Diabetes prevalence in NZO females depends on estrogen action on liver fat content.
In humans and rodents, risk of metabolic syndrome is sexually dimorphic, with an increased incidence in males. Additionally, the protective role of female gonadal hormones is ostensible, as prevalence of type 2 diabetes mellitus (T2DM) increases after menopause. Here, we investigated the influence of estrogen (E2) on the onset of T2DM in female New Zealand obese (NZO) mice. Diabetes prevalence (defined as blood glucose levels >16.6 mmol/l) of NZO females on high-fat diet (60 kcal% fat) in week 22 was 43%. This was markedly dependent on liver fat content in week 10, as detected by computed tomography. Only mice with a liver fat content >9% in week 10 plus glucose levels >10 mmol/l in week 9 developed hyperglycemia by week 22. In addition, at 11 wk, diacylglycerols were elevated in livers of diabetes-prone mice compared with controls. Hepatic expression profiles obtained from diabetes-prone and -resistant mice at 11 wk revealed increased abundance of two transcripts in diabetes-prone mice: Mogat1, which catalyzes the synthesis of diacylglycerols from monoacylglycerol and fatty acyl-CoA, and the fatty acid transporter Cd36. E2 treatment of diabetes-prone mice for 10 wk prevented any further increase in liver fat content and reduced diacylglycerols and the abundance of Mogat1 and Cd36, leading to a reduction of diabetes prevalence and an improved glucose tolerance compared with untreated mice. Our data indicate that early elevation of hepatic Cd36 and Mogat1 associates with increased production and accumulation of triglycerides and diacylglycerols, presumably resulting in reduced hepatic insulin sensitivity and leading to later onset of T2DM.
Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Nuthetal, Germany; German Center for Diabetes Research, Neuherberg, Germany;
Marko
M
Lubura
Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Nuthetal, Germany; German Center for Diabetes Research, Neuherberg, Germany;
Deike
D
Hesse
Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Nuthetal, Germany; German Center for Diabetes Research, Neuherberg, Germany;
Maria
M
Kraemer
Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Nuthetal, Germany; German Center for Diabetes Research, Neuherberg, Germany;
Nicole
N
Hallahan
Institute of Pharmacology, Center for Cardiovascular Research, Charité University Medicine, Berlin, Germany;
Michael
M
Schupp
German Center for Diabetes Research, Neuherberg, Germany; Department of Clinical Nutrition, DIfE, Nuthetal, Germany; Integrated Research and Treatment Center, Center for Sepsis Control and Care, Friedrich Schiller University, and Department of Anaesthesiology and Intensive Care, Jena University Hospital, Jena, Germany;
Christian
C
von Löffelholz
German Center for Diabetes Research, Neuherberg, Germany; Research Unit of Molecular Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, German Center for Diabetes Research, and Institute of Epidemiology II, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany;
Jennifer
J
Kriebel
German Center for Diabetes Research, Neuherberg, Germany; Department of Clinical Nutrition, DIfE, Nuthetal, Germany;
Natalia
N
Rudovich
German Center for Diabetes Research, Neuherberg, Germany; Department of Clinical Nutrition, DIfE, Nuthetal, Germany;
Andreas
A
Pfeiffer
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
Clara
C
John
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
Ludger
L
Scheja
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany;
Joerg
J
Heeren
German Center for Diabetes Research, Neuherberg, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany; and Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Chryssi
C
Koliaki
German Center for Diabetes Research, Neuherberg, Germany; Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute for Diabetes Research, Heinrich Heine University, Düsseldorf, Germany; and Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
Michael
M
Roden
Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Nuthetal, Germany; German Center for Diabetes Research, Neuherberg, Germany; schuermann@dife.de.
Annette
A
Schürmann
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004967:Estrogens / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism*; D015995:Prevalence; D051381:Rats
D004967:Estrogens; D005227:Fatty Acids
New Zealand obese mice; diacylglycerol; estrogen; hepatic steatosis; type 2 diabetes