Fibroblast Growth Factor 21 increases hepatic oxidative capacity but not physical activity or energy expenditure in hepatic PGC-1α deficient mice

摘要

Fibroblast growth factor 21 (FGF21) treatment drives metabolic improvements, including increased metabolic flux and reduced hepatic steatosis, but mechanisms responsible for these effects remain to be fully elucidated. We tested if a targeted reduction in hepatic PGC-1α, which has been shown to occur with obesity, negatively impacted the metabolic effects of FGF21. We infused FGF21 (1 mg/kg/day) or saline in chow-fed wild-type (WT) and liver-specific PGC-1α +/− (LPGC-1α) mice for 4 weeks. FGF21 administration lowered serum insulin and cholesterol (p≤ 0.05), and tended to lower FFAs (p=0.057). LPGC-1α mice exhibited reduced complete hepatic fatty acid oxidation (FAO) (1788 ± 165 (LPGC-1α) compared to 2572 ± 437 (WT) nmol/g/hr; p<0.001), which was normalized with FGF21 treatment (2788 ± 519 nmol/g/hr; P<0.001). FGF21 also increased hepatic incomplete FAO 12% in both groups and extra-mitochondrial FAO 89 and 56% in WT and LPGC-1α mice respectfully (P=0.001), and lowered hepatic TAGs 30–40% (P<0.001). Chronic treatment with FGF21 lowered body weight and fat mass (p< 0.05) while increasing food consumption (p< 0.05), total energy expenditure (TEE) (7.3 ± 0.60 vs. 6.6 ± 0.39 kcals/12 hours in WT mice; p=0.009) and resting (REE) (5.4 ± 0.89 vs. 4.6 ± 0.21 kcals/12 hours in WT mice; p=0.005). Interestingly, FGF21 only increased ambulatory activity in the WT mice (p=0.03) without a concomitant increase in non-resting energy expenditure. In conclusion, while reduced hepatic PGC-1α expression was not necessary for FGF21 to increase FAO, it does appear to mediate FGF21 induced changes in TEE, REE, and ambulatory activity in lean mice.