title: Caloric restriction and intermittent fasting alter hepatic lipid droplet proteome and diacylglycerol species and prevent diabetes in NZO mice.
abstract: Caloric restriction and intermittent fasting are known to improve glucose homeostasis and insulin resistance in several species including humans. The aim of this study was to unravel potential mechanisms by which these interventions improve insulin sensitivity and protect from type 2 diabetes. Diabetes-susceptible New Zealand Obese mice were either 10% calorie restricted (CR) or fasted every other day (IF), and compared to ad libitum (AL) fed control mice. AL mice showed a diabetes prevalence of 43%, whereas mice under CR and IF were completely protected against hyperglycemia. Proteomic analysis of hepatic lipid droplets revealed significantly higher levels of PSMD9 (co-activator Bridge-1), MIF (macrophage migration inhibitor factor), TCEB2 (transcription elongation factor B (SIII), polypeptide 2), ACY1 (aminoacylase 1) and FABP5 (fatty acid binding protein 5), and a marked reduction of GSTA3 (glutathione S-transferase alpha 3) in samples of CR and IF mice. In addition, accumulation of diacylglycerols (DAGs) was significantly reduced in livers of IF mice (P=0.045) while CR mice showed a similar tendency (P=0.062). In particular, 9 DAG species were significantly reduced in response to IF, of which DAG-40:4 and DAG-40:7 also showed significant effects after CR. This was associated with a decreased PKCε activation and might explain the improved insulin sensitivity. In conclusion, our data indicate that protection against diabetes upon caloric restriction and intermittent fasting associates with a modulation of lipid droplet protein composition and reduction of intracellular DAG species.
authors: Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Arthur-Scheunert Allee 114-116, D-14558 Nuthetal, Germany; German Center of Diabetes Research, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany.
authors: Christian
authors: C
authors: Baumeier
authors: Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Arthur-Scheunert Allee 114-116, D-14558 Nuthetal, Germany; German Center of Diabetes Research, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany.
authors: Daniel
authors: D
authors: Kaiser
authors: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany.
authors: Jörg
authors: J
authors: Heeren
authors: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany.
authors: Ludger
authors: L
authors: Scheja
authors: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany.
authors: Clara
authors: C
authors: John
authors: Freie Universität Berlin, Institut für Chemie und Biochemie, Thielallee 63, D-14195 Berlin, Germany.
authors: Christoph
authors: C
authors: Weise
authors: Freie Universität Berlin, Institut für Chemie und Biochemie, Thielallee 63, D-14195 Berlin, Germany.
authors: Murat
authors: M
authors: Eravci
authors: Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Arthur-Scheunert Allee 114-116, D-14558 Nuthetal, Germany; German Center of Diabetes Research, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany.
authors: Merit
authors: M
authors: Lagerpusch
authors: Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Arthur-Scheunert Allee 114-116, D-14558 Nuthetal, Germany; German Center of Diabetes Research, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany.
authors: Gunnar
authors: G
authors: Schulze
authors: Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Arthur-Scheunert Allee 114-116, D-14558 Nuthetal, Germany; German Center of Diabetes Research, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany.
authors: Hans-Georg
authors: HG
authors: Joost
authors: Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Arthur-Scheunert Allee 114-116, D-14558 Nuthetal, Germany; German Center of Diabetes Research, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany.
authors: Robert Wolfgang
authors: RW
authors: Schwenk
authors: Department of Experimental Diabetology, German Institute of Human Nutrition (DIfE), Arthur-Scheunert Allee 114-116, D-14558 Nuthetal, Germany; German Center of Diabetes Research, Ingolstädter Landstraße 1, D-85764 Neuherberg, Germany. Electronic address: schuermann@dife.de.
authors: Annette
authors: A
authors: Schürmann
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D031204:Caloric Restriction; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D004075:Diglycerides / Q000378:metabolism*; D004195:Disease Models, Animal; D005215:Fasting; D005227:Fatty Acids / Q000378:metabolism; D005508:Food Deprivation; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D066292:Lipid Droplets / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000150:complications / Q000178:diet therapy*; D010084:Oxidation-Reduction; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D020543:Proteome / Q000378:metabolism*; D013997:Time Factors
chemical_list: D001786:Blood Glucose; D004075:Diglycerides; D005227:Fatty Acids; D007328:Insulin; D020543:Proteome; C497256:Prkce protein, mouse; D051744:Protein Kinase C-epsilon
keywords: Caloric restriction; Diacylglycerol; Fatty acid oxidation; Insulin resistance; Intermittent fasting; Lipid droplet proteome