NNMT knockdown protects against diet-induced obesity

Nicotinamide N-methyltransferase (Nnmt) methylates nicotinamide using SAM as a methyl donor and generates S-adenosylhomocysteine (SAH). SAM has two major functions: on hand, providing propylamine groups for polyamine biosynthesis; on another hand, donating methyl groups to substrates including histones. NNMT is the most strongly reciprocally regulated gene when comparing gene expression in white adipose tissue (WAT) from adipose specificLenalidomide Glut4-knockout or adipose-specific Glut4-over expressing mice with their respective controls.

Recently, there is a report that NNMT expression is increased in WAT and liver of obese and diabetic mice. Nnmt knockdown in WAT and liver protects against diet-induced obesity by enhancing cellular energy expenditure. NNMT inhibition increases adipose SAM and NAD1 levels and up regulates ODC and SSAT activity as well as Agi-5198expression, owing to the effects of NNMT on histone H3K4 methylation. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine. NNMT inhibition increases oxygen consumption in an ODC-, SSAT- and PAO-dependent manner.

To summary, NNMT is a novel regulator of histone methylation, polyamine flux and NAD1-dependent SIRT1 signaling, and is a unique and attractive target for treating obesity and type 2 diabetes.

Hemodynamic disturbed flow is characterized by flow separation, transient flow reversals, and average low shear forces that define the atherosusceptible regional environment. Flow-induced histone modification and miRNAs have been shown to shape endothelial phenotype identities but differential DNA methylation responses to different flow profiles encountered in vivo and their recapitulation in vitro have not been addressed. DNA methylation is one of the critical epigenetic mechanisms controlling gene expression. In vertebrates, DNA methylation occurs at carbon 5 of cytosine in CpG dinucleotides (5mC).

Differential CpG site methylation was measured by methylation specific PCR, bisulfite pyrosequencing and restriction enzyme-PCR. Epigenetic plasticity including DNA methylation/demethylation dynamics may be important for cellular adaptation responses including endothelial phenotype identity in different arterial hemodynamic environments. DF-induced hypermethylation significantly suppresses KLF4 transcription and regulates its downstream targets NOS3, thrombomodulin (THBD) and MCP-1.

These data are the first demonstrated changes in DNA methylation induced by physiological characteristics of flow and are supported by steady state measurements in endothelial cells isolated from in vivo regions of hemodynamic DF and UF in swine aorta. The consequences of enhanced DNA methylation by hemodynamic DF include inhibition of KLF4 expression that removes a degree of protection against the pro-inflammatory pathways that lead to atherogenesis.

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