment. Some suggested that metformin induces FGF21 production in the liver in an activating transcription factor 4 (ATF4)-dependent way and inhibits mitochondrial respiration which is independent of AMPK and mTORC1 pathways [26]. Others suggested that metformin dose-dependently induces FGF21 expression in hepatocytes in an AMPKdependent pathway [23].…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…2C), supporting that autophagy deficiency is a proinflammatory condition facilitating inflammasome activation by lipid injury. We also studied mitochondrial ROS content that can be increased by mitochondrial dysfunction 25 and plays an important role in inflammasome activation by diverse effectors. 26 While LPS alone has minimal effects on the mitochondrial ROS content determined by MitoSOX Red staining, 25 mitochondrial ROS content was notably increased by PA in combination with LPS in autophagy-competent Mfs (Fig.…”

Section: Enhanced Inflammasome Activation In Autophagydeficient Mfsmentioning

confidence: 99%

“…Mitochondria-specific ROS was determined by flow cytometry using a FACSCalibur flow cytometer (BD Biosciences, San Jose, CA, USA) after staining with 5 mM MitoSOX TM Red (Invitrogen, M36008) for 10 min at 37 C. 25 NAD C :NADH ratio was determined using a commercial kit (BioVision, K337-100) according to the manufacturer's recommendation.…”

Section: Ros Content and Nad C : Nadh Ratiomentioning

confidence: 99%

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

et al. 2016

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(2016) Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis, Autophagy, 12:8, 1390-1403, DOI: 10.1080/15548627.2016 ABSTRACT Autophagy, which is critical for the proper turnover of organelles such as endoplasmic reticulum and mitochondria, affects diverse aspects of metabolism, and its dysregulation has been incriminated in various metabolic disorders. However, the role of autophagy of myeloid cells in adipose tissue inflammation and type 2 diabetes has not been addressed. We produced mice with myeloid cell-specific deletion of Atg7 (autophagy-related 7), an essential autophagy gene (Atg7 conditional knockout [cKO] mice). While Atg7 cKO mice were metabolically indistinguishable from control mice, they developed diabetes when bred to ob/w mice (Atg7 cKO-ob/ob mice), accompanied by increases in the crown-like structure, inflammatory cytokine expression and inflammasome activation in adipose tissue. Mfs (macrophages) from Atg7 cKO mice showed significantly higher interleukin 1 b release and inflammasome activation in response to a palmitic acid plus lipopolysaccharide combination. Moreover, a decrease in the NAD C :NADH ratio and increase in intracellular ROS content after treatment with palmitic acid in combination with lipopolysaccharide were more pronounced in Mfs from Atg7 cKO mice, suggesting that mitochondrial dysfunction in autophagy-deficient Mfs leads to an increase in lipid-induced inflammasome and metabolic deterioration in Atg7 cKO-ob/ob mice. Atg7 cKO mice were more susceptible to experimental colitis, accompanied by increased colonic cytokine expression, T helper 1 skewing and systemic bacterial invasion. These results suggest that autophagy of Mfs is important for the control of inflammasome activation in response to metabolic or extrinsic stress, and autophagy deficiency in Mfs may contribute to the progression of metabolic syndrome associated with lipid injury and colitis.

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“…In addition, FGF21 is a downstream target of PPARγ and is required for the anti-diabetic effects of PPARγ agonists [13]. Moreover, hepatic FGF21 is induced by ATF4, which is activated by metformin [14]. On the other hand, Nrf2 downregulates hepatic FGF21 production [14].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, hepatic FGF21 is induced by ATF4, which is activated by metformin [14]. On the other hand, Nrf2 downregulates hepatic FGF21 production [14]. Nrf2-deficient mice have higher plasma FGF21 levels and higher FGF21 mRNA levels in the liver than wild-type mice [15].…”

Section: Discussionmentioning

confidence: 99%

A Tryptophan Hydroxylase Inhibitor Decreases Hepatic FGF21 Expression and Circulating FGF21 in Mice Fed A High-Fat Diet

Nonogaki¹,

Kaji²,

Murakami³

2018

Neuropsychiatry

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Metformin-induced inhibition of the mitochondrial respiratory chain increases FGF21 expression via ATF4 activation

Cited by 97 publications

References 23 publications

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

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

Autophagy deficiency in myeloid cells increases susceptibility to obesity-induced diabetes and experimental colitis

A Tryptophan Hydroxylase Inhibitor Decreases Hepatic FGF21 Expression and Circulating FGF21 in Mice Fed A High-Fat Diet

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