The increasing prevalence of obesity and metabolic disorders pose a major public health threat facing the United States. Emerging evidence identifies the Transforming Growth Factor (TGF) superfamily, which includes TGFs, activins/inhibins, and bone morphogenetic proteins (BMPs), as a participant in and a possible therapeutic target for obesity and metabolic disorders. For example, in humans, expression levels of TGF, inhibins, and the receptor BMPR1A are positively correlated with obesity. Furthermore, TGF superfamily members regulate adiposity, as well as insulin gene transcription and insulin secretion. Our studies have revealed that the C. elegans BMP homolog, DBL-1, similarly regulates insulin gene transcription and fat accumulation. The C. elegans system provides a complementary approach to mammalian studies on energy homeostasis and fat metabolism, since the fundamental biochemical and genetic mechanisms are the same. A wealth of tools exists for the manipulation and analysis of C. elegans, including mutants, transgenics, dsRNA interference (RNAi), and live imaging techniques. Significantly, these approaches allow for the analysis of cellular and biochemical functions in vivo, in their natural physiological context. Thus, we possess the tools and the preliminary data necessary to elucidate the cellular, genetic, and biochemical mechanisms by which a BMP pathway impinges on metabolic homeostasis. The goal of this proposal is to identify the mechanisms by which DBL-1 regulates fat metabolism at molecular, cellular, and organismal levels. We hypothesize that DBL-1 promotes an anabolic state, in part by downregulation of insulin/IGF-1-like signaling (IIS). We will address the following questions that test our hypothesis: (1) What are the regulatory nodes through which DBL-1/BMP modulates fat composition and accumulation? (2) What is the cellular site of action of the DBL-1 pathway in regulation of fat metabolism? (3) Is DBL-1 regulation of fat metabolism mediated by the IIS pathway? At the completion of the grant period, we expect to have elucidated the mechanisms by which DBL-1/BMP signaling modulates fat accumulation, the tissues in which it mediates this function, and the degree to which the DBL-1/BMP pathway depends on the IIS pathway. This work will identify the most biologically relevant links between these processes, providing the foundation for a better understanding of the risk factors and potential therapeutic targets for obesity in humans. Additionally, this project will provide training opportunities for a graduate student and undergraduate students, who will learn current techniques in molecular biology and microscopy, as well as oral and written communication skills through lab meetings and attendance at professional conferences.
The obesity epidemic in the United States is extremely costly, both financially and in regard to quality of living. A better understanding of the cellular mechanisms involved in fat metabolism and storage will support the search for therapeutic targets and risk factors related to obesity. In this project, we will exploit the advantages of a simple model organism to uncover the conserved genetic and cellular mechanisms underlying fat metabolism and storage.
|Clark, James F; Meade, Michael; Ranepura, Gehan et al. (2018) Caenorhabditis elegans DBL-1/BMP Regulates Lipid Accumulation via Interaction with Insulin Signaling. G3 (Bethesda) 8:343-351|
|Madaan, Uday; Yzeiraj, Edlira; Meade, Michael et al. (2018) BMP Signaling Determines Body Size via Transcriptional Regulation of Collagen Genes in Caenorhabditis elegans. Genetics 210:1355-1367|
|Savage-Dunn, Cathy; Padgett, Richard W (2017) The TGF-? Family in Caenorhabditis elegans. Cold Spring Harb Perspect Biol 9:|