The global rise in metabolic diseases can be attributed to a complex interplay between biology, behavior and environmental factors. This article reviews the current literature concerning DNA methylation-based epigenetic inheritance (intergenerational and transgenerational) of metabolic diseases through the male germ line. Included are a presentation of the basic principles for DNA methylation in developmental programming, and a description of windows of susceptibility for the inheritance of environmentally induced aberrations in DNA methylation and their associated metabolic disease phenotypes. To this end, escapees, genomic regions with the intrinsic potential to transmit acquired paternal epigenetic information across generations by escaping the extensive programmed DNA demethylation that occurs during gametogenesis and in the zygote, are described. The ongoing descriptive and functional examinations of DNA methylation in the relevant biological samples, in conjugation with analyses of non-coding RNA and histone modifications, hold promise for improved delineation of the effect size and mechanistic background for epigenetic inheritance of metabolic diseases.
Louise Ruby Høj Illum, Stine Thorhauge Bak, Sten Lund and Anders Lade Nielsen
Thomas Svava Nielsen, Niels Jessen, Jens Otto L Jørgensen, Niels Møller and Sten Lund
Lipolysis is the process by which triglycerides (TGs) are hydrolyzed to free fatty acids (FFAs) and glycerol. In adipocytes, this is achieved by sequential action of adipose TG lipase (ATGL), hormone-sensitive lipase (HSL), and monoglyceride lipase. The activity in the lipolytic pathway is tightly regulated by hormonal and nutritional factors. Under conditions of negative energy balance such as fasting and exercise, stimulation of lipolysis results in a profound increase in FFA release from adipose tissue (AT). This response is crucial in order to provide the organism with a sufficient supply of substrate for oxidative metabolism. However, failure to efficiently suppress lipolysis when FFA demands are low can have serious metabolic consequences and is believed to be a key mechanism in the development of type 2 diabetes in obesity. As the discovery of ATGL in 2004, substantial progress has been made in the delineation of the remarkable complexity of the regulatory network controlling adipocyte lipolysis. Notably, regulatory mechanisms have been identified on multiple levels of the lipolytic pathway, including gene transcription and translation, post-translational modifications, intracellular localization, protein–protein interactions, and protein stability/degradation. Here, we provide an overview of the recent advances in the field of AT lipolysis with particular focus on the molecular regulation of the two main lipases, ATGL and HSL, and the intracellular and extracellular signals affecting their activity.