Different Perspectives of Metabolism: Gut Feelings and Love Handles

Abstract

Obesity and type 2 diabetes (T2D) are on the rise globally. As obesity is one of the major risk factors for T2D, the two diseases are irrevocably connected with each other. Two organs that play a central role in the disease etiology of obesity and T2D are the adipose tissue and the gut. Both are essential in orchestrating metabolic processes throughout our body. The adipose tissue is the safe storage place in our body for excess energy, but once we exceed its capacity a deteriorating process of metabolic complications starts. Through ectopic lipid accumulation as well as fibrotic, inflammatory adipose tissue expansion, the development of T2D is promoted. A promising target to combat metabolic diseases is a special sub-set of adipocytes, the brown adipocytes. They have the capability of uncoupling the mitochondrial membrane via Uncoupling protein 1 (Ucp1). Through this they burn glucose and lipids for heat production. The gut is the entry point of all the nutrients into the body. However, the gut does not solely digest and absorb nutrients; via enteroendocrine hormones and the gut-brain axis the gut is also in close contact with further distant metabolic organs. Through these connections, the gut plays a central role in the regulation of blood glucose levels, food intake, and satiety. The first project of this thesis focused on the quantification of adipocytes. Transgenic mouse lines allowed us to trace and quantify Adiponectin+ and Ucp1+ cells in a manner unbiased by size or spatial location. Along with obesity, changes in the ambient temperature can remodel the adipose tissue tremendously. We used our mouse models to observe the kinetics of remodeling in response to thermoneutral and cold housing temperatures. In a thermoneutral environment, the number of Ucp1+ cells in the brown adipose tissue (BAT) decreased and the tissue developed a white adipose tissue-like morphology. However, physiologically it remained fully responsive and beta3-adrenergic stimulation could completely recover all Ucp1+ cells back to levels observed at room temperature. In response to cold housing, the number of Ucp1+ cells in the interscapular BAT (iBAT) peaked after one week. This peak was primarily derived from pre-existing adipocytes. In the inguinal white adipose tissue (ingWAT), the presence of Ucp1+ cells, named brite/beige adipocytes, plateaued only after three weeks of cold housing. Lastly, we determined the regenerative potential of the iBAT. By utilizing an Ucp1-DTR construct we could ablate all Ucp1+ cells with diphtheria toxin and study the kinetics of regeneration. One week of cold exposure could fully recover all Ucp1+ cells in the iBAT, and we were able to show that the recovery was driven mainly by precursor cells. The quantification of the adipose tissue remodeling gave us a measureable insight into its remodeling potential and the underlying processes. This knowledge II will hopefully help us to be able to use the remodeling of the adipose tissue to our advantage for the treatment of metabolic diseases. The second project of the presented thesis centered around the gut secreted protein FAM3D and its metabolic function in the context of T2D. It is now widely recognized that gut-secreted proteins are powerful in regulating the metabolism in our body. Today, two classes of approved T2D drugs, namely GLP-1 receptor agonist and DPP4 inhibitors, are based on the function of gut-secreted proteins. FAM3D is another promising drug candidate. Upon adeno-associated virus (AAV) mediated overexpression of FAM3D in diet-induced obese mice an improvement in glucometabolic parameters, namely fasting blood glucose levels or glucose and insulin tolerance, could be observed. We identified FAM3D as insulin sensitizer, which increased glucose uptake into various tissues. Further, reduced hepatic lipid deposition and an amelioration of hepatic steatosis markers were detected, suggesting additional potential of FAM3D for the treatment of non-alcoholic fatty liver disease (NAFLD). We have first indications, that the positive metabolic phenotype of FAM3D is mediated by receptor tyrosine kinase signaling. However, the exact underlying molecular mechanism remains elusive. In summary, this thesis provided insight into the vast remodeling potential of the adipose tissue and characterized the potential of a novel gut secreted protein for the treatment of T2D and NAFLD. This combination allowed us to examine metabolic processes from different perspectives and thus find new solution approaches to resolve obesity and T2D.