Role of miR-128-1 in metabolic abnormalities underpinning type 2 diabetes

Abnormal regulation of cholesterol/lipid and energy homeostasis is associated with metabolic syndrome, type II diabetes, and cardiovascular disease. An improved understanding of the regulatory mechanisms governing cholesterol/lipid and energy homeostasis could yield novel therapeutic avenues to combat cardiometabolic disorders. We recently uncovered microRNAs (miR-33b/a) as key regulators of cholesterol/lipid and energy metabolism. We followed up this initial discovery with an unbiased and systematic meta-analysis of genome-wide association studies linking genomic loci to abnormal blood lipids to identify 69 microRNAs in proximity to signature single nucleotide polymorphisms. Two of these microRNAs (miR-128-1 and miR-148a) were validated as key regulators of cholesterol/lipid and energy homeostasis.both in vitro and in vivo. Intriguingly, miR-128-1 is located in a genomic region on human chromosome 2 that has been strongly linked to positive selection (last 5K years), type 2 diabetes, obesity and circulating cholesterol/lipid abnormalities. Based on strong preliminary data in diet-induced obese (DIO) mice showing that antisense treatment targeting miR-128-1 ameliorates excess adipocity, hepatic steatosis, hyperglycemia and insulin resistance, we posit that miR-128-1 dysregulation may contribute to all of these associations. Accordingly, miR-128-1 appears to directly control the expression of key metabolic proteins such as PGC1α, PPARγ, SIRT1, InsR, and IRS1 in white adipose tissue, liver, and skeletal muscle. We propose here to further investigate the functional role of miR-128-1 in insulin resistance/glucose abnormalities linked to cardiometabolic diseases using miR-128-1 KO mice fed a high-fat diet (DIO model) and miR-128-1 antisense targeting in leptin-deficient (ob/ob) mice. These studies will involve IP-GTT and ITT, echoMRI and melabolic cage studies, as well as in-depth tissue analysis by qRT-PCR, immunoblotting, IHC, and H&E staining to ascertain impact on miR-128-1 regulatory circuits and downstream effects on metabolic homeostasis. Data from these studies should provide further insights into metabolic control by miR-128-1 and whether it may represent anovel therapeutic target for the treatment or prevention of type 2 diabetes, and serve as support for an NIH R01 application to expand these studies.