The acute phase protein orosomucoid 1 is upregulated in early lactation but does not trigger appetite-suppressing STAT3 signaling via the leptin receptor

摘要

Dairy cows consume inadequate amounts of feed inearly lactation and during conditions and diseases suchas excessive fatness, heat stress, and infectious diseases.Affected cows often experience increases in plasma concentrationsof acute phase proteins consistent with thenegative effect of inflammation on appetite. The acutephase protein orosomucoid 1 (ORM1), also known asalpha-1-acid glycoprotein, was recently reported to reduceappetite in the mouse through its ability to bindthe full-length leptin receptor (Ob-Rb) and activateappetite-suppressing signal transducer and activatorof transcription 3 (STAT3) signaling. These observationsraise the possibility that ORM1 exerts appetitesuppressingeffects in dairy cattle during periods ofincreased inflammatory tone. The applicability of thismodel was assessed in 2 ways. First, we asked whetherORM1 is regulated during periods of inadequate appetitesuch as the transition from late pregnancy toearly lactation and periods of increased inflammatorytone. Plasma ORM1 was invariant in late pregnancybut increased 2.5-fold between parturition and d 7 oflactation. Gene expression studies showed that liver wasthe major source of this elevation with little contributionby adipose tissue or mammary gland. Additionalstudies showed that plasma ORM1 was not increasedfurther by excessive fatness or by reproductive dysfunctionin early lactation and was completely unresponsiveto inflammatory stimuli such as heat stress or intravascularadministration of the endotoxin lipopolysaccharideduring established lactation. Second, we tested theability of ORM1 to trigger STAT3 signaling throughOb-Rb using Chinese hamster ovary K1 (CHO-K1)cells transfected with a STAT3 expression plasmid. Inthis configuration, CHO-K1 cells did not express Ob-Rb and were incapable of leptin-induced STAT3 phosphorylation.Leptin responsiveness was conferred byco-transfecting with bovine Ob-Rb, with leptin causingincreases of 5.7-fold in STAT3 phosphorylation and 2.1-fold in the expression of the STAT3-dependent gene,SOCS3. In contrast, neither bovine or human ORM1triggered STAT3 phosphorylation irrespective of doseand period of incubation tested. In summary, bovineORM1 is not increased during periods of increasedinflammatory tone except in early lactation and is incapableof Ob-Rb-dependent STAT3 signaling. Overall,these data are inconsistent with ORM1 mediating theappetite-suppressing effects of inflammation in cattlethrough Ob-Rb.