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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

Lipolysis in primary adipocytes is increased in InsrP1195L/+/HFD mice.(a,b) Glycerol release of primary adipocytes isolated from InsrP1195L/+ and WT mice under ND (a) and HFD (b) (n = 6 per each group). Data are mean ± SEM. *, †; comparison against isoproterenol-stimulated glycerol release (in the absence of insulin) in WT and InsrP1195L/+ mice, respectively. One-way ANOVA plus Bonferroni post-hoc analysis. Iso; isoproterenol, *P < 0.05, **P < 0.01, ***P < 0.001, †P < 0.05, †††P < 0.001, NS; not significant.
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f3: Lipolysis in primary adipocytes is increased in InsrP1195L/+/HFD mice.(a,b) Glycerol release of primary adipocytes isolated from InsrP1195L/+ and WT mice under ND (a) and HFD (b) (n = 6 per each group). Data are mean ± SEM. *, †; comparison against isoproterenol-stimulated glycerol release (in the absence of insulin) in WT and InsrP1195L/+ mice, respectively. One-way ANOVA plus Bonferroni post-hoc analysis. Iso; isoproterenol, *P < 0.05, **P < 0.01, ***P < 0.001, †P < 0.05, †††P < 0.001, NS; not significant.

Mentions: To exclude the influence of the sympathetic nervous system and hyperinsulinemia in InsrP1195L/+ mice, we measured glycerol release in primary adipocytes in vitro. Lipolysis was measured directly using isolated primary adipocytes (Fig. 3a,b). In InsrP1195L/+/ND mice, the basal and isoproterenol-stimulated lipolysis were significantly lower than that in WT/ND mice (Fig. 3a). By contrast, the inhibition of lipolysis by insulin was attenuated in InsrP1195L/+/ND mice. As a result, the lipolytic activity of InsrP1195L/+/ND mice in the presence of isoproterenol plus insulin was lower than that of WT/ND mice. HFD feeding blunted the sensitivity of isoproterenol-stimulated lipolysis in both WT and InsrP1195L/+ mice (Fig. 3b). Therefore, in mice under HFD, the anti-lipolytic action of insulin was evaluated in adipocytes stimulated with a higher dose (300 nM) of isoproterenol. Although the basal lipolysis in InsrP1195L/+/HFD adipocytes was similar to that in WT/HFD adipocytes, isoproterenol-stimulated lipolysis was significantly higher in InsrP1195L/+/HFD adipocytes, and insulin suppressed glycerol release poorly (Fig. 3b). The increased lipolysis by isoproterenol alone (in the absence of co-treatment with insulin) in InsrP1195L/+/HFD adipocytes also suggests that some factors [such as activities of perilipin9 and/or adipocyte triglyceride lipase10 (ATGL)] other than insulin-dependent suppression of phospho-HSL may contribute to the increased lipolysis11.


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)

Lipolysis in primary adipocytes is increased in InsrP1195L/+/HFD mice.(a,b) Glycerol release of primary adipocytes isolated from InsrP1195L/+ and WT mice under ND (a) and HFD (b) (n = 6 per each group). Data are mean ± SEM. *, †; comparison against isoproterenol-stimulated glycerol release (in the absence of insulin) in WT and InsrP1195L/+ mice, respectively. One-way ANOVA plus Bonferroni post-hoc analysis. Iso; isoproterenol, *P < 0.05, **P < 0.01, ***P < 0.001, †P < 0.05, †††P < 0.001, NS; not significant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4663474&req=5

f3: Lipolysis in primary adipocytes is increased in InsrP1195L/+/HFD mice.(a,b) Glycerol release of primary adipocytes isolated from InsrP1195L/+ and WT mice under ND (a) and HFD (b) (n = 6 per each group). Data are mean ± SEM. *, †; comparison against isoproterenol-stimulated glycerol release (in the absence of insulin) in WT and InsrP1195L/+ mice, respectively. One-way ANOVA plus Bonferroni post-hoc analysis. Iso; isoproterenol, *P < 0.05, **P < 0.01, ***P < 0.001, †P < 0.05, †††P < 0.001, NS; not significant.
Mentions: To exclude the influence of the sympathetic nervous system and hyperinsulinemia in InsrP1195L/+ mice, we measured glycerol release in primary adipocytes in vitro. Lipolysis was measured directly using isolated primary adipocytes (Fig. 3a,b). In InsrP1195L/+/ND mice, the basal and isoproterenol-stimulated lipolysis were significantly lower than that in WT/ND mice (Fig. 3a). By contrast, the inhibition of lipolysis by insulin was attenuated in InsrP1195L/+/ND mice. As a result, the lipolytic activity of InsrP1195L/+/ND mice in the presence of isoproterenol plus insulin was lower than that of WT/ND mice. HFD feeding blunted the sensitivity of isoproterenol-stimulated lipolysis in both WT and InsrP1195L/+ mice (Fig. 3b). Therefore, in mice under HFD, the anti-lipolytic action of insulin was evaluated in adipocytes stimulated with a higher dose (300 nM) of isoproterenol. Although the basal lipolysis in InsrP1195L/+/HFD adipocytes was similar to that in WT/HFD adipocytes, isoproterenol-stimulated lipolysis was significantly higher in InsrP1195L/+/HFD adipocytes, and insulin suppressed glycerol release poorly (Fig. 3b). The increased lipolysis by isoproterenol alone (in the absence of co-treatment with insulin) in InsrP1195L/+/HFD adipocytes also suggests that some factors [such as activities of perilipin9 and/or adipocyte triglyceride lipase10 (ATGL)] other than insulin-dependent suppression of phospho-HSL may contribute to the increased lipolysis11.

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