Unsuppressed lipolysis in adipocytes is linked with enhanced gluconeogenesis and altered bile acid physiology in Insr(P1195L/+) mice fed high-fat-diet.
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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.
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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 |
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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. |
View Article: PubMed Central - PubMed
Affiliation: Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba 260-8670 Japan.
No MeSH data available.