Limits...
FGF21 does not require interscapular brown adipose tissue and improves liver metabolic profile in animal models of obesity and insulin-resistance.

Bernardo B, Lu M, Bandyopadhyay G, Li P, Zhou Y, Huang J, Levin N, Tomas EM, Calle RA, Erion DM, Rolph TP, Brenner M, Talukdar S - Sci Rep (2015)

Bottom Line: FGF21 improved glucose tolerance and liver insulin sensitivity in Zuckers without affecting BW and improved liver function by decreased lipogenesis, increased fatty acid oxidation and improved insulin signaling.Upon excision of iBAT (X-BAT) and administration of FGF21 to mice housed at 80 °F or 72 °F, the favorable effects of FGF21 on BW and glucose excursion were fully retained in both sham and X-BAT animals.Finally, our data demonstrates iBAT does not play a role in mediating favorable metabolic effects of FGF21 administration in DIOs housed at 80 °F or 72 °F.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Pfizer, Inc. 610 Main Street, Cambridge, MA 02139, USA.

ABSTRACT
FGF21 is a key metabolic regulator modulating physiological processes and its pharmacological administration improves metabolic profile in preclinical species and humans. We used native-FGF21 and a long-acting FGF21 (PF-05231023), to determine the contribution of liver and brown adipose tissue (BAT) towards metabolic improvements in Zucker rats and DIO mice (DIOs). FGF21 improved glucose tolerance and liver insulin sensitivity in Zuckers without affecting BW and improved liver function by decreased lipogenesis, increased fatty acid oxidation and improved insulin signaling. Through detailed lipidomic analyses of liver metabolites in DIOs, we demonstrate that FGF21 favorably alters liver metabolism. We observed a dose-dependent increase of [(18)F]-FDG-glucose uptake in interscapular BAT (iBAT) of DIOs upon FGF21 administration. Upon excision of iBAT (X-BAT) and administration of FGF21 to mice housed at 80 °F or 72 °F, the favorable effects of FGF21 on BW and glucose excursion were fully retained in both sham and X-BAT animals. Taken together, we demonstrate the liver as an organ that integrates the actions of FGF21 and provide metabolic benefits of FGF21 in Zucker rats and DIOs. Finally, our data demonstrates iBAT does not play a role in mediating favorable metabolic effects of FGF21 administration in DIOs housed at 80 °F or 72 °F.

No MeSH data available.


Related in: MedlinePlus

FGF21 improves hepatic metabolic profile in Zucker rats.Livers from Zucker rats administered 1.32 mg/kg/day native FGF21 for two weeks were harvested. a) representative western blots for precursor and mature SREBP1, b) incorporation of 2-14C-acetate in ex vivo livers, n = 6/group, c) western blots for P-AMPK (Thr 172) and Tubulin, d) 14C incorporation into CO2 from ex vivo liver slices, n = 6/group. e) Acute insulin response in Zuckers administered 1.32 mg/kg/day native FGF21 for two weeks. Western blots for P-Akt and total Akt from the indicated tissues. In Figures a and c, each lane represents a different animal. All gels reported in a), c) and e) were run under the same experimental conditions on the same gels respectively for each of these proteins. In a) each lane represents liver lysates from a separate animal, 4 administered PBS and 4 administered FGF21. All samples were run in the order shown in the figure. In c) data is shown for 3 animals administered PBS and 3 animals administered FGF21. Each protein was run on its own gel. Dotted line indicates where blots were cropped. In e) data is shown for 3 animals administered PBS and 3 administered FGF21. All samples were run in the order shown in the gels. Representative total Akt blot is from liver. Each protein was run on its own gel. Data represented as Mean ± SEM. * p < 0.05 by paired t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4495598&req=5

