The role of tumor necrosis associated factor (TRAF) 1 in cardio metabolic disease Abstract: Cardiovascular disease (CVD) such as atherosclerosis myocardial infarction (MI) and stroke represents the most common cause of death globally and is driven by a cluster of risk factors – obesity hypertension hyperlipidemia and insulin resistance – that is referred to as the Metabolic Syndrome (MS). Chronic low grade inflammation fuels not only atherosclerosis but also critically contributes to adipose tissue dysfunction in MS. Inflammatory pathways also determine acute complications of atherosclerosis such as arterial thrombosis causing MI and stroke. Despite their potent role in mediating CVD common underlying pathways that simultaneously drive the development of risk factors atherosclerosis and its complications have only been poorly defined. Here hypothesized that TRAF 1 a signal adapter that bundles pro inflammatory signaling from TNFRs IL1R and TLRs in an inhibitory fashion is such a modulator. By employing three different but complementary approaches I found that:<br>(1) TRAF 1 is a potent modulator of adipose tissue remodeling. A genetic deficiency of TRAF 1 improved facets of the MS in mice such as obesity insulin resistance and dyslipidemia. Mechanistically I identified increased lipolysis in adipocytes and enhanced energy expenditure by an adrenergic UCP 1 dependent mechanism. Surprisingly TRAF 1 mice exhibited a hyper inflammatory phenotype in adipose tissue confirming TRAF 1’s function as inhibitory signaling molecule in inflammation. These results further nourish the notion that inflammatory cell infiltration does not ultimately cause dysmetabolism under every circumstances.<br>(2) TRAF 1 was previously reported to attenuate inflammation in atherosclerosis by inhibiting leukocyte recruitment. In contrast to these findings I observed that – in the absence of atherosclerosis – TRAF 1 promoted leukocyte recruitment by a direct up regulation of adhesion molecules on myeloid cells but also by augmenting the pool of circulating monocytes. These effects were caused by an inhibition of TRAF 1 regulated apoptosis and an activation of proliferation of hematopoeitic stem cells and monocyte progenitors in the bone marrow. Under steady state conditions however TRAF 1 was a negative regulator of proliferation and leukocyte mobilization from the bone marrow proposing a dual role of TRAF 1 in health and disease.<br>(3) TRAF 1 is constitutively expressed by platelets and human coronary thrombi and co ...