The incidence of obesity and T2D is rising rapidly worldwide, however there is an unmet need for new therapeutics that must be addressed. Notable microRNAs have been revealed as key regulators of metabolic homeostasis, serving as potential single targets to counter multiple aspects of metabolic diseases. MicroRNAs are short, regulatory non-coding RNAs that modulate gene expression through inhibition of protein translation and induction of mRNA degradation. Our mechanistic studies reveal that miR-128-3p acts to dysregulate energy expenditure programs, promoting fat storage and insulin resistance. We find that global knockout (KO) or antisense oligonucleotide (ASO) inhibition of miR-128-3p strongly protects mice from obesity and type 2 diabetes (T2D). However, which tissues are most relevant and the exact mechanisms underlying the protective effects of miR-128-3p inhibition are unknown. Therefore, the objective of my research is to elucidate the molecular mechanisms by which a new generation locked nucleic acid (LNA) ASO designed to target miR-128-3p with high potency treats obesity and T2D.