Prevention of the metabolic syndrome and ectopic fat

The project is focused on the obesity-related complications; Type 2 Diabetes (T2D) and Metabolic Syndrome (MS). Individual changes in the adipose tissue are linked to MS; in particular the ability to store fat in the subcutaneous adipose tissue and thus prevent fat accumulation in ectopic fat depots (liver etc.) and T2D/MS. We found that genetic predisposition to T2D (first-degree relatives, FDR) is linked to an impaired ability to store excess fat in the subcutaneous tissue, which is instead stored in ectopic depots. FDR has an impaired ability to recruit mesenchymal stem cells to adipogenesis in the subcutaneous tissue. The recruitment is dependent on BMP4 and FDR has increased levels of the BMP antagonist Gremlin1. BMP4 also regulates the ability to form oxidative beige/brown fat cells (anti-obesity) in the subcutaneous tissue, which is also inhibited by Gremlin1. Animal models, where we have increased BMP4 levels in the blood of mature mice (gene therapy model), have shown that they are protected from developing obesity and its complications due to increased beige/brown oxidative subcutaneous fat tissue. These findings will be developed into a possible new treatment for T2D/MS. We have also identified that a new family of lipids formed in the subcutaneous adipose tissue is released into the blood and is closely linked to insulin resistance. Administration of these lipids in animal models increases insulin action and improves glucose levels. We will further characterize their effects and plan to test them in humans.