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4. Fibroblast growth factor-21 improves insulin action in nonlactating ewes.

Author

Lamb, Cassandra L., Giesy, Sarah L., McGuckin, Molly M., Perfield, James W., Butterfield, Anthony, Moniruzzaman, Mohammed, Haughey, Norman J., McFadden, Joseph W., and Boisclair, Yves R.

Subjects
ADIPOKINES, INSULIN, SOMATOTROPIN, EWES, GLUCOSE tolerance tests, FIBROBLAST growth factors, BLOOD sugar
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 TNFα) 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 nonlactating 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 extracellular signal-regulated kinase (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. [ABSTRACT FROM AUTHOR]

Published
2022
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9. EXTRA- AND INTRACELLULAR REGULATORS OF METABOLISM IN TRANSITION DAIRY COWS

Author

McGuckin, Molly

Abstract

The list of signals orchestrating metabolic adaptations in dairy cows during the transition from late pregnancy (LP) to early lactation (EL) is incomplete. This dissertation investigated the role of three categories of signals known to drive adaptations in other conditions and species. In Chapter 3, I explored the possibility that the acute phase protein orosomucoid 1 (ORM1) contributes to insufficient appetite during the transition from LP to EL by activating the leptin receptor as it does in rodents. ORM1 increased from LP to EL but was not elevated in other physiological conditions associated with depressed appetite. In addition, ORM1 did not activate signal transducer and activator of transcription 3 via the leptin receptor in vitro. These data do not support ORM1 as a signal regulating appetite via the leptin receptor in cattle. In rodents, increased inflammatory tone in liver and adipose tissue has been implicated in insulin resistance. Dairy cows experience insulin resistance in EL and have elevated circulating biomarkers of inflammation, but little is known about tissue-localized inflammation. In Chapter 4, I asked whether inflammatory tone is increased in liver and adipose tissue during the transition from LP to EL. I measured gene expression of inflammatory genes in these tissues, but changes were unremarkable. Similar results were obtained when measuring inflammatory gene expression in stromal vascular cells (SVC), the cell compartment of adipose tissue enriched with immune cells. These data do not support a rise in local inflammation in liver and adipose tissue of cows experiencing a healthy transition period. miRNAs regulate level and translation of target mRNA and regulate adipose tissue metabolism in rodents. In Chapter 5, I investigated this mode of regulation by sequencing miRNA in LP and EL adipose tissue in dairy cows. Six miRNAs out of 415 total had expression > 500 rpm and differed > 2-fold between LP and EL. Among those, miR-378 was predominantly expressed in adipocytes and regulated by energy balance and plasma insulin. Altough bioinformatics analysis yielded 675 potential mRNA targets, only 57 appears to relate to metabolic changes occuring during the transition period. Functional studies are needed to ascertain the role of miR-378 in adipocytes during the transition from LP to EL.

Published
2023

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