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. 2017 Jan 6;6(3):256-266.
doi: 10.1016/j.molmet.2016.12.007. eCollection 2017 Mar.

Bezafibrate ameliorates diabetes via reduced steatosis and improved hepatic insulin sensitivity in diabetic TallyHo mice

Andras Franko  1 , Susanne Neschen  2 , Jan Rozman  3 , Birgit Rathkolb  4 , Michaela Aichler  5 , Annette Feuchtinger  5 , Laura Brachthäuser  6 , Frauke Neff  6 , Marketa Kovarova  7 , Eckhard Wolf  8 , Helmut Fuchs  2 , Hans-Ulrich Häring  9 , Andreas Peter  9 , Martin Hrabě de Angelis  10
Affiliations

Bezafibrate ameliorates diabetes via reduced steatosis and improved hepatic insulin sensitivity in diabetic TallyHo mice

Andras Franko et al. Mol Metab. .

Abstract

Objective: Recently, we have shown that Bezafibrate (BEZ), the pan-PPAR (peroxisome proliferator-activated receptor) activator, ameliorated diabetes in insulin deficient streptozotocin treated diabetic mice. In order to study whether BEZ can also improve glucose metabolism in a mouse model for fatty liver and type 2 diabetes, the drug was applied to TallyHo mice.

Methods: TallyHo mice were divided into an early (ED) and late (LD) diabetes progression group and both groups were treated with 0.5% BEZ (BEZ group) or standard diet (SD group) for 8 weeks. We analyzed plasma parameters, pancreatic beta-cell morphology, and mass as well as glucose metabolism of the BEZ-treated and control mice. Furthermore, liver fat content and composition as well as hepatic gluconeogenesis and mitochondrial mass were determined.

Results: Plasma lipid and glucose levels were markedly reduced upon BEZ treatment, which was accompanied by elevated insulin sensitivity index as well as glucose tolerance, respectively. BEZ increased islet area in the pancreas. Furthermore, BEZ treatment improved energy expenditure and metabolic flexibility. In the liver, BEZ ameliorated steatosis, modified lipid composition and increased mitochondrial mass, which was accompanied by reduced hepatic gluconeogenesis.

Conclusions: Our data showed that BEZ ameliorates diabetes probably via reduced steatosis, enhanced hepatic mitochondrial mass, improved metabolic flexibility and elevated hepatic insulin sensitivity in TallyHo mice, suggesting that BEZ treatment could be beneficial for patients with NAFLD and impaired glucose metabolism.

Keywords: BEZ, Bezafibrate; BG, blood glucose; Bezafibrate; ED, early onset of diabetes; EM, electron microscopy; FA, fatty acid; Glucose metabolism; HOMA-IR, homeostatic model assessment of insulin resistance; Insulin resistance; LD, late onset of diabetes; Lipid metabolism; NAFLD; NAFLD, non-alcoholic fatty liver disease; NEFA, non-esterified fatty acid; PPAR, peroxisome proliferator-activated receptor; RER, respiratory exchange ratios; SD, standard diet; T2D, type 2 diabetes; TG, triglyceride; qNMR, quantitative nuclear magnetic resonance.

