TY - JOUR
T1 - Alterations of hepatic energy metabolism in murine models of obesity, diabetes and fatty liver diseases
AU - Dewidar, Bedair
AU - Mastrototaro, Lucia
AU - Englisch, Cornelia
AU - Ress, Claudia
AU - Granata, Cesare
AU - Rohbeck, Elisabeth
AU - Pesta, Dominik
AU - Heilmann, Geronimo
AU - Wolkersdorfer, Martin
AU - Esposito, Irene
AU - Reina Do Fundo, Michelle
AU - Zivehe, Fariba
AU - Yavas, Aslihan
AU - Roden, Michael
N1 - Funding Information:
This study is supported in part by the Ministry of Science and Research of the State of North Rhine-Westfalia (MIWF NRW), the German Federal Ministry of Health (BMG), to the German Diabetes Centrer (DDZ) and by a grant of the Federal Ministry for Research (BMBF) to the German Center for Diabetes Research (DZD e.V.). Furthermore, the study is supported in part by grants from the KomIT - Center of Competence for Innovative Diabetes Therapy ( EFRE-0400192 ), the German Research Foundation (DFG, Grant No. 236177352 -SFB 1116/2), the German Diabetes Association (DDG) and the Schmutzler Stiftung to MR and by a DZD grant awarded to BD. GH was supported by Jühling Award. The authors thank Mr. Jan-Marc Leonhard and Mrs. Olga Dürrschmidt for their excellent technical assistance with immunoblotting, ELISA assays and qPCR, and Dr. Daniel Markgraf, Dr. Sandra Trenkamp, and Mr. Tim te Poel for their help with glucose tracer studies.
Funding Information:
This study is supported in part by the Ministry of Science and Research of the State of North Rhine-Westfalia (MIWF NRW), the German Federal Ministry of Health (BMG), to the German Diabetes Centrer (DDZ) and by a grant of the Federal Ministry for Research (BMBF) to the German Center for Diabetes Research (DZD e.V.). Furthermore, the study is supported in part by grants from the KomIT-Center of Competence for Innovative Diabetes Therapy (EFRE-0400192), the German Research Foundation (DFG, Grant No. 236177352-SFB 1116/2), the German Diabetes Association (DDG) and the Schmutzler Stiftung to MR and by a DZD grant awarded to BD. GH was supported by Jühling Award. The authors thank Mr. Jan-Marc Leonhard and Mrs. Olga Dürrschmidt for their excellent technical assistance with immunoblotting, ELISA assays and qPCR, and Dr. Daniel Markgraf, Dr. Sandra Trenkamp, and Mr. Tim te Poel for their help with glucose tracer studies.
Publisher Copyright:
© 2023 The Authors
PY - 2023/8
Y1 - 2023/8
N2 - Background: Disturbed hepatic energy metabolism contributes to non-alcoholic fatty liver (NAFLD), but the development of changes over time and obesity- or diabetes-related mechanisms remained unclear. Methods: Two-day old male C57BL/6j mice received streptozotocin (STZ) or placebo (PLC) and then high-fat (HFD) or regular chow diet (RCD) from week 4 (W4) to either W8 or W16, yielding control [CTRL = PLC + RCD], diabetes [DIAB = STZ + RCD], obesity [OBES = PLC + HFD] and diabetes-related non-alcoholic steatohepatitis [NASH = STZ + HFD] models. Mitochondrial respiration was measured by high-resolution respirometry and insulin-sensitive glucose metabolism by hyperinsulinemic-euglycemic clamps with stable isotope dilution. Findings: NASH showed higher steatosis and NAFLD activity already at W8 and liver fibrosis at W16 (all p < 0.01 vs CTRL). Ballooning was increased in DIAB and NASH at W16 (p < 0.01 vs CTRL). At W16, insulin sensitivity was 47%, 58% and 75% lower in DIAB, NASH and OBES (p < 0.001 vs CTRL). Hepatic uncoupled fatty acid oxidation (FAO)-associated respiration was reduced in OBES at W8, but doubled in DIAB and NASH at W16 (p < 0.01 vs CTRL) and correlated with biomarkers of unfolded protein response (UPR), oxidative stress and hepatic expression of certain enzymes (acetyl-CoA carboxylase 2, Acc2; carnitine palmitoyltransferase I, Cpt1a). Tricarboxylic acid cycle (TCA)-driven respiration was lower in OBES at W8 and doubled in DIAB at W16 (p < 0.0001 vs CTRL), which positively correlated with expression of genes related to lipolysis. Interpretation: Hepatic mitochondria adapt to various metabolic challenges with increasing FAO-driven respiration, which is linked to dysfunctional UPR, systemic oxidative stress, insulin resistance and altered lipid metabolism. In a diabetes model, higher TCA-linked respiration reflected mitochondrial adaptation to greater hepatic lipid turnover. Funding: Funding bodies that contributed to this study were listed in the acknowledgements section.
AB - Background: Disturbed hepatic energy metabolism contributes to non-alcoholic fatty liver (NAFLD), but the development of changes over time and obesity- or diabetes-related mechanisms remained unclear. Methods: Two-day old male C57BL/6j mice received streptozotocin (STZ) or placebo (PLC) and then high-fat (HFD) or regular chow diet (RCD) from week 4 (W4) to either W8 or W16, yielding control [CTRL = PLC + RCD], diabetes [DIAB = STZ + RCD], obesity [OBES = PLC + HFD] and diabetes-related non-alcoholic steatohepatitis [NASH = STZ + HFD] models. Mitochondrial respiration was measured by high-resolution respirometry and insulin-sensitive glucose metabolism by hyperinsulinemic-euglycemic clamps with stable isotope dilution. Findings: NASH showed higher steatosis and NAFLD activity already at W8 and liver fibrosis at W16 (all p < 0.01 vs CTRL). Ballooning was increased in DIAB and NASH at W16 (p < 0.01 vs CTRL). At W16, insulin sensitivity was 47%, 58% and 75% lower in DIAB, NASH and OBES (p < 0.001 vs CTRL). Hepatic uncoupled fatty acid oxidation (FAO)-associated respiration was reduced in OBES at W8, but doubled in DIAB and NASH at W16 (p < 0.01 vs CTRL) and correlated with biomarkers of unfolded protein response (UPR), oxidative stress and hepatic expression of certain enzymes (acetyl-CoA carboxylase 2, Acc2; carnitine palmitoyltransferase I, Cpt1a). Tricarboxylic acid cycle (TCA)-driven respiration was lower in OBES at W8 and doubled in DIAB at W16 (p < 0.0001 vs CTRL), which positively correlated with expression of genes related to lipolysis. Interpretation: Hepatic mitochondria adapt to various metabolic challenges with increasing FAO-driven respiration, which is linked to dysfunctional UPR, systemic oxidative stress, insulin resistance and altered lipid metabolism. In a diabetes model, higher TCA-linked respiration reflected mitochondrial adaptation to greater hepatic lipid turnover. Funding: Funding bodies that contributed to this study were listed in the acknowledgements section.
KW - Fatty liver
KW - High-resolution respirometry
KW - Insulin resistance
KW - Mitochondria
KW - Type 1 diabetes
KW - Type 2 diabetes
KW - Unfolded protein response
UR - http://www.scopus.com/inward/record.url?scp=85165235876&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2023.104714
DO - 10.1016/j.ebiom.2023.104714
M3 - Article
C2 - 37454552
AN - SCOPUS:85165235876
SN - 2352-3964
VL - 94
JO - EBioMedicine
JF - EBioMedicine
M1 - 104714
ER -
