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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

Fat combustion in vivo and lipolysis in WAT under HFD are increased in InsrP1195L/+ mice.(a) Serum leptin levels at 16 weeks (n = 8–10 per each group). (b) Representative CT images (22week of age) at the level of lower end of right kidney. Visceral and subcutaneous fat are indicated in pink and yellow, respectively. (c) Hematoxylin and eosin staining of epididymal fat. (d–g) Oxygen consumption rate (d) and RQ (e) under ND in InsrP1195L/+ and WT mice. Oxygen consumption rate (f) and RQ (g) under HFD in InsrP1195L/+ and WT mice (n = 6–7 per each group). (h) Western blot analysis of phospho-HSL in fasted and refed conditions. (left) A representative result showing increased phospho-HSL in InsrP1195L/+/HFD mice. (right) Quantified result of phospho-HSL levels. (n = 6–9 per each group). (i) Western blot analysis of phospho-Akt induced by insulin (0.1 IU/kg i.v.) in WAT. (left) A representative result showing attenuated phospho-Akt in InsrP1195L/+/HFD mice. (right) Quantified result of phospho-Akt levels. (n = 4–6 per each group). (j) Western blot analysis of phospho-Akt induced by insulin (0.1 IU/kg i.v.) in liver. (left) A representative result showing attenuated phospho-Akt in InsrP1195L/+/HFD mice. (right) Quantified result of phospho-Akt levels. (n = 4–6 per each group). Cropped blots were used. Full-length blots are presented in Supplementary Fig. S6. Data are mean ± SEM. Two-way ANOVA plus Bonferroni post-hoc analysis (a). Significance between treatment and strains by two-tailed Student’s t-test (h–j) and by One-way ANOVA plus Bonferroni post-hoc analysis (d-g, h-j), respectively. *P < 0.05, **P < 0.01, ***P < 0.001, NS; not significant.
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f2: Fat combustion in vivo and lipolysis in WAT under HFD are increased in InsrP1195L/+ mice.(a) Serum leptin levels at 16 weeks (n = 8–10 per each group). (b) Representative CT images (22week of age) at the level of lower end of right kidney. Visceral and subcutaneous fat are indicated in pink and yellow, respectively. (c) Hematoxylin and eosin staining of epididymal fat. (d–g) Oxygen consumption rate (d) and RQ (e) under ND in InsrP1195L/+ and WT mice. Oxygen consumption rate (f) and RQ (g) under HFD in InsrP1195L/+ and WT mice (n = 6–7 per each group). (h) Western blot analysis of phospho-HSL in fasted and refed conditions. (left) A representative result showing increased phospho-HSL in InsrP1195L/+/HFD mice. (right) Quantified result of phospho-HSL levels. (n = 6–9 per each group). (i) Western blot analysis of phospho-Akt induced by insulin (0.1 IU/kg i.v.) in WAT. (left) A representative result showing attenuated phospho-Akt in InsrP1195L/+/HFD mice. (right) Quantified result of phospho-Akt levels. (n = 4–6 per each group). (j) Western blot analysis of phospho-Akt induced by insulin (0.1 IU/kg i.v.) in liver. (left) A representative result showing attenuated phospho-Akt in InsrP1195L/+/HFD mice. (right) Quantified result of phospho-Akt levels. (n = 4–6 per each group). Cropped blots were used. Full-length blots are presented in Supplementary Fig. S6. Data are mean ± SEM. Two-way ANOVA plus Bonferroni post-hoc analysis (a). Significance between treatment and strains by two-tailed Student’s t-test (h–j) and by One-way ANOVA plus Bonferroni post-hoc analysis (d-g, h-j), respectively. *P < 0.05, **P < 0.01, ***P < 0.001, NS; not significant.

Mentions: Glycerol is produced by lipolysis of the triacylglycerols (TG) accumulated in the main energy reservoir, the white adipose tissues (WAT). When compared with WT/HFD mice, InsrP1195L/+/HFD mice had lower body weight (Fig. 1b), lower serum leptin levels (Fig. 2a), and less subcutaneous and visceral fat as assessed by computed tomography (CT) scanning (Fig. 2b), indicating that InsrP1195L/+/HFD mice have reduced fat mass. Histological analysis of epididymal fat revealed that InsrP1195L/+/HFD mice had smaller adipocytes than those of WT/HFD mice, while there was no difference in adipocyte size between InsrP1195L/+/ND and WT/ND mice (Fig. 2c, Supplementary Fig. S1a–d). In addition, the liver of InsrP1195L/+/HFD mice had lower TG content (Supplementary Fig. S2a) and less lipid accumulation in hepatocytes compared with WT/HFD mice (Supplementary Fig. S2c), indicating that ectopic fat accumulation is not a major cause of hyperglycemia in InsrP1195L/+/HFD mice. Alternatively, there was a positive correlation between body weight and TG content in all animal groups (Supplementary Fig. S2b).


