Mif deficiency promotes adiposity in fructose-fed mice

in Journal of Endocrinology
Correspondence should be addressed to A Djordjevic: djordjevica@ibiss.bg.ac.rs
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The macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine involved in inflammation, regulation of energy metabolism and glucocorticoid action. Chronic low-grade inflammation may be caused by fructose intake, contributing to visceral adipose tissue (VAT) dysfunction. Since MIF is a known antagonist of glucocorticoid signaling, and deregulated glucocorticoid signaling can contribute to lipid metabolism disturbances, we hypothesized that altered MIF signaling might underlie fructose-induced adiposity through glucocorticoid action. We analyzed physiological and biochemical parameters, adipose tissue histology, insulin sensitivity and lipid metabolism in WT and MIF−/− C57Bl/6J mice consuming 20% fructose solution for 9 weeks. Glucocorticoid prereceptor metabolism and glucocorticoid receptor (GR) protein level were examined in VAT, together with the expression of glucocorticoid-target genes involved in lipid metabolism. The expression of adipogenic and lipogenic transcriptional regulators peroxisome proliferator-activated receptor gamma (PPARG) and sterol regulatory element-binding protein 1c (SREBP1c) was also assessed. Results showed disturbed insulin sensitivity in all MIF−/− mice, regardless of the diet. Mice on fructose diet had increased energy intake, but increased visceral adiposity and enlarged adipocytes were observed only in fructose-fed MIF−/− mice. Increased VAT corticosterone level and 11 beta-hydroxysteroid dehydrogenase type 1, hexose-6-phosphate dehydrogenase and GR protein levels were observed in the same animals, together with induced expression of examined lipogenic genes and accumulation of PPARG and SREBP1c. In conclusion, the results showed that dietary fructose was associated with increased visceral adiposity through activation of GR-regulated lipogenic genes, but only in the absence of MIF, which set the state of hyperinsulinemia and insulin resistance.

 

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    Physiological and biochemical parameters. Body mass, VAT mass and histological analysis: Data for body mass and weight gain (A), VAT mass (B) and VAT/body mass ratio (C) are presented as mean ± s.e.m. (n = 12 animals per group). Representative hematoxylin-eosin staining of VAT sections from C57BL/6J mice (WT) (D), WT mice on fructose diet (WT FrD) (E), mice with genetically deleted Mif (MIF−/−) (F) and MIF−/− mice on fructose diet (MIF−/− FrD) (G) (magnification ×20, bar = 100 μm). Morphometric data on adipocyte cell diameter (H) and area (I) are presented as mean ± s.e.m. (100 adipocytes per section, three sections per animal and five animals per group). A value of P < 0.05 was considered statistically significant. Two-way ANOVA showed significant effect of fructose on VAT mass (P < 0.01), VAT/body mass ratio (P < 0.05), as well as on the adipocyte cell diameter and area (P < 0.01). Mif deficiency also had significant effect on both VAT and VAT/body mass ratio (P < 0.001), as well as on the adipocyte cell diameter (P < 0.01) and area (P < 0.05). Significant between-group differences from post hoc Tukey test are given as follows: *P < 0.05, **P < 0.01, ***P < 0.001, all groups vs WT; #P < 0.05, ##P < 0.01, MIF−/− FrD vs WT FrD; P < 0.05, MIF−/− FrD vs MIF−/−. Intraperitoneal tests of glucose and insulin tolerance IP-GTT (J) and IP-ITT (K): After determination of fasting glucose concentrations, animals were challenged with intraperitoneal injection of glucose (2 g/kg) or insulin (0.75 IU/kg). Blood glucose was measured 15, 30, 60, 90, and 120 min after injection, and glucose concentration vs time was plotted for C57BL/6J mice (WT), WT mice on fructose diet (WT FrD), mice with genetically deleted Mif (MIF−/−) and MIF−/− mice on fructose diet (MIF−/− FrD). A value of P < 0.05 was considered statistically significant. Data are presented as mean ± s.e.m. (n = 12 animals per group). Significant between-group differences from post hoc Tukey test are given as follows: *P < 0.05, **P < 0.01, ***P < 0.001, all groups vs WT; #P < 0.05, ##P < 0.01, ###P < 0.001, MIF−/− FrD vs WT FrD; P < 0.05, MIF−/− FrD vs MIF−/−.

