Over the past decade, considerable advances have been made in the discovery of gene targets in
metabolic diseases. However, in vivo studies based on molecular biological technologies such as the generation of knockout mice and the construction of
short hairpin RNA vectors require considerable effort and time, which is a major limitation for in vivo functional analysis. Here, we introduce a liver-specific nonviral
small interfering RNA (
siRNA) delivery system into rapid and efficient characterization of hepatic gene targets in
metabolic disease mice. The comparative transcriptome analysis in liver between KKAy diabetic and normal control mice demonstrated that the expression of
monoacylglycerol O-
acyltransferase 1 (Mogat1), an
enzyme involved in
triglyceride synthesis and storage, was highly elevated during the
disease progression. The upregulation of Mogat1 expression in liver was also found in other genetic (db/db) and diet-induced obese mice. The silencing of hepatic Mogat1 via a liver-specific
siRNA delivery system resulted in a dramatic improvement in
blood glucose levels and hepatic steatosis as well as
overweight with no apparent overall toxicities, indicating that hepatic Mogat1 is a promising therapeutic target for
metabolic diseases. The integrated approach with transcriptomics and nonviral
siRNA delivery system provides a blueprint for rapid drug discovery and development.