f2: FGF21 improves hepatic metabolic profile in Zucker rats.Livers from Zucker rats administered 1.32 mg/kg/day native FGF21 for two weeks were harvested. a) representative western blots for precursor and mature SREBP1, b) incorporation of 2-14C-acetate in ex vivo livers, n = 6/group, c) western blots for P-AMPK (Thr 172) and Tubulin, d) 14C incorporation into CO2 from ex vivo liver slices, n = 6/group. e) Acute insulin response in Zuckers administered 1.32 mg/kg/day native FGF21 for two weeks. Western blots for P-Akt and total Akt from the indicated tissues. In Figures a and c, each lane represents a different animal. All gels reported in a), c) and e) were run under the same experimental conditions on the same gels respectively for each of these proteins. In a) each lane represents liver lysates from a separate animal, 4 administered PBS and 4 administered FGF21. All samples were run in the order shown in the figure. In c) data is shown for 3 animals administered PBS and 3 animals administered FGF21. Each protein was run on its own gel. Dotted line indicates where blots were cropped. In e) data is shown for 3 animals administered PBS and 3 administered FGF21. All samples were run in the order shown in the gels. Representative total Akt blot is from liver. Each protein was run on its own gel. Data represented as Mean ± SEM. * p < 0.05 by paired t-test.

Mentions: Since clamp data showed FGF21 administration improved hepatic insulin sensitivity, we wanted to determine the mechanism(s) by which FGF21 mediates this effect. After two weeks of treatment, native FGF21 decreased the mature active form of SREBP1 in the liver without changing the precursor form (Fig. 2a). Consistent with this finding, hepatic lipogenesis, measured ex vivo by incorporation of 2-14C-acetate into total lipid fraction of livers from treated animals was significantly decreased in FGF21-treated Zucker livers compared to control (Fig. 2b). Native FGF21 treatment increased hepatic P-AMPK compared to control (Fig. 2c), and subsequently, ex vivo hepatic lipid oxidation measured by detecting labeled CO2 from 14C-palmitate was significantly increased in FGF21 treated animals compared to controls (Fig. 2d). Since EGP was decreased by FGF21 under clamp conditions, we performed acute insulin administration in fasting animals treated with vehicle and native FGF21 for two weeks. On the day of performing the experiment, the treated animals received one final dose of native FGF21 followed by the assessment of insulin signaling 2 hours later. Consistent with data obtained from clamp studies, P-Akt was significantly increased in liver upon acute insulin administration in FGF21 treated animals compared to controls, however no changes in P-Akt was observed in adipose tissue or muscle (Fig. 2e). These data support the findings that liver is the primary tissue responsible for FGF21 action in Zucker rats.


FGF21 does not require interscapular brown adipose tissue and improves liver metabolic profile in animal models of obesity and insulin-resistance.

Bernardo B, Lu M, Bandyopadhyay G, Li P, Zhou Y, Huang J, Levin N, Tomas EM, Calle RA, Erion DM, Rolph TP, Brenner M, Talukdar S - Sci Rep (2015)

FGF21 improves hepatic metabolic profile in Zucker rats.Livers from Zucker rats administered 1.32 mg/kg/day native FGF21 for two weeks were harvested. a) representative western blots for precursor and mature SREBP1, b) incorporation of 2-14C-acetate in ex vivo livers, n = 6/group, c) western blots for P-AMPK (Thr 172) and Tubulin, d) 14C incorporation into CO2 from ex vivo liver slices, n = 6/group. e) Acute insulin response in Zuckers administered 1.32 mg/kg/day native FGF21 for two weeks. Western blots for P-Akt and total Akt from the indicated tissues. In Figures a and c, each lane represents a different animal. All gels reported in a), c) and e) were run under the same experimental conditions on the same gels respectively for each of these proteins. In a) each lane represents liver lysates from a separate animal, 4 administered PBS and 4 administered FGF21. All samples were run in the order shown in the figure. In c) data is shown for 3 animals administered PBS and 3 animals administered FGF21. Each protein was run on its own gel. Dotted line indicates where blots were cropped. In e) data is shown for 3 animals administered PBS and 3 administered FGF21. All samples were run in the order shown in the gels. Representative total Akt blot is from liver. Each protein was run on its own gel. Data represented as Mean ± SEM. * p < 0.05 by paired t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495598&req=5