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    Phosphorylated and total p38 kinase and their ratio in the VAT. Representative Western blots and relative quantification of total and phospho-p38 kinase and their ratio in the total protein extract of VAT from C57BL/6J mice (WT), WT mice on fructose diet (WT FrD), mice with genetically deleted Mif (MIF−/−) and MIF−/− mice on fructose diet (MIF−/− FrD). Immunoreactivities of total and phosphorylated p38 are normalized to Beta-actin as loading control and the data are presented as mean ± s.e.m. (n = 12 animals per group). A value of P < 0.05 was considered statistically significant. Two-way ANOVA showed that total p38 protein level was significantly affected by Mif deficiency (P < 0.001) and its interaction with fructose diet (P < 0.001). Phosphorylation and activity of p38 was significantly affected only by fructose (P < 0.001). Significant between-group differences from post hoc Tukey test are given as follows: *P < 0.05, ***P < 0.001, all groups vs WT; ###P < 0.001, MIF−/− FrD vs WT FrD; P < 0.05, †††P < 0.001, MIF−/− FrD vs MIF−/−.

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    Glucocorticoid prereceptor metabolism and signaling. Representative Western blots and relative quantification of 11BHSD1 (A), H6PDH (B) and GR (D) protein levels and CORT concentration (C) in total protein extract of VAT from C57BL/6J mice (WT), WT mice on fructose diet (WT FrD), mice with genetically deleted Mif (MIF−/−) and MIF−/− mice on fructose diet (MIF−/− FrD). Data are presented as mean ± s.e.m. (n = 12 animals per group). A value of P < 0.05 was considered statistically significant. Two-way ANOVA showed significant effects of fructose (P < 0.01) and Mif deficiency (P < 0.05) for both 11BHSD1 and H6PDH protein level, while GR was affected only by fructose treatment (P < 0.01). CORT concentration in VAT was affected by fructose diet (P < 0.05), as well as by its interaction with Mif deficiency (P < 0.05). Significant between-group differences from post hoc Tukey test are given as follows: *P < 0.05, **P < 0.01, ***P < 0.001, all groups vs WT; #P < 0.05, MIF−/− FrD vs WT FrD; ††P < 0.01, MIF−/− FrD vs MIF−/−.

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    Relative levels of mRNA for genes involved in VAT lipid metabolism. Relative quantification Hsl, Atgl, Pepck, Lpl, Fas and Acc mRNA level, normalized to Hprt1 housekeeping gene, in the VAT of C57BL/6J mice (WT), WT mice on fructose diet (WT FrD), mice with genetically deleted Mif (MIF−/−) and MIF−/− mice on fructose diet (MIF−/− FrD). Data are presented as mean ± s.e.m. (n = 12 animals per group) of the triplicate analysis of RNA samples. A value of P < 0.05 was considered statistically significant. According to two-way ANOVA the effect of fructose was detected for Atgl (P < 0.001), Pepck (P < 0.001), Fas (P < 0.05) and Acc (P < 0.05) mRNA levels. Mif deficiency significantly affected expression of Atgl (P < 0.01), Pepck (P < 0.001), Lpl (P < 0.001), Fas (P < 0.01) and Acc (P < 0.01). Interaction between fructose and the absence of MIF was detected for Atgl (P < 0.01), Pepck (P < 0.001), Lpl (P < 0.001), Fas (P < 0.05) and Acc (P < 0.05) mRNA levels. Significant between-group differences from post hoc Tukey test are given as follows: *P < 0.05, **P < 0.01, ***P < 0.001, all groups vs WT; ##P < 0.01, ###P < 0.001, MIF−/− FrD vs WT FrD; P < 0.05, ††P < 0.01, †††P < 0.001, MIF−/− FrD vs MIF−/−.

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    Transcriptional regulators of VAT lipid metabolism. Representative Western blots and relative quantification of PPARG (A) and SREBP1c (B) total protein levels in the VAT of C57BL/6J mice (WT), WT mice on fructose diet (WT FrD), mice with genetically deleted Mif (MIF−/−) and MIF−/− mice on fructose diet (MIF−/− FrD). Beta-actin was used as a loading control. Data are presented as mean ± s.e.m. (n = 12 animals per group). A value of P < 0.05 was considered statistically significant. Two-way ANOVA showed significant effects of fructose diet on both PPARG (P < 0.01) and SREBP1c (P < 0.001), while the deficiency of Mif affected only SREBP1c protein level (P < 0.01). Between-group differences from post hoc Tukey test are given as follows: *P < 0.05, ***P < 0.001, all groups vs WT; ##P < 0.01, MIF−/− FrD vs WT FrD; P < 0.05, ††P < 0.01, MIF−/− FrD vs MIF−/−.

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