Increased Hepatic PDGF-AA Signaling Mediates Liver Insulin Resistance in Obesity-Associated Type 2 Diabetes

Abderrahmani, Amar; Yengo, Loïc; Caïazzo, Robert; Canouil, Mickaël; Cauchi, Stéphane; Raverdy, Violeta; Plaisance, Valérie; Pawlowski, Valérie; Lobbens, Stéphane; Maillet, Julie OʼSullivan; Rolland, Laure; Boutry, Raphaël; Quéniat, Gurvan; Kwapich, Maxime; Tenenbaum, Mathie; Bricambert, Julien; Saussenthaler, Sophie; Anthony, Elodie; Jha, Pooja; Derop, Julien; Sand, Olivier; Rabearivelo, Iandry; Leloire, Audrey; Pigeyre, Marie; Daujat-Chavanieu, Martine; Gerbal‐Chaloin, Sabine; Dayeh, Tasnim; Lassailly, Guillaume; Maury, Philippe; Staels, Bart; Auwerx, Johan; Schürmann, Annette; Postic, Catherine; Schafmayer, Clemens; Hampe, Jochen; Bonnefond, Amélie; Pattou, François; Froguel, Philippe

doi:10.2337/db17-1539

Cited by 70 publications

(61 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Insulin acts via the insulin receptor to increase glucose uptake in all metabolic tissues while suppressing gluconeogenesis and inducing lipogenesis in the liver (Saltiel and Kahn, 2001;Samuel and Shulman, 2016;Vecchio et al, 2018). PDGF-AA acts through PDGFR-α and/or PDGFR-β to suppress hepatocyte insulin sensitivity (Abderrahmani et al, 2018), while PDGF-BB decreases insulin sensitivity in both the liver and white adipose tissue (Raines et al, 2011;Onogi et al, 2017). SCF promotes Pgc1α transcription and mitochondrial biogenesis in brown fat (Huang et al, 2014).…”

Section: Epidermal Growth Factormentioning

confidence: 99%

“…Both PDGFA overexpression and hypomethylation at a CpG site in PDGFA are associated with an increased risk of developing insulin resistance, type 2 diabetes, and steatohepatitis. In obese patients, increased liver PDGF-AA levels are positively associated with insulin resistance (Abderrahmani et al, 2018). In humans, PDGF-BB levels in urine are significantly increased in type 2 diabetic patients as compared to healthy individuals (Bessa et al, 2012).…”

Section: Pdgf-a and Pdgf-bmentioning

confidence: 99%

“…In addition, renal biopsies show overexpression of PDGF-BB in patients with diabetic nephropathy, suggesting that PDGF-BB might contribute to the development of fibrosis (Bessa et al, 2012). Mechanistically, PDGF-AA is thought to contribute to insulin resistance by suppressing the expression of the insulin receptor and insulin receptor substrate-1 (Abderrahmani et al, 2018). Consistent with these studies, hepatic insulin sensitivity can be restored by PDGF-AA-blocking antibodies and PDGF receptor inhibitors, supporting the notion that the increased PDGF-AA signaling contributes to insulin resistance (Abderrahmani et al, 2018).…”

Section: Pdgf-a and Pdgf-bmentioning

confidence: 99%

See 2 more Smart Citations

Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands

et al. 2020

View full text Add to dashboard Cite

Integrative Physiology, a section of the journal Frontiers in PhysiologyMetabolic diseases, such as diabetes, obesity, and fatty liver disease, have now reached epidemic proportions. Receptor tyrosine kinases (RTKs) are a family of cell surface receptors responding to growth factors, hormones, and cytokines to mediate a diverse set of fundamental cellular and metabolic signaling pathways. These ligands signal by endocrine, paracrine, or autocrine means in peripheral organs and in the central nervous system to control cellular and tissue-specific metabolic processes. Interestingly, the expression of many RTKs and their ligands are controlled by changes in metabolic demand, for example, during starvation, feeding, or obesity. In addition, studies of RTKs and their ligands in regulating energy homeostasis have revealed unexpected diversity in the mechanisms of action and their specific metabolic functions. Our current understanding of the molecular, biochemical and genetic control of energy homeostasis by the endocrine RTK ligands insulin, FGF21 and FGF19 are now relatively well understood. In addition to these classical endocrine signals, non-endocrine ligands can govern local energy regulation, and the intriguing crosstalk between the RTK family and the TGFβ receptor family demonstrates a signaling network that diversifies metabolic process between tissues. Thus, there is a need to increase our molecular and mechanistic understanding of signal diversification of RTK actions in metabolic disease. Here we review the known and emerging molecular mechanisms of RTK signaling that regulate systemic glucose and lipid metabolism, as well as highlighting unexpected roles of non-classical RTK ligands that crosstalk with other receptor pathways.

