Physiological and hormonal regulation of insulin action in the pregnant and growing ewe

161 pagesVisceral adipose tissue depots have been implicated as major contributors to the insulin resistance of obesity in humans and rodents, but whether they are similarly as important in ruminants is unknown. Understanding the metabolic influence of fat depots is important to balance animal performance with maternal health in pregnancy and lactation. To explore this issue, lean and obese ewes were obtained by feeding to energy requirements or allowing unlimited energy consumption for a 50-day premating period and during pregnancy; both groups were energy-restricted during lactation. Ewes were evaluated in mid- and late pregnancy and in early lactation for adiposity by computed tomography (CT) and for insulin resistance by glucose (GTT) and insulin tolerance tests (ITT). By CT scan analysis, obese ewes were 2-fold fatter by mid-pregnancy; similar differences remained in late pregnancy and in lactation. Adiposity was further evaluated by using the CT scans to quantify internal (sum of omental, mesenteric, perirenal, and retroperitoneal) and external fat (remaining fat not included in internal fat). Unexpectedly, external fat accounted for greater than 2/3 of lipid accretion during pregnancy and mobilization during lactation. Obese ewes were more insulin resistant than lean ewes during pregnancy, but this effect disappeared during lactation. Surprisingly, correlation analysis suggested external fat as a more significant contributor to insulin resistance than internal fat. Overall, the dynamics of external fat appear to be a more important determinant of insulin action in pregnant and lactating ewes. Further work is needed to determine if a specific depot (i.e., intermuscular fat) is driving the influence of external fat. In the second part of this dissertation, we asked whether exogenous administration of the hormone fibroblast growth factor-21 (FGF21) can improve insulin action in growing sheep. FGF21 is a known insulin-sensitizer in well-fed, obese rodents and primates. However, it was recently shown to have no such effect in energy-deficient early lactating dairy cows. Whether this reflects absence of insulin-sensitizing FGF21 action in ruminants or simply loss of action during energy insufficiency was unknown. Therefore, we studied FGF21 in well-fed growing sheep. First, we showed that the FGF21 system is similarly organized in sheep compared with other species. Briefly, liver is the main tissue expressing FGF21 and adipose is an important target tissue. Next, we administered recombinant human FGF21 (FGF21) or excipient solution (control) to the sheep via subcutaneous injection and found FGF21 acutely reduced both plasma glucose and insulin concentrations. Finally, chronic FGF21 administration improved insulin response as evaluated by GTT, as well as increased circulating adiponectin. Furthermore, FGF21 increased epinephrine-stimulated lipolysis. These results are similar to those reported in rodents and primates, but contrast with work previously obtained in energy-deficient dairy cattle. Energy balance may therefore be an important determinant of FGF21 action, but further work is needed in the same ruminant species to confirm these findings.2023-09-1