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)

Fat combustion in vivo and lipolysis in WAT under HFD are increased in InsrP1195L/+ mice.(a) Serum leptin levels at 16 weeks (n = 8–10 per each group). (b) Representative CT images (22week of age) at the level of lower end of right kidney. Visceral and subcutaneous fat are indicated in pink and yellow, respectively. (c) Hematoxylin and eosin staining of epididymal fat. (d–g) Oxygen consumption rate (d) and RQ (e) under ND in InsrP1195L/+ and WT mice. Oxygen consumption rate (f) and RQ (g) under HFD in InsrP1195L/+ and WT mice (n = 6–7 per each group). (h) Western blot analysis of phospho-HSL in fasted and refed conditions. (left) A representative result showing increased phospho-HSL in InsrP1195L/+/HFD mice. (right) Quantified result of phospho-HSL levels. (n = 6–9 per each group). (i) Western blot analysis of phospho-Akt induced by insulin (0.1 IU/kg i.v.) in WAT. (left) A representative result showing attenuated phospho-Akt in InsrP1195L/+/HFD mice. (right) Quantified result of phospho-Akt levels. (n = 4–6 per each group). (j) Western blot analysis of phospho-Akt induced by insulin (0.1 IU/kg i.v.) in liver. (left) A representative result showing attenuated phospho-Akt in InsrP1195L/+/HFD mice. (right) Quantified result of phospho-Akt levels. (n = 4–6 per each group). Cropped blots were used. Full-length blots are presented in Supplementary Fig. S6. Data are mean ± SEM. Two-way ANOVA plus Bonferroni post-hoc analysis (a). Significance between treatment and strains by two-tailed Student’s t-test (h–j) and by One-way ANOVA plus Bonferroni post-hoc analysis (d-g, h-j), respectively. *P < 0.05, **P < 0.01, ***P < 0.001, NS; not significant.
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f2: Fat combustion in vivo and lipolysis in WAT under HFD are increased in InsrP1195L/+ mice.(a) Serum leptin levels at 16 weeks (n = 8–10 per each group). (b) Representative CT images (22week of age) at the level of lower end of right kidney. Visceral and subcutaneous fat are indicated in pink and yellow, respectively. (c) Hematoxylin and eosin staining of epididymal fat. (d–g) Oxygen consumption rate (d) and RQ (e) under ND in InsrP1195L/+ and WT mice. Oxygen consumption rate (f) and RQ (g) under HFD in InsrP1195L/+ and WT mice (n = 6–7 per each group). (h) Western blot analysis of phospho-HSL in fasted and refed conditions. (left) A representative result showing increased phospho-HSL in InsrP1195L/+/HFD mice. (right) Quantified result of phospho-HSL levels. (n = 6–9 per each group). (i) Western blot analysis of phospho-Akt induced by insulin (0.1 IU/kg i.v.) in WAT. (left) A representative result showing attenuated phospho-Akt in InsrP1195L/+/HFD mice. (right) Quantified result of phospho-Akt levels. (n = 4–6 per each group). (j) Western blot analysis of phospho-Akt induced by insulin (0.1 IU/kg i.v.) in liver. (left) A representative result showing attenuated phospho-Akt in InsrP1195L/+/HFD mice. (right) Quantified result of phospho-Akt levels. (n = 4–6 per each group). Cropped blots were used. Full-length blots are presented in Supplementary Fig. S6. Data are mean ± SEM. Two-way ANOVA plus Bonferroni post-hoc analysis (a). Significance between treatment and strains by two-tailed Student’s t-test (h–j) and by One-way ANOVA plus Bonferroni post-hoc analysis (d-g, h-j), respectively. *P < 0.05, **P < 0.01, ***P < 0.001, NS; not significant.
Mentions: Glycerol is produced by lipolysis of the triacylglycerols (TG) accumulated in the main energy reservoir, the white adipose tissues (WAT). When compared with WT/HFD mice, InsrP1195L/+/HFD mice had lower body weight (Fig. 1b), lower serum leptin levels (Fig. 2a), and less subcutaneous and visceral fat as assessed by computed tomography (CT) scanning (Fig. 2b), indicating that InsrP1195L/+/HFD mice have reduced fat mass. Histological analysis of epididymal fat revealed that InsrP1195L/+/HFD mice had smaller adipocytes than those of WT/HFD mice, while there was no difference in adipocyte size between InsrP1195L/+/ND and WT/ND mice (Fig. 2c, Supplementary Fig. S1a–d). In addition, the liver of InsrP1195L/+/HFD mice had lower TG content (Supplementary Fig. S2a) and less lipid accumulation in hepatocytes compared with WT/HFD mice (Supplementary Fig. S2c), indicating that ectopic fat accumulation is not a major cause of hyperglycemia in InsrP1195L/+/HFD mice. Alternatively, there was a positive correlation between body weight and TG content in all animal groups (Supplementary Fig. S2b).

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