Collaborative Research: Revisiting the homeorhetic mechanisms of lactation: The role of ceramide

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This collaborative project investigates the role of ceramide lipids in regulating glucose dynamics during lactation in sheep. Increasing the efficiency of nutrient use in farm animals is a potential means to increase global food security and reduce negative environmental impact. Increasing the efficiency to produce nutrient-dense milk from sheep and cows with less nutrient waste is one example. To achieve this goal, it is necessary to understand the mechanisms of lactation in these animals. Reduced insulin-stimulated uptake of glucose by maternal muscle and increased glucose utilization by the mammary gland are physiological adjustments that occur after birth to support milk synthesis, but it is not clear how these responses are coordinated. This project expands upon evidence suggesting that ceramide may increase nutrient supply to the mammary gland for milk synthesis. The effects of increasing and decreasing ceramide levels will be quantified in ewes, and mechanisms of ceramide’s effects on muscle will be studied in muscle cell culture. Research will be integrated within an education and outreach program focused on improving public understanding of food animal production and the role of novel strategies (e.g., biotechnology) in increasing milk synthesis. Two students per year from the State University of New York at Cortland will conduct research through the Research Experiences for Undergraduates (REU) program, and two Cornell graduate students will contribute to the research. The REU and graduate students, along with faculty, will learn how to communicate science to the public effectively through a collaboration with the nearby Sciencenter museum. An exhibit for the Sciencenter and the Great New York State Fair will be developed to teach the public about sustainable animal agriculture.A fundamental homeorhetic mechanism that develops to support the onset of lactation is the reduction of insulin sensitivity in skeletal muscle, which spares glucose for the mammary synthesis of milk, contributing to survival of the neonate. Classic studies infer that maternal insulin resistance is mediated by pituitary somatotropin (ST) and uncoupling of the somatotropic axis (i.e., reduced insulin-like growth factor-1 secretion from liver). The researchers propose that this traditional view of homeorhesis is incomplete, and have identified ceramide as a potential mediator of ST action, glucose partitioning, and lactation. The hypothesis that ceramide causes maternal insulin resistance to support milk synthesis in mammals will be tested. Whole animal studies will establish whether the inhibition of ceramide synthesis increases insulin sensitivity to decrease milk production, and whether the induction of ceramide synthesis is a means to decrease insulin sensitivity to sustain milk production. In addition, the mechanisms of insulin antagonism that involve ceramide in myotubes will be delineated. Experience utilizing lipidomics and studying insulin kinetics, as well as a justified Ovis aries (sheep) model, will be leveraged to define the homeorhetic role of ceramide during mammalian lactation. Results may lead to new ways to increase milk production efficiency, which would benefit the associated agricultural industries. Undergraduate and graduate students will participate in the research project, and undergraduates in an animal science communications course will generate podcasts targeted to the general public.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.