Limits...
Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPARγ Levels.

Liu J, Dong H, Zhang Y, Cao M, Song L, Pan Q, Bulmer A, Adams DB, Dong X, Wang H - Sci Rep (2015)

Bottom Line: Moderate elevations in bilirubin levels have anti-diabetic effects.Serum lipid, leptin, adiponectin, insulin, total and direct bilirubin levels were measured.Expression of factors involved in adipose metabolism including sterol regulatory element-binding protein (SREBP-1), insulin receptor (IR), and PPARγ in liver were measured by RT-PCR and Western blot.

View Article: PubMed Central - PubMed

Affiliation: College of Animal Science and Veterinary Medicine, Qingdao, P.R. China.

ABSTRACT
Obesity can cause insulin resistance and type 2 diabetes. Moderate elevations in bilirubin levels have anti-diabetic effects. This study is aimed at determining the mechanisms by which bilirubin treatment reduces obesity and insulin resistance in a diet-induced obesity (DIO) mouse model. DIO mice were treated with bilirubin or vehicle for 14 days. Body weights, plasma glucose, and insulin tolerance tests were performed prior to, immediately, and 7 weeks post-treatment. Serum lipid, leptin, adiponectin, insulin, total and direct bilirubin levels were measured. Expression of factors involved in adipose metabolism including sterol regulatory element-binding protein (SREBP-1), insulin receptor (IR), and PPARγ in liver were measured by RT-PCR and Western blot. Compared to controls, bilirubin-treated mice exhibited reductions in body weight, blood glucose levels, total cholesterol (TC), leptin, total and direct bilirubin, and increases in adiponectin and expression of SREBP-1, IR, and PPARγ mRNA. The improved metabolic control achieved by bilirubin-treated mice was persistent: at two months after treatment termination, bilirubin-treated DIO mice remained insulin sensitive with lower leptin and higher adiponectin levels, together with increased PPARγ expression. These results indicate that bilirubin regulates cholesterol metabolism, adipokines and PPARγ levels, which likely contribute to increased insulin sensitivity and glucose tolerance in DIO mice.

No MeSH data available.


Related in: MedlinePlus

Administration of bilirubin reduces body weight and increases insulin sensitivity in DIO mice.(a) Changes in body weights of DIO mice treated with bilirubin (DIO + BR) or vehicle (DIO + V) compared to control mice fed standard diet (CHOW). (b) Daily non-fasting blood glucose levels in DIO + BR, DIO + V, and CHOW mice during bilirubin treatment. (c) Average food intake per mouse per 24-h period in DIO mice receiving BR or vehicle. (d) Intraperitoneal glucose tolerance test (GTT) of DIO mice and CHOW controls before bilirubin treatment; (e) area under the curve of GTT. (f) Insulin tolerance test (ITT) of DIO mice and CHOW mice before bilirubin treatment; (g) reverse area under the baseline above curve. (h) GTT of DIO + BR, DIO + V, and CHOW mice 14 days after the first bilirubin injection; (i) area under the curve. (j) ITT of DIO + BR, DIO + V, and CHOW mice at 14 days after the first bilirubin injection; (k) reverse area under the baseline above curve. At least 6-8 mice were included in each group; **p < 0.01, *p < 0.05, Student’s t test. DIO + BR: DIO mice treated with bilirubin; DIO + V: DIO mice treated with vehicle; CHOW: mice fed standard diet.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4446899&req=5

f1: Administration of bilirubin reduces body weight and increases insulin sensitivity in DIO mice.(a) Changes in body weights of DIO mice treated with bilirubin (DIO + BR) or vehicle (DIO + V) compared to control mice fed standard diet (CHOW). (b) Daily non-fasting blood glucose levels in DIO + BR, DIO + V, and CHOW mice during bilirubin treatment. (c) Average food intake per mouse per 24-h period in DIO mice receiving BR or vehicle. (d) Intraperitoneal glucose tolerance test (GTT) of DIO mice and CHOW controls before bilirubin treatment; (e) area under the curve of GTT. (f) Insulin tolerance test (ITT) of DIO mice and CHOW mice before bilirubin treatment; (g) reverse area under the baseline above curve. (h) GTT of DIO + BR, DIO + V, and CHOW mice 14 days after the first bilirubin injection; (i) area under the curve. (j) ITT of DIO + BR, DIO + V, and CHOW mice at 14 days after the first bilirubin injection; (k) reverse area under the baseline above curve. At least 6-8 mice were included in each group; **p < 0.01, *p < 0.05, Student’s t test. DIO + BR: DIO mice treated with bilirubin; DIO + V: DIO mice treated with vehicle; CHOW: mice fed standard diet.

