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These cofactors are critical regulators of cellular energy metabolism, polyamine flux, epigenetic remodeling, and SIRT1 activity in the NAD + salvage pathway.[12, 27, 40] The increased levels of SAM and NAD + we observed in cultured adipocytes following NNMT inhibition are consistent with the upregulation of SAM and NAD + observed in the WAT of DIO mice treated with NNMT ASO, which correlated with increased cellular energy expenditure, reduced adiposity, and protection against diet-induced obesity.[12] In the present study, systemic treatment of DIO mice with a small molecule NNMT inhibitor caused significant loss of body weight and WAT mass, reduction in adipocyte size, and corresponding improvements in the plasma lipid profile (i.e., decreased circulating cholesterol levels)

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These studies will be critical for understanding the research utility of this pathway and identifying optimal applications for future investigational development