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.