Characterisation of epicardial adipose tissue and myocardial fat infiltration in humans

Obesity and type 2 diabetes are characterized by mild systemic inflammation, enlargement of fat depots, and uncontrolled release of free fatty acids into the circulation; they are both strongly associated with metabolic and cardiovascular disorders, such as dyslipidemia, coronary heart disease, high blood pressure and myocardial infarct. White adipose tissue has been widely accepted to be much more than a static fuel storage organ. Its capability of regulating homeostatic and metabolic mechanisms has been underlined during the last 20 years; several studies have proposed adipose tissue as an endocrine organ, secreting hormones, adipokines and other biologically active agents acting locally or in a systemic manner. Adipose tissue depots are not uniform; their characteristics change in different areas of the body, displaying distinct structural and functional properties and having different putative roles in pathologies. Epicardial adipose tissue (EAT) is a peculiar adipose tissue depot, which has recently been the center of many studies. It’s located predominantly on the right free wall of the heart, surrounding coronary arteries and being directly in contact with the myocardial layer. EAT has been shown to secrete many different adipokines and is supposed to have a role in the generation and progression of coronary artery diseases. The aim of this thesis was to better characterize EAT and the underlying myocardial layer. In paper 1 we investigated adipocyte cell size and adiponectin secretion comparing EAT, visceral AT (VAT) and subcutaneous AT (SAT). EAT resulted to have smaller adipocytes and lower adiponectin secretion levels. Adipocyte size, both in EAT and in SAT, is positively related with insulin resistance, shows negative association with local adiponectin gene expression, and bigger in subjects with coronary artery disease. Adiponectin gene expression is significantly lower in EAT than in SAT. In paper 2 we focused our attention on the effect of diabetic state on EAT, showing higher MCP-1, CD-68, lower adiponectin level, and bigger adipocytes in subjects with than those without diabetes. We also analyzed thorough immunohistochemistry and present as unpublished data, the characteristics of fat and macrophagic infiltration of the myocardium of the same cohort of patients. Additionally, the result of a one year internship conducted at Lipid Laboratory in KI Sweden, has been included in the thesis, as paper 3. Leaving the subject of EAT, the paper is focused on adipose tissue and it’s molecular and genetic aspects in obesity. Since the gene Niemann-Pick C1 (NPC-1) has recently being implicated in susceptibility to obesity, through a genome wide association study, we dig into the relationship between NPC-1 and obesity in humans. The analysis of NPC-1 mRNA ad protein in obesity, showed that NPC1 mRNA was significantly increased in obese individuals in SAT and VAT and down-regulated by weight loss. NPC-1 mRNA was enriched in isolated fat cells of WAT, in SAT versus VAT, but not modified during adipocyte differentiation. NPC-1 protein mirrored expression of mRNA in lean and obese individuals