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Figures

Figure 1
Figure 1
Levels of blood glucose, plasma lipid, insulin, and glucose tolerance test. A. The figure represents the averages of weekly measured blood glucose values (values for week 9 are also showed as Suppl. Figure 1A). TallyHo mice were split into two groups according to the 9 weeks old blood glucose values (early onset of diabetes (ED) group: >200 mg/dl, late onset of diabetes (LD) group: <200 mg/dl). BEZ (or SD) feeding was started at 9 weeks of age and lasted for 8 weeks. Standard diet (SD), BEZ diet (BEZ). B. Plasma non-esterified fatty acids (NEFA) and C. triglyceride (TG) levels. D. Fasted blood glucose (BG) values. E. Plasma insulin levels. F. Homeostatic model assessment of insulin resistance (HOMA-IR) values. G. Glucose tolerance test (GTT) and H. area under the curve (AUC) evaluation. Columns represent averages ± standard deviations; n = 6–12. *denotes significant differences between ED, BEZ vs. ED, SD; **p < 0.01, ***p < 0.001; #denotes significant differences between ED, SD vs. LD, SD; ##p < 0.01, ###p < 0.001; §denotes significant differences between LD, BEZ vs. LD, SD; §§§p < 0.001.
Figure 2
Figure 2
Pancreas architecture. A. Pancreata were stained with anti-insulin (green) and anti-glucagon (red) antibodies and visualized by fluorescence microscopy. Cell nuclei were stained with DAPI (blue). The white bar represents 50 μm. Representative areas are shown. B. Insulin area normalized to islet area and C. total insulin area normalized to pancreas area were calculated using Architect software. D. Islet number was manually counted and values were normalized to total pancreas area. Columns represent averages ± standard deviations; n = 5. *denotes significant differences between ED, BEZ vs. ED, SD; *p < 0.05, **p < 0.01; #denotes significant differences between ED, SD vs. LD, SD; ##p < 0.01; §denotes significant differences between LD, BEZ vs. LD, SD; §§p < 0.01.
Figure 3
Figure 3
Body composition and indirect calorimetry. A. Body weight. B. Fat and C. lean mass were measured by qNMR (Suppl. Figure 3A,B) and normalized to body weights in %. D. Average oxygen consumption normalized to body weights. E. Respiratory exchange ratios (RERs) were calculated by dividing carbon dioxide production (VCO2) by oxygen consumption (VO2) (Suppl. Figure 4A–D). The gray rectangle represents 12-h dark phase (0-time point represents 1 p.m.). F. ΔRER was calculated as RERmax − RERmin. Columns represent averages ± standard deviations; n = 8–12. *denotes significant differences between ED, BEZ vs. ED, SD; *p < 0.05, **p < 0.01, ***p < 0.001; #denotes significant differences between ED, SD vs. LD, SD; #p < 0.05, ###p < 0.001; §denotes significant differences between LD, BEZ vs. LD, SD; §§p < 0.01, §§§p < 0.001.
Figure 4
Figure 4
Euglycemic-hyperinsulinemic clamp. A. Steady state BG levels during the clamp. B. Glucose infusion rate (GINF). C. Endogenous glucose production (EGP). D. Whole body glucose uptake. Columns represent averages ± standard deviations; n = 8 animals. §denotes significant differences between LD, BEZ vs. LD, SD; §p < 0.05, §§§p < 0.001.
Figure 5
Figure 5
Hepatic lipid content. A. Hematoxylin and eosin staining of the liver, the black bar represents 50 μm. Representative areas are shown. B. Liver total TG levels and C. relative liver TG fatty acid (FA) composition. n – “number” denotes the position of double bounds counted from the omega carbon. Saturated FA (SFA), monounsaturated FA (MUFA) and polyunsaturated FA (PUFA), pre: precursor. D. The relative content of total SFA, MUFA and PUFA in TG fraction denoted as % of total FA. E. ED, SD group normalized relative mRNA levels of the indicated transcripts. Scd: Stearoyl-CoA-desaturase, Fasn: fatty acid synthase. Columns represent averages ± standard deviations; A, C, D and E represent n = 4–7; B represents n = 8–9 animals. *denotes significant differences between ED, BEZ vs. ED, D; *p < 0.05, **p < 0.01, ***p < 0.001. #denotes significant differences between ED, SD vs. LD, SD; ###p < 0.001; §denotes significant differences between LD, BEZ vs. LD, SD; §§§p < 0.001.
Figure 6
Figure 6
Hepatic mitochondrial mass. A. Liver mitochondrial mass and architecture were assessed by transmission EM, the black bar denotes 2 μm. Representative areas are shown. B. Mitochondrial number was quantified in five independent regions and normalized to the analyzed area (μm2). C. Hepatic citrate synthase (CS) protein level was analyzed using western blot, and the intensity of the bands was normalized to tubulin and depicted as ratio to LD, SD group. Representative pictures are shown in Suppl. Figure 6A. D. Hepatic gene expression was studied using real-time PCR and depicted as ratio to LD, SD group. CS: citrate synthase E. Our data demonstrated that BEZ improves glucose metabolism in TallyHo mice. In this scheme, the possible underlying mechanisms observed in LD mice are depicted, which are probably involved in the beneficial effects of BEZ. Columns represent averages ± standard deviations; A–B represent n = 4; C–D represent n = 7–9 animals. *denotes significant differences between ED, BEZ vs. ED, SD; **p < 0.01, ***p < 0.001; §denotes significant differences between LD, BEZ vs. LD, SD; §p < 0.05, §§§p < 0.001.
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