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

Role of interscapular BAT in FGF21 pharmacology.iBAT was excised (X-BAT), or sham surgery was performed in DIO mice and administered 0.85 mg/kg FGF21 or vehicle continuously via an osmotic minipump for 14 days. At 80 °F which is close to the thermoneutral zone in mice, a) BW, b) OGTT, c) oxygen consumption, d) CO2 production. The same experiment was performed in mice housed at 72 °F. e) BW, f) OGTT. UCP1 mRNA from inguinal white adipose tissue normalized to cyclin B as housekeeping gene from mice housed at g) 80 °F and h) 72 °F. n = 7–8 animals/group. Data represented as Mean ± SEM. *p < 0.05 by one way Anova and Dunnett’s posthoc test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Role of interscapular BAT in FGF21 pharmacology.iBAT was excised (X-BAT), or sham surgery was performed in DIO mice and administered 0.85 mg/kg FGF21 or vehicle continuously via an osmotic minipump for 14 days. At 80 °F which is close to the thermoneutral zone in mice, a) BW, b) OGTT, c) oxygen consumption, d) CO2 production. The same experiment was performed in mice housed at 72 °F. e) BW, f) OGTT. UCP1 mRNA from inguinal white adipose tissue normalized to cyclin B as housekeeping gene from mice housed at g) 80 °F and h) 72 °F. n = 7–8 animals/group. Data represented as Mean ± SEM. *p < 0.05 by one way Anova and Dunnett’s posthoc test.

Mentions: Since FGF21 increased [18F]-FDG uptake in DIO mice and FGF21 increases EE, we wanted to determine the contribution of BAT in this process. We excised either iBAT (X-BAT) or performed sham surgery in DIO mice that were housed under thermoneutral (80 °F) conditions, followed by continuous administration of either vehicle or native FGF21 for two weeks via a subcutaneously implanted minipump. As expected, FGF21 decreased BW in sham animals but interestingly, FGF21 decreased BW in X-BAT animals equally as observed in sham mice, compared to vehicle in sham or X-BAT mice (Fig. 4a). Glucose excursion during OGTT was decreased equally in sham, or X-BAT animals administered FGF21 (Fig. 4b). To detect potential changes in EE, we used CLAMS chambers to monitor metabolic rate of these animals. Consistent with previous reports, FGF21 treatment increased oxygen consumption (Fig. 4c) and CO2 production (Fig. 4d) however, these changes were similar in sham and X-BAT animals compared to control. FGF21 increased O2 consumption and CO2 production in sham, or X-BAT at night, compared to day, whereas there was no difference in animals administered vehicle (Fig. 4c,d). There was no change in ambulatory activity in FGF21 animals compared to control in sham and X-BAT mice (Supplementary Fig. S1b). Since mice are typically housed at ambient temperature (72 °F), we asked whether excision of iBAT would have any impact on the metabolic endpoints upon FGF21 treatment. Consistent with observations in sham and X-BAT animals housed at 80 °F, FGF21 decreased BW (Fig. 4e) and improved glucose excursion during OGTT (Fig. 4f) equally in sham, or X-BAT treated animals housed at 72 °F.


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)

Role of interscapular BAT in FGF21 pharmacology.iBAT was excised (X-BAT), or sham surgery was performed in DIO mice and administered 0.85 mg/kg FGF21 or vehicle continuously via an osmotic minipump for 14 days. At 80 °F which is close to the thermoneutral zone in mice, a) BW, b) OGTT, c) oxygen consumption, d) CO2 production. The same experiment was performed in mice housed at 72 °F. e) BW, f) OGTT. UCP1 mRNA from inguinal white adipose tissue normalized to cyclin B as housekeeping gene from mice housed at g) 80 °F and h) 72 °F. n = 7–8 animals/group. Data represented as Mean ± SEM. *p < 0.05 by one way Anova and Dunnett’s posthoc test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: Role of interscapular BAT in FGF21 pharmacology.iBAT was excised (X-BAT), or sham surgery was performed in DIO mice and administered 0.85 mg/kg FGF21 or vehicle continuously via an osmotic minipump for 14 days. At 80 °F which is close to the thermoneutral zone in mice, a) BW, b) OGTT, c) oxygen consumption, d) CO2 production. The same experiment was performed in mice housed at 72 °F. e) BW, f) OGTT. UCP1 mRNA from inguinal white adipose tissue normalized to cyclin B as housekeeping gene from mice housed at g) 80 °F and h) 72 °F. n = 7–8 animals/group. Data represented as Mean ± SEM. *p < 0.05 by one way Anova and Dunnett’s posthoc test.
Mentions: Since FGF21 increased [18F]-FDG uptake in DIO mice and FGF21 increases EE, we wanted to determine the contribution of BAT in this process. We excised either iBAT (X-BAT) or performed sham surgery in DIO mice that were housed under thermoneutral (80 °F) conditions, followed by continuous administration of either vehicle or native FGF21 for two weeks via a subcutaneously implanted minipump. As expected, FGF21 decreased BW in sham animals but interestingly, FGF21 decreased BW in X-BAT animals equally as observed in sham mice, compared to vehicle in sham or X-BAT mice (Fig. 4a). Glucose excursion during OGTT was decreased equally in sham, or X-BAT animals administered FGF21 (Fig. 4b). To detect potential changes in EE, we used CLAMS chambers to monitor metabolic rate of these animals. Consistent with previous reports, FGF21 treatment increased oxygen consumption (Fig. 4c) and CO2 production (Fig. 4d) however, these changes were similar in sham and X-BAT animals compared to control. FGF21 increased O2 consumption and CO2 production in sham, or X-BAT at night, compared to day, whereas there was no difference in animals administered vehicle (Fig. 4c,d). There was no change in ambulatory activity in FGF21 animals compared to control in sham and X-BAT mice (Supplementary Fig. S1b). Since mice are typically housed at ambient temperature (72 °F), we asked whether excision of iBAT would have any impact on the metabolic endpoints upon FGF21 treatment. Consistent with observations in sham and X-BAT animals housed at 80 °F, FGF21 decreased BW (Fig. 4e) and improved glucose excursion during OGTT (Fig. 4f) equally in sham, or X-BAT treated animals housed at 72 °F.

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