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Abstract
Obesity and associated metabolic syndrome (MetS) pose two of the greatest risks for development of non-communicable diseases, such as cardiovascular disease, type 2 diabetes mellitus, metabolic dysfunction-associated fatty liver disease, and even cancer. Together, obesity and MetS induce a state of chronic inflammation that results in impaired metabolic function. In order to target the inflammation caused by obesity and MetS, we investigated the therapeutic effects of two anti-inflammatory human milk oligosaccharide conjugates comprised of either lacto-N-fucopentaose III (LNFPIII) or lacto-N-neotetraose (LNnT). Herein, we demonstrate that LNFPIII, but not LNnT, conjugates reduce total weight gain, lessen adipose tissue depot size, decrease fasting blood glucose levels, improve glucose and insulin homeostasis, and ease hepatic lipid accumulation and liver damage. We report that both LNFPIII and LNnT modulate an assortment of hematopoietic, chemoattractant, innate, and adaptive cytokines, as well as impact incretin effect hormones and adipokines. We also report that LNFPIII and LNnT conjugates alter the intestinal microbiome in unique manners, such that LNFPIII conjugates drive outgrowth of distinct species Bacteroidetes and Verrucomicrobia, while LNnT conjugates encourage growth of specific species of Actinobacteria. These studies indicate that LNFPIII conjugates, but not LNnT conjugates, are promising drugs for obesity and MetS. Furthermore, it is clear that both conjugates possess distinct mechanisms. Since there is little known about the mechanism of either LNFPIII or LNnT conjugates, we later developed monoclonal antibodies (mAbs) against the conjugates. We identified a single mAb that recognized both LNFPIII and LNnT conjugates and utilized this mAb in follow-up mechanistic studies to aid in determination of putative receptors for the compounds. Future studies will focus on continuing experiments using the generated mAb, in order to define the mechanisms of action for both conjugates.