Regulation of adipokine production by DNA methylation in mouse models for obesity, insulin resistance and current therapies

Obesity and type 2 diabetes (T2D) are associated with distinct changes in DNA methylation in liver, muscle, subcutaneous adipose tissue and blood (Kirchner et al., 2016, Molecular Metabolism; Kirchner et al., 2015, SOARD; Barres et al., 2013, Cell Reports; Multhaupt et al., 2015, Cell Metabolism). A genome-wide measurement of DNA methylation in purified subcutaneous adipocytes revealed that DNA methylation in the leptin promoter and in intron 1 of the leptin gene lep is up to 10% decreased in diet-induced obese versus lean mice (Multhaupt et al., 2015). This decrease in DNA methylation is accompanied by an increase in lep expression and leptin plasma concentrations.

The underlying hypothesis of this proposal is that DNA methylation leads to an altered expression of adipokines which in turn contributes to the development of obesity and insulin resistance. This hypothesis will be tested using longitudinal mouse studies that are designed to reveal the time-point at which alterations in DNA methylation occur. My previous studies validate that the alterations will occur after maximal 3 month of high-fat diet feeding when adiposity and insulin resistance is fully established. 

In a second aim we want to reverse these changes using models of human obesity and T2D-therapies. 


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