Mentions: The effects of bilirubin administration on body weight, blood glucose level, and insulin sensitivity in DIO mice were determined. Animals were treated with bilirubin (20 μmol/kg) intraperitoneally twice per day for 14 days. This dose and dosing schedule has shown efficacy and was well tolerated in previously published islet transplantation and obese mouse models3536. Feeding a high fat diet (Table 1) to C57BL/6 mice for 24 weeks resulted in significant increases in body weight (47.5 ± 3.7 g in DIO vs. 30.29 ± 3.5 in mice fed standard diet (CHOW), Fig. 1a). Bilirubin administration (DIO + BR) significantly reduced body weights in DIO mice (Fig. 1a). Blood glucose levels were reduced in bilirubin treated mice from 193.5 ± 37.1 mg/dl to 112.2 ± 8.9 mg/dl (Fig. 1b). Bilirubin treated mice ate less than DIO controls; however, this difference was not significant (p = 0.06, Fig. 1c). Bilirubin treatment resulted in improved glucose uptake and insulin utilization as evidenced by reduced blood glucose levels as well as reduced areas under the curve (GTT, Fig. 1h,j) or reverse areas above the curve (ITT, Fig. 1i,k), compared to GTT (Fig. 1d,e) and ITT (Fig. 1f,g) results before starting treatment. These data confirmed that bilirubin treatment reduced obesity and blood glucose levels and improved glucose tolerance and insulin sensitivity in DIO mice.


Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPARγ Levels.

Liu J, Dong H, Zhang Y, Cao M, Song L, Pan Q, Bulmer A, Adams DB, Dong X, Wang H - Sci Rep (2015)

Administration of bilirubin reduces body weight and increases insulin sensitivity in DIO mice.(a) Changes in body weights of DIO mice treated with bilirubin (DIO + BR) or vehicle (DIO + V) compared to control mice fed standard diet (CHOW). (b) Daily non-fasting blood glucose levels in DIO + BR, DIO + V, and CHOW mice during bilirubin treatment. (c) Average food intake per mouse per 24-h period in DIO mice receiving BR or vehicle. (d) Intraperitoneal glucose tolerance test (GTT) of DIO mice and CHOW controls before bilirubin treatment; (e) area under the curve of GTT. (f) Insulin tolerance test (ITT) of DIO mice and CHOW mice before bilirubin treatment; (g) reverse area under the baseline above curve. (h) GTT of DIO + BR, DIO + V, and CHOW mice 14 days after the first bilirubin injection; (i) area under the curve. (j) ITT of DIO + BR, DIO + V, and CHOW mice at 14 days after the first bilirubin injection; (k) reverse area under the baseline above curve. At least 6-8 mice were included in each group; **p < 0.01, *p < 0.05, Student’s t test. DIO + BR: DIO mice treated with bilirubin; DIO + V: DIO mice treated with vehicle; CHOW: mice fed standard diet.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4446899&req=5

