Atherobesity - DFG KFO 152 "Fett und Gefäß"

Summary

The objective of the DFG Clinical Research Unit Atherobesity: Adipose Tissue and Vasculature is to clarify the causes of an increased risk of cardiovascular diseases in obese patients – through to molecular mechanisms. With this the basis for successful strategies for prevention and intervention of the obesity-associated early atherosclerosis shall be created. The Research Unit starts from the hypothesis, that the fatty tissue of obese patients sends signals, which contribute to an interference of the endothelial function and atherosclerosis. For this purpose the expertise of three complementary medical disciplines (paediatric endocrinology, endocrinology/ diabetology, cardiology/ angiology) will be combined with a scientific work group (biochemistry).

In the 1st funding period we tested the hypothesis that as early as in the childhood, there is a connection between obesity, atherogenic serumprofile and endothelial dysfunction, which could be positively influenced by a targeted intervention (P1). Within a clinical trial was analyzed, whether a chronic inflammatory activation in adipose tissue is reversible through physical activity and medicinal interventions and whether adipocytes or immune cells in fatty tissue play a decisive role in this process (P2). Additionally biological differences between visceral and subcutaneous adipose tissue were analyzed in clinical trials and animal experiments and in connection with the individual human endothelial function (P3). Using in-vitro analysis it should be proofed, whether adipocytes influence the endothelial function directly through free fatty acids and adipokine (P4). New atherogenic molecules should also be identified (P4). Direct interactions of the signalling pathways of adipokine especially adiponectin and insuline were analyzed in cell models in a molecular oriented project. The focus was on mechanisms with relevance for the endothelium (P5).

In the current 2nd funding period, the KFO 152 could be extended with additional subprojects. The research work of the 1st phase will be continued in follow-up projects. One aim is, to characterize the direct relationship between the development of obesity and early stages of atherosclerosis in childhood and to analyze the interaction between atherogenic factors derived from adipose tissue and the regenerative capacity of endothelium (P1). In subproject 3 (P3), we identified molecules, which contribute to predominant abdominal visceral fat accumulation and may underly the link between visceral obesity and metabolic and cardiovascular comorbidities of obesity. In TP3, we test the hypothesis, that bone morphogenetic proteins (BMP) -2, -4, -7, their receptors BMPR1, BMPR2 as well as progranulin play a functional role in the development of visceral obesity, and immune cell infiltration into adipose tissue (TP3). From TP3, we developed a novel project (TP6), in which we test the hypothesis that disruption of replication initiating factor 1 (Repin1) protects against high fat diet induced obesity and steatosis hepatis using a whole body and tissue-specific Repin1 knockout mouse models (TP6). In subproject 5 (TP5), we aim to characterize the function, molecular binding partners, and related mechanisms of the adipokines adiponectin, vaspin and chemerin (TP5). From this project, we developed a new ”offspring” project (TP7), which tests the hypothesis that nicotinamid-phosphoribosyltransferase (Nampt) plays an important role in linking NAD-biosynthesis to metabolism and longevity (TP7). In a novel project, we aim to unravel adipose tissue dysfunction and altered adipokine secretion related mechanisms with male infertility (TP8). We further integrate a project investigating common genetic regulators of increased obesity and atherosclerosis risk using well established mouse models, LDL-receptor deficient mice, BALB/c and C57BL/6 mice (TP9).

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