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Unsuppressed lipolysis in adipocytes is linked with enhanced gluconeogenesis and altered bile acid physiology in Insr(P1195L/+) mice fed high-fat-diet.

Lee EY, Sakurai K, Zhang X, Toda C, Tanaka T, Jiang M, Shirasawa T, Tachibana K, Yokote K, Vidal-Puig A, Minokoshi Y, Miki T - Sci Rep (2015)

Bottom Line: We found that the expressions of genes involved in bile acid (BA) metabolism were altered in Insr(P1195L/+)/HFD liver.Among these, the expression of Cyp7a1, a BA synthesis enzyme, was insulin-dependent and was markedly decreased in Insr(P1195L/+)/HFD liver.These findings suggest that unsuppressed lipolysis in adipocytes elicited by HFD feeding is linked with enhanced gluconeogenesis from glycerol and with alterations in BA physiology in Insr(P1195L/+)/HFD liver.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670 Japan.

ABSTRACT
High-fat diet (HFD) triggers insulin resistance and diabetes mellitus, but their link remains unclear. Characterization of overt hyperglycemia in insulin receptor mutant (Insr(P1195L/+)) mice exposed to HFD (Insr(P1195L/+)/HFD mice) revealed increased glucose-6-phosphatase (G6pc) expression in liver and increased gluconeogenesis from glycerol. Lipolysis in white adipose tissues (WAT) and lipolysis-induced blood glucose rise were increased in Insr(P1195L/+)/HFD mice, while wild-type WAT transplantation ameliorated the hyperglycemia and the increased G6pc expression. We found that the expressions of genes involved in bile acid (BA) metabolism were altered in Insr(P1195L/+)/HFD liver. Among these, the expression of Cyp7a1, a BA synthesis enzyme, was insulin-dependent and was markedly decreased in Insr(P1195L/+)/HFD liver. Reduced Cyp7a1 expression in Insr(P1195L/+)/HFD liver was rescued by WAT transplantation, and the expression of Cyp7a1 was suppressed by glycerol administration in wild-type liver. These findings suggest that unsuppressed lipolysis in adipocytes elicited by HFD feeding is linked with enhanced gluconeogenesis from glycerol and with alterations in BA physiology in Insr(P1195L/+)/HFD liver.

No MeSH data available.


Related in: MedlinePlus

BA physiology is diversely altered in InsrP1195L/+/HFD liver.(a–d) mRNA expressions of genes involved in BA synthesis (n = 8–12 per each group). (e,f) mRNA expressions of genes involved in BA transport (n = 8–12 per each group). (g) Relative BA composition in liver in refed condition (n = 3). (h) The ratio of muricholates to cholates, calculated with the molar percentage of tauro α-, tauro β-, and tauro ω-mucricholates and taurocholate. (i) mRNA expression of Cyp7a1 after oral glucose loading in Kir6.2−/− mice (n = 7–12 per each group). (j) mRNA expression of Cyp7a1 in fat transplanted InsrP1195L/+/HFD mice (n = 5–7 per each group). (k) mRNA expression of Cyp7a1 in the WT liver after intraperitoneal glycerol administration (n = 7–10 per each group). Data are mean ± SEM. Two-way ANOVA plus Bonferroni post-hoc analysis (a–f). Significance between treatment by two-tailed Student’s t-test (i). One-way ANOVA plus Bonferroni post-hoc analysis (g,h,j,k). *P < 0.05, **P < 0.01, ***P < 0.001, NS; not significant.
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f6: BA physiology is diversely altered in InsrP1195L/+/HFD liver.(a–d) mRNA expressions of genes involved in BA synthesis (n = 8–12 per each group). (e,f) mRNA expressions of genes involved in BA transport (n = 8–12 per each group). (g) Relative BA composition in liver in refed condition (n = 3). (h) The ratio of muricholates to cholates, calculated with the molar percentage of tauro α-, tauro β-, and tauro ω-mucricholates and taurocholate. (i) mRNA expression of Cyp7a1 after oral glucose loading in Kir6.2−/− mice (n = 7–12 per each group). (j) mRNA expression of Cyp7a1 in fat transplanted InsrP1195L/+/HFD mice (n = 5–7 per each group). (k) mRNA expression of Cyp7a1 in the WT liver after intraperitoneal glycerol administration (n = 7–10 per each group). Data are mean ± SEM. Two-way ANOVA plus Bonferroni post-hoc analysis (a–f). Significance between treatment by two-tailed Student’s t-test (i). One-way ANOVA plus Bonferroni post-hoc analysis (g,h,j,k). *P < 0.05, **P < 0.01, ***P < 0.001, NS; not significant.

