During the periparturient period of dairy cows, adipose tissues (AT) lipolysis fulfills, in part, energy deficits driven by parturition and lactogenesis. Lipolysis induces a remodeling process within AT that is characterized by inflammation with infiltration of macrophages (ATM). In healthy cows, lipolysis rate decreases and AT inflammation resolves as lactation progresses. However, when lipolysis is dysregulated, AT inflammation is maintained leading to metabolic and infectious diseases.
An additional factor that is strongly connected with the presentation of periparturient diseases is the sharp increase in circulating bacterial endotoxins. We propose that endotoxemia triggers lipolysis dysregulation through toll-like receptors signaling leading to proinflammatory polarization of ATM and adipocyte insulin resistance.
Our hypothesis is that endotoxemia induces adipose tissue macrophage proinflammatory polarization and impairs adipocyte insulin sensitivity, leading to lipolysis dysregulation. We will investigate this hypothesis by pursuing two specific aims, and utilizing models of AT lipolysis complemented with functional assays and single-cell RNAseq analyses. Aim 1 will determine how endotoxins enhance adipocytes’ lipolytic responses through changes in adipocytes’ insulin sensitivity and ATM phenotype. Aim 2 will determine how endotoxemia potentiates AT lipolytic response during negative energy balance and polarizes ATM to pro-inflammatory phenotypes.
This proposal will elucidate the mechanisms by which endotoxemia induces lipolysis dysregulation and increases periparturient dairy cows’ susceptibility to diseases. Our long-term goal is to develop nutritional and pharmacological tools to prevent lipolysis dysregulation during catabolic periods. We expect these tools will benefit herd health, improve dairy cows’ welfare, and increase the economic sustainability of dairy farming.
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