f2: FGF21 improves hepatic metabolic profile in Zucker rats.Livers from Zucker rats administered 1.32 mg/kg/day native FGF21 for two weeks were harvested. a) representative western blots for precursor and mature SREBP1, b) incorporation of 2-14C-acetate in ex vivo livers, n = 6/group, c) western blots for P-AMPK (Thr 172) and Tubulin, d) 14C incorporation into CO2 from ex vivo liver slices, n = 6/group. e) Acute insulin response in Zuckers administered 1.32 mg/kg/day native FGF21 for two weeks. Western blots for P-Akt and total Akt from the indicated tissues. In Figures a and c, each lane represents a different animal. All gels reported in a), c) and e) were run under the same experimental conditions on the same gels respectively for each of these proteins. In a) each lane represents liver lysates from a separate animal, 4 administered PBS and 4 administered FGF21. All samples were run in the order shown in the figure. In c) data is shown for 3 animals administered PBS and 3 animals administered FGF21. Each protein was run on its own gel. Dotted line indicates where blots were cropped. In e) data is shown for 3 animals administered PBS and 3 administered FGF21. All samples were run in the order shown in the gels. Representative total Akt blot is from liver. Each protein was run on its own gel. Data represented as Mean ± SEM. * p < 0.05 by paired t-test.
Mentions: Since clamp data showed FGF21 administration improved hepatic insulin sensitivity, we wanted to determine the mechanism(s) by which FGF21 mediates this effect. After two weeks of treatment, native FGF21 decreased the mature active form of SREBP1 in the liver without changing the precursor form (Fig. 2a). Consistent with this finding, hepatic lipogenesis, measured ex vivo by incorporation of 2-14C-acetate into total lipid fraction of livers from treated animals was significantly decreased in FGF21-treated Zucker livers compared to control (Fig. 2b). Native FGF21 treatment increased hepatic P-AMPK compared to control (Fig. 2c), and subsequently, ex vivo hepatic lipid oxidation measured by detecting labeled CO2 from 14C-palmitate was significantly increased in FGF21 treated animals compared to controls (Fig. 2d). Since EGP was decreased by FGF21 under clamp conditions, we performed acute insulin administration in fasting animals treated with vehicle and native FGF21 for two weeks. On the day of performing the experiment, the treated animals received one final dose of native FGF21 followed by the assessment of insulin signaling 2 hours later. Consistent with data obtained from clamp studies, P-Akt was significantly increased in liver upon acute insulin administration in FGF21 treated animals compared to controls, however no changes in P-Akt was observed in adipose tissue or muscle (Fig. 2e). These data support the findings that liver is the primary tissue responsible for FGF21 action in Zucker rats.

Bottom Line: FGF21 improved glucose tolerance and liver insulin sensitivity in Zuckers without affecting BW and improved liver function by decreased lipogenesis, increased fatty acid oxidation and improved insulin signaling.Upon excision of iBAT (X-BAT) and administration of FGF21 to mice housed at 80 °F or 72 °F, the favorable effects of FGF21 on BW and glucose excursion were fully retained in both sham and X-BAT animals.Finally, our data demonstrates iBAT does not play a role in mediating favorable metabolic effects of FGF21 administration in DIOs housed at 80 °F or 72 °F.

View Article: PubMed Central - PubMed

Affiliation: Cardiovascular Metabolic and Endocrine Diseases (CVMED) Pfizer, Inc. 610 Main Street, Cambridge, MA 02139, USA.

ABSTRACT
FGF21 is a key metabolic regulator modulating physiological processes and its pharmacological administration improves metabolic profile in preclinical species and humans. We used native-FGF21 and a long-acting FGF21 (PF-05231023), to determine the contribution of liver and brown adipose tissue (BAT) towards metabolic improvements in Zucker rats and DIO mice (DIOs). FGF21 improved glucose tolerance and liver insulin sensitivity in Zuckers without affecting BW and improved liver function by decreased lipogenesis, increased fatty acid oxidation and improved insulin signaling. Through detailed lipidomic analyses of liver metabolites in DIOs, we demonstrate that FGF21 favorably alters liver metabolism. We observed a dose-dependent increase of [(18)F]-FDG-glucose uptake in interscapular BAT (iBAT) of DIOs upon FGF21 administration. Upon excision of iBAT (X-BAT) and administration of FGF21 to mice housed at 80 °F or 72 °F, the favorable effects of FGF21 on BW and glucose excursion were fully retained in both sham and X-BAT animals. Taken together, we demonstrate the liver as an organ that integrates the actions of FGF21 and provide metabolic benefits of FGF21 in Zucker rats and DIOs. Finally, our data demonstrates iBAT does not play a role in mediating favorable metabolic effects of FGF21 administration in DIOs housed at 80 °F or 72 °F.

No MeSH data available.


Related in: MedlinePlus