Mentions: As fat-specific insulin receptor deficient mice (FIRKO mice) failed to exhibit glucose intolerance, we examined the contribution of insulin resistance in liver. To clarify its molecular mechanism, we performed microarray analysis in liver of InsrP1195L/+/HFD and WT/HFD mice, and found that expressions of several genes involved in BA physiology were altered. We therefore quantified mRNA expressions of the enzymes involved in BA synthesis (Fig. 6a–d) and BA transporters (Fig. 6e,f). Expression of Cyp7a1, the rate-limiting enzyme of BA synthesis, was significantly increased by re-feeding similarly in WT/ND mice and InsrP1195L/+/ND mice, while that in WT/HFD mice was significantly elevated under fasted condition, and did not show further increase by re-feeding. Interestingly, Cyp7a1 expression in InsrP1195L/+/HFD mice was markedly decreased by re-feeding (Fig. 6a). By contrast, expression of Cyp7b1, another enzyme of BA synthesis, was increased in InsrP1195L/+/HFD mice (Fig. 6b). Expression of Cyp27a1 was not altered among the 4 animal groups (Fig. 6c). Expression of Cyp8b1, the sterol 12α-hydroxylase required for generation of CA, was decreased in InsrP1195L/+/HFD mice (Fig. 6d). In addition, we examined expressions of BA transporters, Slc10a1 and Slco1a1 (Fig. 6e,f). Expression of Slco1a1 but not Slc10a1 was significantly increased in InsrP1195L/+/HFD mice.


Unsuppressed lipolysis in adipocytes is linked with enhanced gluconeogenesis and altered bile acid physiology in Insr(P1195L/+) mice fed high-fat-diet.

Lee EY, Sakurai K, Zhang X, Toda C, Tanaka T, Jiang M, Shirasawa T, Tachibana K, Yokote K, Vidal-Puig A, Minokoshi Y, Miki T - Sci Rep (2015)

