Hyperglycemia in InsrP1195L/+/HFD mice is ameliorated b

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	© Copyright Policy - open-access Related In: Results - Collection License Show All Figures getmorefigures.php?uid=PMC4663474&req=5 f5: Hyperglycemia in InsrP1195L/+/HFD mice is ameliorated by transplantation of wild-type subcutaneous WAT.(a,b) Body weight (a) and blood glucose levels (b) (n = 13–15 per each group). (c) The blood glucose levels at 16-hr fasted and 3 hrs after food replenishment at 18–20 weeks of age (n = 7–10 per each group). (d,e) Western blot analysis of phospho-HSL levels in fasted and refed conditions. (d) A representative result showing increased phospho-HSL in InsrP1195L/+/HFD mice. Endo., endogenous fat; Trans., transplanted fat. Cropped blots were used. Full-length blots are presented in Supplementary Fig. S6. (e) Quantified result of phospho-HSL levels. (n = 4 per each group). (f) mRNA expressions of G6pc in liver on fasted and refed conditions (nv6–8 per each group). (g) Serum adiponectin levels (n = 8 per each group). Data are mean ± SEM. Significance between treatment (un-transplanted InsrP1195L/+/HFD and transplanted InsrP1195L/+/HFD mice) at individual time points by two-tailed Student’s t-test (a–c,f). One-way ANOVA plus Bonferroni post-hoc analysis (e,g). P < 0.05, P < 0.01, P < 0.001, NS; not significant. Mentions:** To assess the involvement of increased lipolysis in WAT of InsrP1195L/+/HFD mice on the development of hyperglycemia, we transplanted wild-type subcutaneous WAT to InsrP1195L/+ mice. Although transplanted InsrP1195L/+/HFD mice gained weight similarly to un-transplanted InsrP1195L/+/HFD mice (Fig. 5a), the blood glucose levels in fed conditions were significantly lower than those of un-transplanted InsrP1195L/+/HFD mice at 14 and 16 weeks of age (Fig. 5b). In addition, the rise in blood glucose levels of transplanted InsrP1195L/+/HFD mice on re-feeding was significantly reduced compared with those of un-transplanted InsrP1195L/+/HFD mice (Fig. 5c). As the phospho-HSL level in the transplanted fat pad was similar to that of endogenous WAT in WT/HFD mice (Fig. 5d,e), suppression of lipolysis in the transplant might well have ameliorated the systemic hyperglycemia of InsrP1195L/+/HFD mice. As expected, the increased G6pc expression in InsrP1195L/+/HFD liver on re-feeding was markedly reduced by the transplantation of wild-type subcutaneous fat to the mice (Fig. 5f). To assess the involvement of anti-inflammatory cytokines released from the transplant, we measured serum adiponectin levels (Fig. 5g). In our experimental conditions with 45% HFD, adiponectin was not decreased in WT/HFD mice. By contrast, adiponectin of InsrP1195L/+/HFD mice was significantly lower than that of InsrP1195L/+/ND mice. Notably, fat transplantation to InsrP1195L/+/HFD mice did not increase adiponectin, suggesting that change in adiponectin did not contribute to improved glycemia.

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

Hyperglycemia in InsrP1195L/+/HFD mice is ameliorated by transplantation of wild-type subcutaneous WAT.(a,b) Body weight (a) and blood glucose levels (b) (n = 13–15 per each group). (c) The blood glucose levels at 16-hr fasted and 3 hrs after food replenishment at 18–20 weeks of age (n = 7–10 per each group). (d,e) Western blot analysis of phospho-HSL levels in fasted and refed conditions. (d) A representative result showing increased phospho-HSL in InsrP1195L/+/HFD mice. Endo., endogenous fat; Trans., transplanted fat. Cropped blots were used. Full-length blots are presented in Supplementary Fig. S6. (e) Quantified result of phospho-HSL levels. (n = 4 per each group). (f) mRNA expressions of G6pc in liver on fasted and refed conditions (nv6–8 per each group). (g) Serum adiponectin levels (n = 8 per each group). Data are mean ± SEM. Significance between treatment (un-transplanted InsrP1195L/+/HFD and transplanted InsrP1195L/+/HFD mice) at individual time points by two-tailed Student’s t-test (a–c,f). One-way ANOVA plus Bonferroni post-hoc analysis (e,g). *P < 0.05, **P < 0.01, ***P < 0.001, NS; not significant.

Related In: Results - Collection

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f5: Hyperglycemia in InsrP1195L/+/HFD mice is ameliorated by transplantation of wild-type subcutaneous WAT.(a,b) Body weight (a) and blood glucose levels (b) (n = 13–15 per each group). (c) The blood glucose levels at 16-hr fasted and 3 hrs after food replenishment at 18–20 weeks of age (n = 7–10 per each group). (d,e) Western blot analysis of phospho-HSL levels in fasted and refed conditions. (d) A representative result showing increased phospho-HSL in InsrP1195L/+/HFD mice. Endo., endogenous fat; Trans., transplanted fat. Cropped blots were used. Full-length blots are presented in Supplementary Fig. S6. (e) Quantified result of phospho-HSL levels. (n = 4 per each group). (f) mRNA expressions of G6pc in liver on fasted and refed conditions (nv6–8 per each group). (g) Serum adiponectin levels (n = 8 per each group). Data are mean ± SEM. Significance between treatment (un-transplanted InsrP1195L/+/HFD and transplanted InsrP1195L/+/HFD mice) at individual time points by two-tailed Student’s t-test (a–c,f). One-way ANOVA plus Bonferroni post-hoc analysis (e,g). *P < 0.05, **P < 0.01, ***P < 0.001, NS; not significant.

Mentions: To assess the involvement of increased lipolysis in WAT of InsrP1195L/+/HFD mice on the development of hyperglycemia, we transplanted wild-type subcutaneous WAT to InsrP1195L/+ mice. Although transplanted InsrP1195L/+/HFD mice gained weight similarly to un-transplanted InsrP1195L/+/HFD mice (Fig. 5a), the blood glucose levels in fed conditions were significantly lower than those of un-transplanted InsrP1195L/+/HFD mice at 14 and 16 weeks of age (Fig. 5b). In addition, the rise in blood glucose levels of transplanted InsrP1195L/+/HFD mice on re-feeding was significantly reduced compared with those of un-transplanted InsrP1195L/+/HFD mice (Fig. 5c). As the phospho-HSL level in the transplanted fat pad was similar to that of endogenous WAT in WT/HFD mice (Fig. 5d,e), suppression of lipolysis in the transplant might well have ameliorated the systemic hyperglycemia of InsrP1195L/+/HFD mice. As expected, the increased G6pc expression in InsrP1195L/+/HFD liver on re-feeding was markedly reduced by the transplantation of wild-type subcutaneous fat to the mice (Fig. 5f). To assess the involvement of anti-inflammatory cytokines released from the transplant, we measured serum adiponectin levels (Fig. 5g). In our experimental conditions with 45% HFD, adiponectin was not decreased in WT/HFD mice. By contrast, adiponectin of InsrP1195L/+/HFD mice was significantly lower than that of InsrP1195L/+/ND mice. Notably, fat transplantation to InsrP1195L/+/HFD mice did not increase adiponectin, suggesting that change in adiponectin did not contribute to improved glycemia.