Abstract
In rodents, fibroblast growth factor 21 (FGF21) has emerged as a key metabolic regulator produced by liver. To gather preliminary data on the potential importance of FGF1, co-regulated genes, and upstream metabolic genes, we examined the hepatic mRNA expression in response to nutrition and inflammation in dairy cows. In experiment 1, induction of ketosis through feed restriction on d 5 postpartum upregulated FGF21, its co-receptor KLB, and PPARA but only elicited a numerical increase in serum FGF21 concentration. In experiment 2, cows in control (CON) or receiving 50 g/d of L-carnitine (C50) from -14 through 21 d had increased FGF21, PPARA, and NFIL3 on d 10 compared with d 2 postpartum. In contrast, compared with CON and C50, 100 g/d L-carnitine (C100) resulted in lower FGF21, KLB, ANGPTL4, and ARNTL expression on d 10. In experiment 3, cows were fed during the dry period either a higher-energy (OVE; 1.62 Mcal/kg DM) or lower-energy (CON; 1.34 Mcal/kg DM) diet and received 0 (OVE:N, CON:N) or 200 μg of LPS (OVE:Y, CON:Y) into the mammary gland at d 7 postpartum. For FGF21 mRNA expression in CON, the LPS challenge (CON:Y) prevented a decrease in expression between d 7 and 14 postpartum such that cows in CON:N had a 4-fold lower expression on d 14 compared with d 7. The inflammatory stimulus induced by LPS in CON:Y resulted in upregulation of PPARA on d 14 to a similar level as cows in OVE:N. In OVE:Y, expression of PPARA was lower than CON:N on d 7 and remained unchanged on d 14. On d 7, LPS led to a 4-fold greater serum FGF21 only in OVE but not in CON cows. In fact, OVE:Y reached the same serum FGF21 concentration as CON:N, suggesting a carryover effect of dietary energy level on signaling mechanisms within liver. Overall, results indicate that nutrition, ketosis, and inflammation during the peripartal period can alter hepatic FGF21, co-regulated genes, and upstream metabolic genes to various extents. The functional outcome of these changes merits further study, and in particular the mechanisms regulating transcription in response to changes in energy balance and feed intake.
Highlights
Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator of the FGF family that is produced by the liver and in rodents has an important role in the regulation of glucose and lipid metabolism [1, 2]
The mRNA expression of CPT1A and PPARA was not measured in this study because they were reported by Loor et al.[16]
During periods of negative energy balance (NEB), high-producing cows become more susceptible to developing ketosis, leading to further increases in NEFA, BHBA, hepatic TAG concentration, hepatic mRNA expression of PPARA and angiopoietin-like 4 (ANGPTL4, a hepatokine), and other genes associated with ketogenesis and gluconeogenesis[16]
Summary
Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator of the FGF family that is produced by the liver and in rodents has an important role in the regulation of glucose and lipid metabolism [1, 2]. Hepatic FGF21 plays a role in regulation of hepatic oxidation of fatty acids and gluconeogenesis in response to fasting and during consumption of high-fat diets [5]. Schoenberg et al [8] working with periparturient cows reported that the onset of negative energy balance (NEB) after calving was associated with increased plasma FGF21 concentration and greater FGF21 mRNA expression in liver. Carnitine has an important role in various metabolic functions including mitochondrial long-chain fatty acid (LCFA) oxidation, and has been shown to dramatically decrease or prevent liver lipid accumulation in laboratory animals [9, 10] and dairy cows [11]. In rodents the onset of infection, inflammation, trauma, and malignancy induces the acute-phase response (APR), which leads to a decrease in hepatic oxidation of fatty acids and ketogenesis [13,14]. Feingold et al [15] proposed that FGF21 is a positive APR protein that could help protect animals from the toxic effects of LPS and sepsis
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