Leptin as a Potential Regulator of FGF21

Asrih, Mohamed; Veyrat-Durebex, Christelle; Poher, Anne-Laure; Lyautey, Jacqueline; Rohner‐Jeanrenaud, Françoise; Jornayvaz, François R.

doi:10.1159/000443070

Cited by 33 publications

(30 citation statements)

References 44 publications

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“…Our studies demonstrated that FGF-21 binds to its receptor initiating some signalling cascades to increase glucose uptake via regulation of the glucose tranporter-1 (GLUT-1) and simultaneously participates in glycogen storage in the liver. Although several studies focused on the identification of FGF21 mediators, such as PPARalpha and leptin, the information of the FGF21-specific signalling pathway is still very limited at present [34]. FGF-21 enhances glucose uptake by hepatocytes, suppresses hepatic glucose production and increases liver glycogen in vivo .…”

Section: Discussionmentioning

confidence: 99%

Liver Plays a Major Role in FGF-21 Mediated Glucose Homeostasis

Liu

Cao

Hou

et al. 2018

Cell Physiol Biochem

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Background/Aims: The liver is a vital organ in vertebrates and has a wide range of functions, including glucose absorption, glycogen storage and glucose production. Fibroblast growth factor (FGF)-21 is a metabolic regulator that is primarily produced by the liver. In this paper, we studied the effect of FGF-21 on glucose metabolism in the liver. Methods: The glucose uptake of cells was detected by 2-Deoxy-d-[³H] glucose; the synergy between insulin and FGF-21 was evaluated. The mRNA expression of GLUT1-4, G6Pase and PEPCK was detected by real-time PCR. Glycogen synthesis was examined by the anthrone method. Blood samples to monitor glucose in db/db diabetic mice were obtained by tail snip. Glucose metabolism in the liver and adipose tissues was observed by fluorescence microscopy. Results: In this study, FGF-21 stimulated glucose uptake by liver cells in both a dose and time-dependent manner, and at the same time, FGF-21 specifically stimulated GLUT1 expression in the liver cells. Furthermore, FGF-21 demonstrated a synergistic effect with insulin on glucose absorption, which is in accordance with enhanced GLUT-1 and -4 expression. Treatment with FGF-21 increased glycogen storage in liver cells. Consistent with in vitro results, FGF-21 lowered the plasma glucose level and stimulated GLUT1 expression and glycogen synthesis in db/db diabetic mice. Simultaneously, FGF-21 inhibited the gene expression of G6Pase and PEPCK. Conclusion: Our results suggest that FGF-21 clears up plasma glucose by stimulating glucose absorption in the liver of diabetic animals and decreases glucose release from the liver by inhibiting gluconeogenesis. Overall, these data indicate that the liver is an important target organ of FGF-21 to regulate glucose metabolism.

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Section: Discussionmentioning

confidence: 99%

Liver Plays a Major Role in FGF-21 Mediated Glucose Homeostasis

Liu

Cao

Hou

et al. 2018

Cell Physiol Biochem

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“…Adipose tissue regulates insulin sensitivity and energy homeostasis of peripheral tissues via the secretion of adipokines. The first adipokine to be discovered was leptin, which promotes metabolic health by increasing fat oxidation in muscle cells and modulates several metabolic regulators such as fibroblast growth factor 21 [3]. More recently, the ectoenzyme autotaxin (ATX) was discovered converting lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA) [4].…”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidic Acid Inhibits Insulin Signaling in Primary Rat Hepatocytes via the LPA3 Receptor Subtype and is Increased in Obesity

