Obesity is one of the greatest public health challenges of the 21st century. In 2016, 39% of the world’s adults were overweight, of which over 650 million adults were obese.
Current treatments mainly aim at limiting energy intake, but have very little efficacy, implying the involvement of additional factors. Beside the genetic contribution to the disease, in the last years much attention has been given to epigenetic deregulation as major contributor to metabolic disorders. Epigenetic refers to heritable changes in gene expression (active versus inactive genes), which occur without alteration in DNA sequence. There is a strong interplay between environmental/genetic factors and epigenetic changes in the establishment of obesity. Genes and environment can interact through their influence on the epigenome, and epigenetic marks can directly lead to increased adiposity. Although epigenetic changes may cause obesity, it is often not really clear if they precede obesity, or vice versa. Adipose tissues (AT), classified as white (WAT) and brown (BAT) are key organs for metabolic disorders. WAT is the major energy store site of the body. Conversely, BAT is rich in mitochondria and has energy expenditure properties. Owing to its ability to dissipate energy as heat, BAT has attracted scientific interest as an antiobesity tissue.
Preliminary data generated in the lab pointed toward a role for the epigenetic regulator Suv4-20h in improving BAT activity through epigenetic modification. Hence, my project aims at defining how Suv4-20h proteins influence metabolism regulation in response to environmental stimuli. Moreover, I want to identify and characterize the molecular mechanism(s) through which Suv4-20h proteins regulate adipogenesis. My hypothesis is that interfering with Suv4-20h activity in BAT results in increased metabolic activity and weight loss. Through in vivo, ex-vivo, in vitro and genome-wide studies we characterized the role of Suv420h proteins in the regulation of metabolism and body weight. We found that Suv420h proteins respond to environmental stimuli by directly inhibiting the expression of PPAR-γ, a master transcriptional regulator of glycemic metabolism, adipogenesis, energy balance and lipid biosynthesis. Mice lacking Suv420h proteins specifically in BAT display a strong PPAR-γ activation signature, increased BAT mitochondria respiration, improved glucose tolerance, reduction in AT and resistance to obesity. In addition, we found significant Suv4-20h1 and Suv4-20h2 upregulation and PPAR-γ downregulation in human obesity.
To the best of our knowledge, Suv420h1/2 are the first HMTases inhibiting BAT metabolism. Moreover, we describe the first epidrug able to activate BAT metabolic activity. Our results promote Suv4-20h proteins as key epigenetic regulator of PPAR-γ and the pathways controlling metabolism and weight balance in response to environmental stimuli.
