Epigenetic Modification of the Leptin Promoter in Diet-Induced Obese Mice and the Effects of N-3 Polyunsaturated Fatty Acids

Abstract

We report evidence of a detailed epigenetic modification of the leptin promoter and the effects of n-3 polyunsaturated fatty acids (n-3 PUFAs), which is closely associated with the leptin gene transcription in obesity. In the adipose tissue of diet induced obese (DIO) mice, methylation of the CpG island and the binding of methyl-CpG-binding domain protein 2 (MBD2) and DNA methyltransferases (DNMTs) at the leptin promoter are increased and RNA Pol II is decreased. Additionally, histones H3 and H4 are hypoacetylated, lysine 4 of histone H3 (H3K4) is hypomethylated and the binding of histone deacetylases (HDACs) 1, 2 and 6 is increased at the leptin promoter in the DIO mice. These modifications may serve a feedback role to maintain leptin concentrations within a normal range. The regulation of leptin transcriptional expression by n-3 PUFAs is mediated, at least in part, by epigenetic targets, such as MBD2 and histone modifications.

AQP7 Up-Regulation in the Skeletal Muscles of Mice with Diet Induced Obesity

“…In animal experiments, even in isocaloric diets, leptin levels were higher in rat group fed with either the high fat diet or the high protein diet compared with those fed with the high carbohydrate diet [22]. In addition leptin and insulin concentrarions of mice with DIO were also described to be high in comparison with those of control mice [23,24]. Even under the circumstances of the elevated concentrations of leptin and insulin, both of which suppress the expression of AQP7 [15,25,26] phosphatidylinositol 3 kinase pathway, the AQP7 expression of skeletal muscles of mice with DIO was up-regulated in our present study.…”

Leptin resistance in obesity: An epigenetic landscape

“…A recent study showed that DNA methylation of the leptin promoter varied with obesity. In the adipose tissue of diet induced obese (DIO) mice, the methylated fraction of the leptin promoter was decreased by feeding a high-fat diet at the initial stage; however, it increased after 12 weeks of feeding a high-fat diet compared to control and low-fat diet mice [77]. In peripheral blood samples from human obese adolescents, methylation of the LEP promoter was shown to be negatively associated with BMI [78].…”

Epigenetics and obesity cardiomyopathy: From pathophysiology to prevention and management

“…It is believed that histone modifications serve a feedback mechanism to keep leptin levels somewhat constant within a normal range. In addition, n-3 polyunsaturated fatty acids (n-3 PUFAs) may counter adiposity via epigenetic regulation of leptin including histone modifications (Shen et al, 2014). Moreover, mitogen-activated protein kinase phosphatase 3 (MKP-3) may exert a pivotal role in obesity-induced hyperglycemia through facilitating hepatic glucose output.…”