Fayyaz

Japtok

Schumacher

et al. 2017

Cell Physiol Biochem

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Background/Aims: Obesity is a main risk factor for the development of hepatic insulin resistance and it is accompanied by adipocyte hypertrophy and an elevated expression of different adipokines such as autotaxin (ATX). ATX converts lysophosphatidylcholine to lysophosphatidic acid (LPA) and acts as the main producer of extracellular LPA. This bioactive lipid regulates a broad range of physiological and pathological responses by activation of LPA receptors (LPA_1-6). Methods: The activation of phosphatidylinositide 3-kinases (PI₃K) signaling (Akt and GSK-3ß) was analyzed via western blotting in primary rat hepatocytes. Incorporation of glucose into glycogen was measured by using radio labeled glucose. Real-time PCR analysis and pharmacological modulation of LPA receptors were performed. Human plasma LPA levels of obese (BMI > 30, n = 18) and normal weight individuals (BMI 18.5-25, n = 14) were analyzed by liquid chromatography tandem-mass spectrometry (LC-MS/MS). Results: Pretreatment of primary hepatocytes with LPA resulted in an inhibition of insulin-mediated Gck expression, PI₃K activation and glycogen synthesis. Pharmacological approaches revealed that the LPA₃-receptor subtype is responsible for the inhibitory effect of LPA on insulin signaling. Moreover, human plasma LPA concentrations (16: 0 LPA) of obese participants (BMI > 30) are significantly elevated in comparison to normal weight individuals (BMI 18.5-25). Conclusion: LPA is able to interrupt insulin signaling in primary rat hepatocytes via the LPA₃ receptor subtype. Moreover, the bioactive lipid LPA (16: 0) is increased in obesity.

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“…Leptin is closely linked with several growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor 21 (FGF21), and insulin-like growth factor-1 (IGF-1) [5], [6], [7] (Table 1) [1], [4], [8], [9], [10], [11]. A study on human subjects detected an increased gene expression of leptin and IGF-1 in the subcutaneous fat of the obese group, while the expression of IGF-1 in the visceral fat was higher in the control group (non-obese cholecystectomy cases) [12].…”

Section: Introductionmentioning

confidence: 99%

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

Ray

2017

Hormone Molecular Biology and Clinical Investigation

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Abstract:Obesity is associated with the risk of several health disorders including certain cancers. Among obesity-related cancers, postmenopausal breast carcinoma is a well-studied one. Apart from an increase in certain types of lipids in obesity, excess adipose tissue releases many hormone-like cytokines/adipokines, which are usually pro-inflammatory in nature. Leptin is one of such adipokines and significantly linked with the intracellular signaling pathways of other growth factors such as insulin-like growth factor-1 (IGF-1), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2). In general, HER2 is overexpressed in roughly 30% of breast carcinomas; its presence indicates aggressive tumor behavior. Conversely, HER2 has certain effects in normal conditions such as differentiation of preadipocytes, cardiovascular health and vitamin D metabolism. HER2 has no known endogenous ligand, but it may form dimers with other three members of the epidermal growth factor receptor (EGFR) family and can activate downstream signaling pathways. Furthermore, HER2 is intimately connected with several enzymes, e.g. fatty acid synthase (FASN), phosphatidylinositol 3-kinase (PI3K), AKT and mechanistic target of rapamycin (mTOR), all of which play significant regulatory roles in lipogenic pathways or lipid metabolism. In obesity-related carcinogenesis, characteristics like insulin resistance and elevated IGF-1 are commonly observed. Both IGF-1 and leptin can modulate EGFR and HER2 signaling pathways. Although clinical studies have shown mixed results, the behavior of HER2+ tumor cells including HER2 levels can be altered by several factors such as obesity, leptin and fatty acids. A precise knowledge is useful in new therapeutic approaches against HER+ tumors.

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Leptin as a Potential Regulator of FGF21

Cited by 33 publications

References 44 publications

Liver Plays a Major Role in FGF-21 Mediated Glucose Homeostasis

Liver Plays a Major Role in FGF-21 Mediated Glucose Homeostasis

Lysophosphatidic Acid Inhibits Insulin Signaling in Primary Rat Hepatocytes via the LPA3 Receptor Subtype and is Increased in Obesity

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

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