The role of APMAP in adipogenesis and energy metabolism

Obesity and type 2 diabetes mellitus (T2DM) are strongly connected diseases and constitute an increasingly prevalent health (and economic) problem. To date, worldwide ~1 billion people are affected by overweight and ~250 million people by T2DM. It is widely understood that obesity can lead to insulin resistance on the way to T2DM. Excess food intake, a sedentary life style and genetic factors are responsible for this development. Thus, the identification of genes that predispose individuals to obesity, insulin resistance and T2DM could provide "tools" for developing strategies and/or therapeutics to combat obesity and its consequences. Recently, we identified APMAP (adipocyte plasma membrane-associated protein) as an important player in adipogenesis. We showed APMAP to be up-regulated in murine and human adipogenic cell models and in a genetic mouse model of obesity. Silencing APMAP in 3T3-L1 cells strongly impaired the differentiation into adipocytes. Moreover, we could show that APMAP is a functional target of PPARgamma, the master regulator of adipogenesis. In addition, we provided evidence that the extracellular C-terminus of APMAP harboring a predicted carbohydrate transport domain is required for the function of APMAP in adipocyte differentiation. Importantly, our preliminary data in mature 3T3-L1 adipocytes showed that transient silencing of APMAP reduced insulin stimulated glucose uptake, while APMAP overexpression induced basal and insulin stimulated glucose uptake. Thus, to unravel the physiological function of APMAP we first aim to generate whole body APMAP-knock-out (ko) mice. These mice will be an appropriate model to study whether APMAP deficiency also leads to reduced adipogenesis and triglyceride accumulation in vivo. Expecting these mice to have a lean phenotype, we will investigate whether APMAP-ko mice are resistant to diet-induced obesity. Second, we aim to generate adipose tissue-specific APMAP-ko mice by crossing APMAP-floxed mice to aP2-Cre mice. As aP2 is only activated after fat cell differentiation, we assume the resulting mice to develop normal fat depots and therefore to serve as a proper model for studying the role of APMAP on glucose metabolism in otherwise normal adipose tissue. Additionally, we will study the function of APMAP in glucose uptake in vitro. We anticipate that the characterization of our mouse models will provide new insights into the process of adipogenesis and the development of metabolic disorders which are linked to an imbalance of the amount of adipose tissue and/or to disturbed glucose metabolism. We expect that the results of our studies will provide clues for developing novel tools to fight the increasing health and economic burden of metabolic disorders.

This project dealt with the elucidation of the physiological role of a protein that is highly expressed in adipose tissues. We previously showed that it regulates fat cell (adipocyte) development in cell culture. Because its role in body physiology remained unclear, the aim of this project was to unravel its influence on metabolism and obesity-development in whole body knockout mice. Obesity and its associated diseases like type II diabetes turned into a worldwide epidemic that comprises not only a health, but also an economic burden. In 2014, over 40% of worlds population was classified as overweight or obese. Interestingly, the majority lives in countries where it is more likely to die from obesity than malnutrition. This is understandably accompanied by enormous health costs. Obesity is a multifactorial disease that is not only caused by over-nutrition and the well-known couch-potato-lifestyle, but is also largely attributable to genetic factors. Therefore, a detailed understanding of biochemical pathways that influence fat cell development and metabolism is crucial to develop new strategies in fighting obesity. In our lab, we use high-throughput methods like DNA-Chips to identify new candidate genes that influence fat cell development and metabolism. Afterwards, we pick promising candidates and characterize their function. Our previous data showed that this candidate gene is necessary for the development of fat cells in vitro, but its physiological function remained unknown. Thus, we aimed to characterize this protein with the help of a knock-out mouse model that lacks its expression. Our data shows, that our candidate protein interacts with extracellular matrix proteins that are important for remodeling the extracellular matrix surrounding adipocytes. During the progression of obesity, extracellular matrix properties change and can cause fibrosis that is in turn a hallmark of tissue dysfunction. Adipose tissue dysfunction is a major contributor to insulin resistance. Through interaction of our candidate protein with the extracellular matrix enzymes, fibrosis might be attenuated which ameliorates glucose handling in obese mice. Thus, the data of this project contributes to a deeper understanding of adipocytes metabolism. Moreover, it describes a new candidate that links obesity and type II diabetes.