Effect of conditions and diseases associated with systemic inflammation on the plasma concentration of growth differentiation factor 15 (GDF15) in dairy cows.

Plasma growth differentiation factor 15 (GDF15) was analyzed in dairy cows during the transition period, following treatment with the endotoxin lipopolysaccharide (LPS), during heat stress, and in the presence of infectious diseases. Events associated with these conditions include systemic inflammation and reduced appetite. GDF15 may be relevant to these conditions given its discovery as an overexpressed cDNA in an activated immune cell line and its emergence as an anorexic signal. An i.v. LPS bolus to early lactating cows increased plasma GDF15 from a baseline concentration of 45.2 ± 7.7 pg/mL to a peak concentration of 511.1 ± 92.2 pg/mL within 3 h of administration followed by a return to baseline concentration 33 h later. Dry matter intake over the first 24 h post LPS was negatively related to the area under the curve of plasma GDF15. LPS increased GDF15 expression by 6-fold in liver but had no effect on GDF15 concentration after ex vivo addition to whole blood, identifying liver and not circulating immune cells as a source. In dairy heifers, mammary parenchyma and uterus expressed GDF15 at levels comparable to that of liver, suggesting the capacity of these tissues to increase GDF15 production in response to local endotoxins. In support of this hypothesis, administration of intramammary LPS to early lactating cows raised plasma GDF15 from a baseline concentration of 46.1 ± 4.1 to a peak of 189.3 ± 30.0 pg/mL 9 h later followed by a decline to baseline concentration over the next 15 h. Intramammary LPS caused a 2.1-fold increase in GDF15 expression in liver and a 9.3-fold increase in the mammary gland. We next asked whether plasma GDF15 was increased by naturally occurring events leading to endotoxin exposure (e.g., transition period, heat stress, and infectious diseases). In dairy cows free of clinical diseases, plasma GDF15 increased progressively over the last 3 wk of gestation from 32.6 ± 5.7 pg/mL to a peak of 96.5 ± 22.8 pg/mL on the day of parturition; plasma GDF15 returned to baseline levels by d 3 of lactation and remained at that level over the next 18 d of lactation. Plasma GDF15 was measured over a 7-d period in cows fed ad libitum under thermoneutral or heat stress conditions and in cows fed under thermoneutral conditions to the intake of heat-stressed cows. The reduction of feed intake in pair-fed and heat-stressed cows caused a time-dependent increase in plasma GDF15, but heat stress had no additional effect. Finally, plasma GDF15 was measured in early lactating dairy cows remaining heathy or diagnosed with retained placenta, metritis, or mastitis. Relative to healthy cows, cows with metritis and mastitis had 1.7- and 2.7-fold greater plasma GDF15 concentrations, respectively, whereas cows with retained placenta did not differ. Overall, these data show upregulation of GDF15 production by conditions associated with the presence of endotoxins and raise the possibility that GDF15 may be a member of a highly redundant system designed to reduce appetite during periods of systemic inflammation.