BA physiology is diversely altered in InsrP1195L/+/HFD liver.(a–d) mRNA expressions of genes involved in BA synthesis (n = 8–12 per each group). (e,f) mRNA expressions of genes involved in BA transport (n = 8–12 per each group). (g) Relative BA composition in liver in refed condition (n = 3). (h) The ratio of muricholates to cholates, calculated with the molar percentage of tauro α-, tauro β-, and tauro ω-mucricholates and taurocholate. (i) mRNA expression of Cyp7a1 after oral glucose loading in Kir6.2−/− mice (n = 7–12 per each group). (j) mRNA expression of Cyp7a1 in fat transplanted InsrP1195L/+/HFD mice (n = 5–7 per each group). (k) mRNA expression of Cyp7a1 in the WT liver after intraperitoneal glycerol administration (n = 7–10 per each group). Data are mean ± SEM. Two-way ANOVA plus Bonferroni post-hoc analysis (a–f). Significance between treatment by two-tailed Student’s t-test (i). One-way ANOVA plus Bonferroni post-hoc analysis (g,h,j,k). *P < 0.05, **P < 0.01, ***P < 0.001, NS; not significant.
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f6: BA physiology is diversely altered in InsrP1195L/+/HFD liver.(a–d) mRNA expressions of genes involved in BA synthesis (n = 8–12 per each group). (e,f) mRNA expressions of genes involved in BA transport (n = 8–12 per each group). (g) Relative BA composition in liver in refed condition (n = 3). (h) The ratio of muricholates to cholates, calculated with the molar percentage of tauro α-, tauro β-, and tauro ω-mucricholates and taurocholate. (i) mRNA expression of Cyp7a1 after oral glucose loading in Kir6.2−/− mice (n = 7–12 per each group). (j) mRNA expression of Cyp7a1 in fat transplanted InsrP1195L/+/HFD mice (n = 5–7 per each group). (k) mRNA expression of Cyp7a1 in the WT liver after intraperitoneal glycerol administration (n = 7–10 per each group). Data are mean ± SEM. Two-way ANOVA plus Bonferroni post-hoc analysis (a–f). Significance between treatment by two-tailed Student’s t-test (i). One-way ANOVA plus Bonferroni post-hoc analysis (g,h,j,k). *P < 0.05, **P < 0.01, ***P < 0.001, NS; not significant.
Mentions: As fat-specific insulin receptor deficient mice (FIRKO mice) failed to exhibit glucose intolerance, we examined the contribution of insulin resistance in liver. To clarify its molecular mechanism, we performed microarray analysis in liver of InsrP1195L/+/HFD and WT/HFD mice, and found that expressions of several genes involved in BA physiology were altered. We therefore quantified mRNA expressions of the enzymes involved in BA synthesis (Fig. 6a–d) and BA transporters (Fig. 6e,f). Expression of Cyp7a1, the rate-limiting enzyme of BA synthesis, was significantly increased by re-feeding similarly in WT/ND mice and InsrP1195L/+/ND mice, while that in WT/HFD mice was significantly elevated under fasted condition, and did not show further increase by re-feeding. Interestingly, Cyp7a1 expression in InsrP1195L/+/HFD mice was markedly decreased by re-feeding (Fig. 6a). By contrast, expression of Cyp7b1, another enzyme of BA synthesis, was increased in InsrP1195L/+/HFD mice (Fig. 6b). Expression of Cyp27a1 was not altered among the 4 animal groups (Fig. 6c). Expression of Cyp8b1, the sterol 12α-hydroxylase required for generation of CA, was decreased in InsrP1195L/+/HFD mice (Fig. 6d). In addition, we examined expressions of BA transporters, Slc10a1 and Slco1a1 (Fig. 6e,f). Expression of Slco1a1 but not Slc10a1 was significantly increased in InsrP1195L/+/HFD mice.

Bottom Line: We found that the expressions of genes involved in bile acid (BA) metabolism were altered in Insr(P1195L/+)/HFD liver.Among these, the expression of Cyp7a1, a BA synthesis enzyme, was insulin-dependent and was markedly decreased in Insr(P1195L/+)/HFD liver.These findings suggest that unsuppressed lipolysis in adipocytes elicited by HFD feeding is linked with enhanced gluconeogenesis from glycerol and with alterations in BA physiology in Insr(P1195L/+)/HFD liver.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670 Japan.

ABSTRACT
High-fat diet (HFD) triggers insulin resistance and diabetes mellitus, but their link remains unclear. Characterization of overt hyperglycemia in insulin receptor mutant (Insr(P1195L/+)) mice exposed to HFD (Insr(P1195L/+)/HFD mice) revealed increased glucose-6-phosphatase (G6pc) expression in liver and increased gluconeogenesis from glycerol. Lipolysis in white adipose tissues (WAT) and lipolysis-induced blood glucose rise were increased in Insr(P1195L/+)/HFD mice, while wild-type WAT transplantation ameliorated the hyperglycemia and the increased G6pc expression. We found that the expressions of genes involved in bile acid (BA) metabolism were altered in Insr(P1195L/+)/HFD liver. Among these, the expression of Cyp7a1, a BA synthesis enzyme, was insulin-dependent and was markedly decreased in Insr(P1195L/+)/HFD liver. Reduced Cyp7a1 expression in Insr(P1195L/+)/HFD liver was rescued by WAT transplantation, and the expression of Cyp7a1 was suppressed by glycerol administration in wild-type liver. These findings suggest that unsuppressed lipolysis in adipocytes elicited by HFD feeding is linked with enhanced gluconeogenesis from glycerol and with alterations in BA physiology in Insr(P1195L/+)/HFD liver.

No MeSH data available.


Related in: MedlinePlus