f1: Administration of bilirubin reduces body weight and increases insulin sensitivity in DIO mice.(a) Changes in body weights of DIO mice treated with bilirubin (DIO + BR) or vehicle (DIO + V) compared to control mice fed standard diet (CHOW). (b) Daily non-fasting blood glucose levels in DIO + BR, DIO + V, and CHOW mice during bilirubin treatment. (c) Average food intake per mouse per 24-h period in DIO mice receiving BR or vehicle. (d) Intraperitoneal glucose tolerance test (GTT) of DIO mice and CHOW controls before bilirubin treatment; (e) area under the curve of GTT. (f) Insulin tolerance test (ITT) of DIO mice and CHOW mice before bilirubin treatment; (g) reverse area under the baseline above curve. (h) GTT of DIO + BR, DIO + V, and CHOW mice 14 days after the first bilirubin injection; (i) area under the curve. (j) ITT of DIO + BR, DIO + V, and CHOW mice at 14 days after the first bilirubin injection; (k) reverse area under the baseline above curve. At least 6-8 mice were included in each group; **p < 0.01, *p < 0.05, Student’s t test. DIO + BR: DIO mice treated with bilirubin; DIO + V: DIO mice treated with vehicle; CHOW: mice fed standard diet.
Mentions: The effects of bilirubin administration on body weight, blood glucose level, and insulin sensitivity in DIO mice were determined. Animals were treated with bilirubin (20 μmol/kg) intraperitoneally twice per day for 14 days. This dose and dosing schedule has shown efficacy and was well tolerated in previously published islet transplantation and obese mouse models3536. Feeding a high fat diet (Table 1) to C57BL/6 mice for 24 weeks resulted in significant increases in body weight (47.5 ± 3.7 g in DIO vs. 30.29 ± 3.5 in mice fed standard diet (CHOW), Fig. 1a). Bilirubin administration (DIO + BR) significantly reduced body weights in DIO mice (Fig. 1a). Blood glucose levels were reduced in bilirubin treated mice from 193.5 ± 37.1 mg/dl to 112.2 ± 8.9 mg/dl (Fig. 1b). Bilirubin treated mice ate less than DIO controls; however, this difference was not significant (p = 0.06, Fig. 1c). Bilirubin treatment resulted in improved glucose uptake and insulin utilization as evidenced by reduced blood glucose levels as well as reduced areas under the curve (GTT, Fig. 1h,j) or reverse areas above the curve (ITT, Fig. 1i,k), compared to GTT (Fig. 1d,e) and ITT (Fig. 1f,g) results before starting treatment. These data confirmed that bilirubin treatment reduced obesity and blood glucose levels and improved glucose tolerance and insulin sensitivity in DIO mice.

Bottom Line: Moderate elevations in bilirubin levels have anti-diabetic effects.Serum lipid, leptin, adiponectin, insulin, total and direct bilirubin levels were measured.Expression of factors involved in adipose metabolism including sterol regulatory element-binding protein (SREBP-1), insulin receptor (IR), and PPARγ in liver were measured by RT-PCR and Western blot.

View Article: PubMed Central - PubMed

Affiliation: College of Animal Science and Veterinary Medicine, Qingdao, P.R. China.

ABSTRACT
Obesity can cause insulin resistance and type 2 diabetes. Moderate elevations in bilirubin levels have anti-diabetic effects. This study is aimed at determining the mechanisms by which bilirubin treatment reduces obesity and insulin resistance in a diet-induced obesity (DIO) mouse model. DIO mice were treated with bilirubin or vehicle for 14 days. Body weights, plasma glucose, and insulin tolerance tests were performed prior to, immediately, and 7 weeks post-treatment. Serum lipid, leptin, adiponectin, insulin, total and direct bilirubin levels were measured. Expression of factors involved in adipose metabolism including sterol regulatory element-binding protein (SREBP-1), insulin receptor (IR), and PPARγ in liver were measured by RT-PCR and Western blot. Compared to controls, bilirubin-treated mice exhibited reductions in body weight, blood glucose levels, total cholesterol (TC), leptin, total and direct bilirubin, and increases in adiponectin and expression of SREBP-1, IR, and PPARγ mRNA. The improved metabolic control achieved by bilirubin-treated mice was persistent: at two months after treatment termination, bilirubin-treated DIO mice remained insulin sensitive with lower leptin and higher adiponectin levels, together with increased PPARγ expression. These results indicate that bilirubin regulates cholesterol metabolism, adipokines and PPARγ levels, which likely contribute to increased insulin sensitivity and glucose tolerance in DIO mice.

No MeSH data available.


Related in: MedlinePlus