Adipose Tissue Biology and the Development of Type 2 Diabetes Mellitus

As of 2014, the World Health Organization estimated 1.9 billion overweight people, of which 600 million were obese. Yearly, 3.4 million people die from overweight and obesity, when excluding the effects of associated diseases. Overweight is one of the strongest risk factors for development of Type 2 Diabetes Mellitus (T2DM), of which the treatment accounts for 12 percent of world wide total health expenditure (2015). The individual tragedies that obesity causes are even worse than the estimated world wide health costs of 673 billion dollars. Since numbers of obesity incidences still rise despite of dietary guidelines being formulated and implemented, further basic research on adipose tissue and diabetes is urgently required. Scientists continue to search for a causal link between obesity and the development of T2DM. Besides literature reviewing the role of a certain type of adipose tissue in mediating the anti-obesity effect of fibroblast growth factor 21 (FGF21), this thesis is about the adipose tissue organ's plasticity and its role in the development of T2DM. First, I addressed very basic scientific questions about the adipose organ through the quantification of adipocyte cell numbers and their character by applying a newly developed quantitative polymerase chain reaction based method. Using this tool, we could establish and improve the tamoxifen protocol of Adipoq-tracer and Ucp1-tracer-depleter mouse models. Secondly, we aimed to prove that induction of adipose tissue specific insulin resistance causes development of T2DM. For this purpose we generated a CreERT2-loxP genetic mouse model of tamoxifen inducible fat-specific Insulin receptor knockout (iFIRKO). Inducing insulin resistance in lean and obese adult mice, we found a temporary development of T2DM that was reversed already 3 weeks after the knockout, but adipose tissue mass remained reduced. iFIRKO mice are long term protected from the obesogenic effect of high fat diet. Furthermore, we prevented development of hyperphagia and polydipsia in iFIRKO mice with two antioxidants Apocynin and N-acetylcystein (Nac) and strongly reduced hyperglycemia by Apocynin alone. Finally, we could confirm food intake reduction and blood glucose lowering capacity of Apocynin and Nac in the hyperphagic obesity model of Leptin knockout mice. We conclude that insulin resistance in adipose tissue can protect from obesity, but also causes T2DM. This development of T2DM can be targeted downstream of the Leptin Receptor through the use of Apocynin and Nac