Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk
Liver-derived circulating factors deeply affect the metabolism of distal organs. Herein, we took advantage of the hepatocyte-specific PTEN knockout mice (LPTENKO), a model of hepatic steatosis associated with increased muscle insulin sensitivity and decreased adiposity, to identify potential secrete...
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MDPI AG
2022-04-01
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| Series: | International Journal of Molecular Sciences |
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| author | Flavien Berthou Cyril Sobolewski Daniel Abegg Margot Fournier Christine Maeder Dobrochna Dolicka Marta Correia de Sousa Alexander Adibekian Michelangelo Foti |
| author_facet | Flavien Berthou Cyril Sobolewski Daniel Abegg Margot Fournier Christine Maeder Dobrochna Dolicka Marta Correia de Sousa Alexander Adibekian Michelangelo Foti |
| author_sort | Flavien Berthou |
| collection | DOAJ |
| description | Liver-derived circulating factors deeply affect the metabolism of distal organs. Herein, we took advantage of the hepatocyte-specific PTEN knockout mice (LPTENKO), a model of hepatic steatosis associated with increased muscle insulin sensitivity and decreased adiposity, to identify potential secreted hepatic factors improving metabolic homeostasis. Our results indicated that protein factors, rather than specific metabolites, released by PTEN-deficient hepatocytes trigger an improved muscle insulin sensitivity and a decreased adiposity in LPTENKO. In this regard, a proteomic analysis of conditioned media from PTEN-deficient primary hepatocytes identified seven hepatokines whose expression/secretion was deregulated. Distinct expression patterns of these hepatokines were observed in hepatic tissues from human/mouse with NAFLD. The expression of specific factors was regulated by the PTEN/PI3K, PPAR or AMPK signaling pathways and/or modulated by classical antidiabetic drugs. Finally, loss-of-function studies identified FGF21 and the triad AHSG, ANGPTL4 and LECT2 as key regulators of insulin sensitivity in muscle cells and in adipocytes biogenesis, respectively. These data indicate that hepatic PTEN deficiency and steatosis alter the expression/secretion of hepatokines regulating insulin sensitivity in muscles and the lipid metabolism in adipose tissue. These hepatokines could represent potential therapeutic targets to treat obesity and insulin resistance. |
| first_indexed | 2024-03-09T11:44:37Z |
| format | Article |
| id | doaj.art-8ee15058d76c484e9069db329c8790f1 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T11:44:37Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-8ee15058d76c484e9069db329c8790f12023-11-30T23:24:35ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-04-01237395910.3390/ijms23073959Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs CrosstalkFlavien Berthou0Cyril Sobolewski1Daniel Abegg2Margot Fournier3Christine Maeder4Dobrochna Dolicka5Marta Correia de Sousa6Alexander Adibekian7Michelangelo Foti8Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, SwitzerlandDepartment of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, SwitzerlandDepartment of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USADepartment of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, SwitzerlandDepartment of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, SwitzerlandDepartment of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, SwitzerlandDepartment of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, SwitzerlandDepartment of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USADepartment of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, 1206 Geneva, SwitzerlandLiver-derived circulating factors deeply affect the metabolism of distal organs. Herein, we took advantage of the hepatocyte-specific PTEN knockout mice (LPTENKO), a model of hepatic steatosis associated with increased muscle insulin sensitivity and decreased adiposity, to identify potential secreted hepatic factors improving metabolic homeostasis. Our results indicated that protein factors, rather than specific metabolites, released by PTEN-deficient hepatocytes trigger an improved muscle insulin sensitivity and a decreased adiposity in LPTENKO. In this regard, a proteomic analysis of conditioned media from PTEN-deficient primary hepatocytes identified seven hepatokines whose expression/secretion was deregulated. Distinct expression patterns of these hepatokines were observed in hepatic tissues from human/mouse with NAFLD. The expression of specific factors was regulated by the PTEN/PI3K, PPAR or AMPK signaling pathways and/or modulated by classical antidiabetic drugs. Finally, loss-of-function studies identified FGF21 and the triad AHSG, ANGPTL4 and LECT2 as key regulators of insulin sensitivity in muscle cells and in adipocytes biogenesis, respectively. These data indicate that hepatic PTEN deficiency and steatosis alter the expression/secretion of hepatokines regulating insulin sensitivity in muscles and the lipid metabolism in adipose tissue. These hepatokines could represent potential therapeutic targets to treat obesity and insulin resistance.https://www.mdpi.com/1422-0067/23/7/3959hepatokinesPTENFGF21obesityinsulin resistanceNAFLD |
| spellingShingle | Flavien Berthou Cyril Sobolewski Daniel Abegg Margot Fournier Christine Maeder Dobrochna Dolicka Marta Correia de Sousa Alexander Adibekian Michelangelo Foti Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk International Journal of Molecular Sciences hepatokines PTEN FGF21 obesity insulin resistance NAFLD |
| title | Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk |
| title_full | Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk |
| title_fullStr | Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk |
| title_full_unstemmed | Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk |
| title_short | Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk |
| title_sort | hepatic pten signaling regulates systemic metabolic homeostasis through hepatokines mediated liver to peripheral organs crosstalk |
| topic | hepatokines PTEN FGF21 obesity insulin resistance NAFLD |
| url | https://www.mdpi.com/1422-0067/23/7/3959 |
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