Effect of circulating glucagon and free fatty acids on hepatic FGF21 production in dairy cows.

Modern dairy cows meet the energy demand of early lactation by calling on hormonally driven mechanisms to increase the use of lipid reserves. In this context, we recently reported that fibroblast growth factor-21 (FGF21), a hormone required for efficient use of lipid reserves in rodents, is upregulated in periparturient dairy cows. Increased plasma FGF21 in early lactation coincides with elevated circulating concentrations of glucagon (GCG) and nonesterified fatty acids (NEFA). To assess the relative contribution of these factors in regulating FGF21, two experiments were performed in energy-sufficient, nonpregnant, nonlactating dairy cows. In the first study, cows were injected with saline or GCG every 8 h over a 72-h period. GCG increased hepatic FGF21 mRNA by an average of fivefold over matched controls but had no effect on plasma FGF21. In the second study, cows were infused and injected with saline, infused with Intralipid and injected with saline, or infused with Intralipid and injected with GCG. Infusions and injections were administered intravenously over 16 h and subcutaneously every 8 h, respectively. Intralipid infusion increased plasma NEFA from 92 to 550 µM within 3 h and increased plasma FGF21 from 1.3 to >11 ng/ml 6 h later; FGF21 mRNA increased by 34-fold in liver but remained invariant in adipose tissue. GCG injections during the Intralipid infusion had no additional effects on plasma NEFA, liver FGF21 mRNA, or plasma FGF21. These data implicate plasma NEFA as a key factor triggering hepatic production and increased circulating concentrations of FGF21 in early lactation.

Inflammatory biomarkers are associated with ketosis in periparturient Holstein cows.

Ketosis is a prevalent periparturient metabolic disorder and we hypothesize that lipopolysaccharide (LPS) infiltration may play a key role in its etiology. Study objectives were to characterize biomarkers of inflammation during the transition period in healthy and clinically diagnosed ketotic cows. Cows were retrospectively categorized into one of two groups: healthy and clinically diagnosed ketotic. Two data sets were utilized; the first dataset (Study A) was obtained as a subset of cows (n=16) enrolled in a larger experiment conducted at the Iowa State University Dairy utilizing Holstein cows (8 healthy; 8 ketotic), and the second dataset (Study B; 22 healthy; 22 ketotic) was obtained from a commercial farm. For both experiments, blood samples were collected prior to and following calving. Ketotic cows in both studies had reduced milk production compared to healthy cows (P<0.01). Post-calving, ketotic cows had increased serum amyloid A (4.2 and 1.8 fold in studies A and B, respectively; P=0.03 and P=0.04), haptoglobin (>6 fold and ~4 fold; P=0.04 and P=0.03), and lipopolysaccharide binding protein (66 and 45%; P<0.01 and P=0.02) compared with their healthy counterparts. Antepartum circulating LPS in ketotic cows was increased (2.3 fold; P=0.01) compared to healthy cows in Study B. In summary, increased biomarkers of inflammation appear to be closely associated with ketosis in transition dairy cows.

Plasma FGF21 is elevated by the intense lipid mobilization of lactation.

In many mammals, lactation success depends on substantial use of lipid reserves and requires integrated metabolic activities between white adipose tissue (WAT) and liver. Mechanisms responsible for this integration in lactation are poorly understood, but data collected in other conditions of elevated lipid use suggest a role for fibroblast growth factor-21 (FGF21). To address this possibility in the context of lactation, we studied high-yielding dairy cows during the transition from late pregnancy (LP) to early lactation (EL). Plasma FGF21 was nearly undetectable in LP, peaked on the day of parturition, and then stabilized at lower, chronically elevated concentrations during the energy deficit of EL. Plasma FGF21 was similarly increased in the absence of parturition when an energy-deficit state was induced by feed restricting late-lactating dairy cows, implicating energy insufficiency as a cause of chronically elevated FGF21 in EL. Gene expression studies showed that liver was a major source of plasma FGF21 in EL with little or no contribution by WAT, skeletal muscle, and mammary gland. Meaningful expression of the FGF21 coreceptor ß-Klotho was restricted to liver and WAT in a survey of 15 tissues that included the mammary gland. Expression of ß-Klotho and its subset of interacting FGF receptors was modestly affected by the transition from LP to EL in liver but not in WAT. Overall, these data suggest a model whereby liver-derived FGF21 regulates the use of lipid reserves during lactation via focal actions on liver and WAT.