Effect of metabolic disturbances on the plasma concentration and hepatic expression of the appetite-reducing hormone growth differentiation factor 15 (GDF15) in dairy cows

Early-lactating dairy cows are vulnerable to metabolic dysfunctions and diseases and the consequent negative effects of these disturbances on appetite. The exaggerated response of early-lactating cows to metabolic disturbances is illustrated by their response to a hyperinsulinemic-euglycemic clamp (HEC) performed over a 48-h period. Initiation of HEC on d 7 of early lactation (EL) reduced feed intake by 33% but had no effect when performed in late pregnancy (LP, 31 d prepartum). We asked whether growth differentiation factor 15 (GDF15), a novel hormone inhibiting feed intake via activation of neuronal centers, could explain the effect of HEC on appetite in EL. This focus was prompted by increased GDF15 production in primates and rodents experiencing metabolic stressors. In plasma samples collected immediately before and after a 48-h period of HEC in EL and LP, HEC increased plasma GDF15 exclusively in EL, and this increase was positively associated with the reduction in feed intake. The major site of GDF15 production in EL was identified as liver on the basis of 7.7- to 87-fold higher expression than adipose tissue or muscle and increased hepatic GDF15 mRNA abundance during HEC. The HEC stimulated hepatic expression of the GDF15 transcriptional activators ATF4 and CHOP across physiological states and expression of the indicator of amino acid deficiency ASNS in EL but not LP. We next asked whether plasma GDF15 is also regulated by a subset of metabolic disturbances prevailing in EL cows (elevated plasma fatty acids, excessive liver triglyceride, and ketosis). The effect of increased plasma fatty acids was evaluated by i.v. infusion of a lipid emulsion (intralipid) in nonpregnant, nonlactating cows in the absence or presence of glucagon treatment. Intralipid caused a progressive rise in plasma GDF15; this stimulatory effect was increased in the presence of glucagon, resulting in a 2.4-fold increase over control after 13 h of infusion. Positive effects of intralipid were associated with increased hepatic expression of GDF15 and its transcriptional activators ATF4 and sXBP1; presence of glucagon increased GDF15 mRNA further but had no additional effect on ATF4 or sXBP1. Indices of GDF15 production were examined in healthy cows segregated on d 7 of lactation as having low (<5.2%) and high (>11.5%) liver triglyceride; neither plasma GDF15 nor hepatic GDF15 mRNA differed between the 2 groups. Finally, plasma GDF15 was measured in early-lactating dairy cows remaining healthy or diagnosed with clinical ketosis. Plasma GDF15 was 1.8-fold higher in ketotic than healthy cows. Overall, these data show upregulation of GDF15 production by a subset of metabolic factors and raise the possibility that GDF15 could contribute to the lower appetitive drive of early-lactating cows experiencing metabolic disturbances.