The Role of Metabolic Signaling in Nutrient Partitioning During Lactation

Released on by Virginia Pszczolkowski
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  • The Role of Metabolic Signaling in Nutrient Partitioning During Lactation Book Detail

  • Author : Virginia Pszczolkowski
  • Release Date : 2023
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  • File Size : 50,50 MB
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The Role of Metabolic Signaling in Nutrient Partitioning During Lactation by Virginia Pszczolkowski PDF Summary

Book Description: This thesis examines the hypothesis that metabolic signaling regulates how nutrients are partitioned to support milk synthesis during lactation, with particular emphasis on the dairy cow. First we explored the role of the protein complex mTORC1, a cellular hub of metabolic regulation, in mediating dietary amino acid regulation of murine lactation. Kinase activity of mTORC1 positively regulates cellular anabolic signaling, including protein translation and fat synthesis. Amino acids are both the substrate for protein synthesis-including milk protein-and intracellular signaling molecules that stimulate mTORC1. Feeding lactating animals a protein-restricted diet, therefore, should limit the substrate supply for milk synthesis, as well as reduces anabolic signaling driving that synthesis. Increasing the synthesis of milk components, by definition, means that those components' precursors are simultaneously being partitioned to the synthesizing tissue. We hypothesized that inhibiting mTORC1 activity would reduce lactation performance similarly to restricting protein. We fed lactating mice isoenergetic diets containing adequate protein or restricted protein, and treated half of the adequate protein dams with the mTORC1 inhibitor rapamycin. The dams receiving rapamycin under an adequate protein background and the dams receiving the protein-restricted diet all exhibited reduced pup growth and milk production. In this way, we demonstrated that pharmacologic inhibition of mTORC1 mimics dietary protein restriction in lactating mouse dams, positioning mTORC1 signaling as essential in milk production and successful lactation.Next, we further examined mTORC1 signaling in MAC-T, an immortalized mammary epithelial cell line. Amino acids function to induce mTORC1 localization to the lysosome, where its insulin-activated binding partner Rheb resides. In other models, it has been established that in order for mTORC1 activity to commence following amino acid-driven lysosomal localization, insulin signaling must also be present. We hypothesized that this was also the case in MAC-T. By testing the response in mTORC1 activity to varying concentrations of individual amino acids and insulin, we found that, out of the 10 essential amino acids, only Arg, Ile, Leu, Met, and Thr activate mTORC1 signaling in MAC-T cells, and that this activation requires concurrent stimulation by insulin for greatest response. Following the establishment of which amino acids best interact with insulin to regulate mTORC1 activity in a mammary epithelial cell line, we then sought to test this interaction in lactating cows. We hypothesized that the combination of insulin with Leu and Met-two of the amino acids identified as key in our in vitro study-would result in improved mammary utilization of nutrients for milk synthesis. In this cow study, we raised circulating insulin by means of the hyperinsulinemic-euglycemic clamp, and increased circulating Leu and Met by abomasal infusion. We found that the simplicity suggested by our in vitro experiment belies the complexity of lactation in a cow: there was no interaction between insulin and the amino acids, nor did either treatment independently result in any positive effects on mammary utilization of nutrients or milk production. We did, however, observe responses in plasma concentrations of several nutrients and metabolites, including free fatty acids and amino acids, which were reduced in response to insulin. Insulin is a particularly complex hormone in the context of a lactating dairy cow, because despite the necessity of insulin signaling for cellular metabolic functions like mTORC1 activity in the mammary cells, insulin can also reduce the availability of nutrients for the mammary gland by inducing uptake in non-mammary tissues. Because we did not see evidence that the free fatty acids nor amino acids decreased in circulation were being utilized by the mammary glands for milk synthesis, it is likely that in the context of this experiment, insulin instead stimulated nutrient uptake by other insulin sensitive tissues, partitioning nutrients away from the mammary glands. As insulin partitions nutrients away from the mammary glands, we then sought to investigate the effect of serotonin in nutrient partitioning, a hormone that in lactating cows has been shown to decrease circulating insulin concentration, act as an autocrine-paracrine regulator of mammary and calcium homeostasis in lactation, and perform a variety of other metabolic roles outside of lactation. We raised peripheral serotonin in lactating cows by intravenously infusing them with the serotonin precursor 5-HTP and conducted several experiments in these cows over the course of three weeks to investigate how serotonin may participate in nutrient partitioning to the mammary glands. In performing an intravenous glucose tolerance test on the cows, we determined that elevated serotonin both reduced the insulin response and blunted the decrease in free fatty acids following the glucose challenge, without altering the glucose dynamics themselves. The maintenance of normoglycemia under lower insulin conditions, coupled with elevated free fatty acids, suggests that serotonin stimulates insulin-independent glucose disposal, and increases free fatty acid availability for mammary gland usage. When we then assessed serotonin's broader effects on metabolic function, mammary extraction of nutrients, and subsequent milk production, we found transiently decreased circulating insulin, increased circulating free fatty acids, and increased mammary free fatty acid extraction, all of which indicate increased free fatty acid partitioning to the mammary glands. This partitioning was not, however, borne out in improved milk production, which was instead decreased in concert with infusion of 5-HTP. Elevated serotonin also increased the incidence and frequency of loose manure during and shortly after infusion, in line with its known effects on gut motility, and reduced feed intake in a manner antithetical to the support of lactation. This work in serotonin may have been limited by the experimental approach used, with 5-HTP rather than serotonin itself administered in a bolus fashion, potentially driving strongly transient effects in both the periphery and central nervous system. This could effect serotonergic responses that are disparate from what is possible with endogenous mammary serotonin production alone. Overall, through the work of this dissertation, we have identified the importance of insulin in cellular signaling within the mammary epithelial cells to drive milk synthesis, but also that, within the physiologic context of a lactating animal, insulin has non-mammary functions that may contradict its signaling role in mammary cells, reducing substrate availability for milk synthesis. As with insulin, peripheral serotonin is part of a complex system that can yield equally complex outcomes. While serotonin can improve milk substrate availability in the circulation and improve the mammary extraction of some of those substrates, it can simultaneously reduce the availability of other substrates by limiting their availability and absorption from the diet. Broadly, understanding how amino acids, insulin, and serotonin interact to regulate metabolism function during lactation will better position lactation physiologists and nutritionists to understand and manipulate metabolism during lactation. In this way, this work advances the pursuit of improved productive efficiency and treatment and prevention of metabolic disorders in dairy cows.

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