show abstract

Section: Epidermal Growth Factormentioning

confidence: 99%

Section: Pdgf-a and Pdgf-bmentioning

confidence: 99%

Section: Pdgf-a and Pdgf-bmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands

et al. 2020

View full text Add to dashboard Cite

show abstract

“…This state is associated with lipids accumulation not only in adipose tissue, but also in other tissues, such as skeletal muscle and the liver. Lipids storage in non-adipose tissue is thought to lead to several metabolic disturbances, including insulin resistance, type 2 diabetes (T2D) and cardiovascular disease [1][2][3][4]. Obesity has reached epidemic proportions worldwide, therefore insulin resistance and type 2 diabetes have become one of the most common chronic metabolic disorders.…”

Section: Introductionmentioning

confidence: 99%

“…Hepatic insulin resistance is mainly manifested by ineffective inhibition of the gluconeogenesis by insulin, which in consequence leads to an increase in blood glucose level. Excessive intrahepatic lipids accumulation is closely related to the occurrence of insulin resistance and non-alcoholic fatty liver disease (NAFLD) [1][2][3]. Most publications regarding hepatic insulin resistance and NAFLD in association with hepatic lipids, refer to triacylglycerols and cholesterol, which accumulate in the liver in the largest amount [5,6].…”

Section: Introductionmentioning

confidence: 99%

Ceramide Content in Liver Increases Along with Insulin Resistance in Obese Patients

Hady

Błachnio-Zabielska

Szczerbiński

et al. 2019

JCM

View full text Add to dashboard Cite

The liver plays a central role in the glucose and lipid metabolism. Studies performed on animal models have shown an important role of lipid accumulation in the induction of insulin resistance. We sought to explain whether in obese humans, the insulin resistance is associated with hepatic ceramide accumulation. The experiments were conducted on obese men and women. Each gender was divided into three groups: Normal glucose tolerance group (NGT), Impaired glucose tolerance group (IGT), and Type 2 diabetic subjects (T2D). Ceramide (Cer) content was analyzed with the use of LC/MS/MS. An oral glucose tolerance test (OGTT), glycosylated hemoglobin (HbA1c), percentage body fat (FAT%), and body mass index (BMI) was also measured. Total hepatic ceramide was significantly higher in T2D females as compared to NGT females (p < 0.05), whereas in males, total ceramide was significantly higher in IGT and T2D as compared to NGT (p < 0.05). In both, men and women, the highest increase in T2D subjects, was observed in C16:0-Cer, C18:0:-Cer, C22:0-Cer, and C24:0-Cer (p < 0.05) as compared to NGT group. Interestingly, glucose (at 0 and at 120 in OGTT) and HbA1c positively correlated with the ceramide species that most increased in T2D patients (C16:0-Cer, C18:0-Cer, C22:0-Cer, and C24:0-Cer). In men glucose and HbA1c significantly correlated with only C22:0-Cer. This is one of the few studies comparing hepatic ceramide content in severely obese patients. We found that, ceramide content increased in diabetic patients, both in men and women, and the content of ceramide correlated with glycemic parameters. These data indicate ceramide contribution to the induction of hepatic insulin resistance.

show abstract

The effect of high‐fat diet and inhibition of ceramide production on insulin action in liver

Zabielski

Daniluk

Hady

et al. 2018

Journal Cellular Physiology

View full text Add to dashboard Cite

Liver, as one of the most important organs involved in lipids and glucose metabolism, is perceived as a key tissue for pharmacotherapy of insulin resistance (IRes) and type 2 diabetes. Ceramides (Cer) are biologically active lipids, which accumulation is associated with the induction of muscle IRes. We sought to determine the role of intrahepatic bioactive lipids production on insulin action in liver of insulin-resistant rats and after myriocin administration. The experiments were conducted on male Wistar rats divided into three groups: Control, fed high-fat diet (HFD), and fed HFD and treated with myriocin (HFD/Myr). Before sacrifice, the animals were infused with a [U- C]palmitate to calculate lipid synthesis rate by means of tracer incorporation technique in particular lipid groups. Liver Cer, diacylglycerols (DAG), acyl-carnitine concentration, and isotopic enrichment were analyzed by LC/MS/MS. Proteins involved in lipid metabolism and insulin pathway were analyzed by western blot analysis. An OGTT and ITT was also performed. HFD-induced IRes and increased both the synthesis rate and the content of DAG and Cer, which was accompanied by inhibition of an insulin pathway. Interestingly, myriocin treatment reduced synthesis rate not only of Cer but also DAG and improved insulin sensitivity. We conclude that the insulin-sensitizing action of myriocin in the liver is a result of the lack of inhibitory effect of lipids on the insulin pathway, due to the reduction of their synthesis rate. This is the first study showing how the synthesis rate of individual lipid groups in liver changes after myriocin administration.

show abstract

Increased Hepatic PDGF-AA Signaling Mediates Liver Insulin Resistance in Obesity-Associated Type 2 Diabetes

Cited by 70 publications

References 56 publications

Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands

Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands

Ceramide Content in Liver Increases Along with Insulin Resistance in Obese Patients

The effect of high‐fat diet and inhibition of ceramide production on insulin action in liver

Contact Info

Product

Resources

About