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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-induced gluconeogenesis is increased in InsrP1195L/+/HFD mice.(a,b) Serum glycerol (a) and blood glucose levels (b) after CL316432 administration (n = 5–10 per each group). (c,d) Expression of G6pc (c) and Pck1 (d) in the WT liver after intraperitoneal glycerol administration (n = 7–10 per each group). Data are mean ± SEM. Only the statistical difference between WT/HFD and InsrP1195L/+/HFD mice is depicted by asterisk in b. Significance between strains (WT/HFD and InsrP1195L/+/HFD mice) at individual time points by two-tailed Student’s t-test (a,b) One-way ANOVA plus Bonferroni post-hoc analysis (c,d). *P < 0.05, **P < 0.01, ***P < 0.001.
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f4: Lipolysis-induced gluconeogenesis is increased in InsrP1195L/+/HFD mice.(a,b) Serum glycerol (a) and blood glucose levels (b) after CL316432 administration (n = 5–10 per each group). (c,d) Expression of G6pc (c) and Pck1 (d) in the WT liver after intraperitoneal glycerol administration (n = 7–10 per each group). Data are mean ± SEM. Only the statistical difference between WT/HFD and InsrP1195L/+/HFD mice is depicted by asterisk in b. Significance between strains (WT/HFD and InsrP1195L/+/HFD mice) at individual time points by two-tailed Student’s t-test (a,b) One-way ANOVA plus Bonferroni post-hoc analysis (c,d). *P < 0.05, **P < 0.01, ***P < 0.001.

Mentions: We also examined whether the increase in lipolysis could contribute to hyperglycemia in InsrP1195L/+/HFD mice under in vivo conditions. We treated the mice with CL316432, a β3-adrenergic receptor-specific agonist, and monitored the changes in serum glycerol (Fig. 4a) and blood glucose (Fig. 4b) levels. Although the serum glycerol levels were similarly increased in WT/HFD mice and InsrP1195L/+/HFD mice, the blood glucose levels after CL316432 administration were significantly higher in InsrP1195L/+/HFD mice, indicating that enhanced lipolysis exacerbates hyperglycemia 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)

Lipolysis-induced gluconeogenesis is increased in InsrP1195L/+/HFD mice.(a,b) Serum glycerol (a) and blood glucose levels (b) after CL316432 administration (n = 5–10 per each group). (c,d) Expression of G6pc (c) and Pck1 (d) in the WT liver after intraperitoneal glycerol administration (n = 7–10 per each group). Data are mean ± SEM. Only the statistical difference between WT/HFD and InsrP1195L/+/HFD mice is depicted by asterisk in b. Significance between strains (WT/HFD and InsrP1195L/+/HFD mice) at individual time points by two-tailed Student’s t-test (a,b) One-way ANOVA plus Bonferroni post-hoc analysis (c,d). *P < 0.05, **P < 0.01, ***P < 0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Lipolysis-induced gluconeogenesis is increased in InsrP1195L/+/HFD mice.(a,b) Serum glycerol (a) and blood glucose levels (b) after CL316432 administration (n = 5–10 per each group). (c,d) Expression of G6pc (c) and Pck1 (d) in the WT liver after intraperitoneal glycerol administration (n = 7–10 per each group). Data are mean ± SEM. Only the statistical difference between WT/HFD and InsrP1195L/+/HFD mice is depicted by asterisk in b. Significance between strains (WT/HFD and InsrP1195L/+/HFD mice) at individual time points by two-tailed Student’s t-test (a,b) One-way ANOVA plus Bonferroni post-hoc analysis (c,d). *P < 0.05, **P < 0.01, ***P < 0.001.
Mentions: We also examined whether the increase in lipolysis could contribute to hyperglycemia in InsrP1195L/+/HFD mice under in vivo conditions. We treated the mice with CL316432, a β3-adrenergic receptor-specific agonist, and monitored the changes in serum glycerol (Fig. 4a) and blood glucose (Fig. 4b) levels. Although the serum glycerol levels were similarly increased in WT/HFD mice and InsrP1195L/+/HFD mice, the blood glucose levels after CL316432 administration were significantly higher in InsrP1195L/+/HFD mice, indicating that enhanced lipolysis exacerbates hyperglycemia 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