Fibroblast growth factor-21 improves insulin action in nonlactating ewes

Abstract

During metabolically demanding physiological states, ruminants and other mammals coordinate nutrient use among tissues by varying the set point of insulin action. This set point is regulated in part by metabolic hormones with some antagonizing (e.g., growth hormone and TNFa) and others potentiating (e.g., adiponectin) insulin action. Fibroblast growth factor-21 (FGF21) was recently identified as a sensitizing hormone in rodent and primate models of defective insulin action. FGF21 administration, however, failed to improve insulin action in dairy cows during the naturally occurring insulin resistance of lactation, raising the possibility that ruminants as a class of animals or lactation as a physiological state are unresponsive to FGF21. To start addressing this question, we asked whether FGF21 could improve insulin action in non-lactating ewes. Gene expression studies showed that the ovine FGF21 system resembles that of other species, with liver as the major site of FGF21 expression and adipose tissue as a target tissue based on high expression of the FGF21 receptor complex and activation of p44/42 ERK1/2 following exogenous FGF21 administration. FGF21 treatment for 13 days reduced plasma glucose and insulin over the entire treatment period and improved glucose disposal during a glucose tolerance test. FGF21 increased plasma adiponectin by day 3 of treatment but had no effect on the plasma concentrations of total, C16:0-, or C18:0-ceramide. Overall, these data confirm that the insulin-sensitizing effects of FGF21 are conserved in ruminants and raise the possibility that lactation is an FGF21 resistant state.

Ceramide on the road to insulin resistance and immunometabolic disorders in transition dairy cows: driver or passenger?

“…Despite not measuring plasma and tissue ceramides, chronic FGF21 infusion did not affect indices of adiponectin production in lactating dairy cows, including plasma adiponectin and adiponectin mRNA abundance (141). In contrast, Lamb et al (142) observed that FGF21 administration increased plasma adiponectin but did not affect plasma C16:0-and C24:0-ceramide and total ceramides in nonlactating ewes. Therefore, whether the FGF21-adiponectinceramide axis is present in early-lactation dairy cows experiencing NEB remains a matter for further research.…”

“…In contrast, Lamb et al. ( 142 ) observed that FGF21 administration increased plasma adiponectin but did not affect plasma C16:0- and C24:0-ceramide and total ceramides in nonlactating ewes. Therefore, whether the FGF21-adiponectin-ceramide axis is present in early-lactation dairy cows experiencing NEB remains a matter for further research.…”

“…However, Krumm et al (141) found that FGF21 treatment did not impact plasma glucose or insulin levels, suggesting that FGF21 fails to function as an insulin sensitizer during early lactation. A recent study showed that chronic FGF21 treatment increased glucose disposal with a glucose tolerance test in non-lactating ewes (142). The difference in results between early-lactation cows and non-lactating ewes indicates that insulin-sensitizing effects of FGF21 are conserved in ruminants, increasing the possibility that lactation is an FGF21-resistant condition (142).…”

Die Leberverfettung der Milchkuh: Teil 1

“…Die Diskrepanz zwischen den Befunden bei monogastrischen Tieren (und des Menschen) und Kühen haben Lamb et a. [79] bei nicht laktierenden Schafen geprüft. In diesen Versuchen werden die Widersprüche zwischen Wiederkäuern und Nicht-Wiederkäuern auf die Glukose-und NEFA-Konzentration und auf die Insulinsensitivität nicht beobachtet.…”

“…In diesen Versuchen werden die Widersprüche zwischen Wiederkäuern und Nicht-Wiederkäuern auf die Glukose-und NEFA-Konzentration und auf die Insulinsensitivität nicht beobachtet. Lamb et al [79] vermuten die Möglichkeit einer FGF21-Resistenz als Folge der Laktation. Wenn das bei Kühen p.p.…”