Obesity is an epidemic health problem worldwide, and is a significant risk factor for many human diseases, including diabetes, dyslipidemias, non-alcoholic fatty liver, gallstones, cardiovascular disease, Alzheimer’s disease and even some cancers. Obesity develops when energy intake exceed energy expenditure. Despite this simple nature, the maintenance of energy balance is complex. The long-term research interest in Dr. Tseng’s lab is to understand the regulation of energy homeostasis and use it to develop potential therapeutic approaches for obesity and related diseases.
Role of developmental signals in the determination of brown versus white adipose cell fate
Excess adipose tissue is the defining characteristic of obesity. Two functionally different types of adipose tissues are present in mammals: white adipose tissue, which is the primary site of energy storage, and brown adipose tissue, which is specific to thermogenic energy expenditure. Given its specialized function to dissipate chemical energy, brown adipose tissue provides a natural defense against cold and obesity. Several developmental signaling molecules have been shown to impact development of different adipose depots. These include members of the transforming growth factor β (TGF)-β and bone morphogenetic protein (BMPs) family, the fibroblast growth factor (FGF) family, the wingless (Wnt) family, the hedgehog family and others. Combining cellular, molecular and physiological approaches, Dr. Tseng and her colleagues have discovered that BMP7 specifically promotes brown adipocyte differentiation and function. Treatment of mice with BMP7 results in an increase in brown fat mass and reduced weight gain. Current ongoing studies in Dr. Tseng’s lab are to further determine the role of BMPs in the control of brown versus white adipogenesis and whole body energy metabolism using a variety of in vitro and in vivo approaches. In addition to BMPs, Dr. Tseng and her colleagues continue to identify additional factors that differentially regulate the development and function of brown versus white adipose tissue using genomics, proteomics, and small molecule screenings.
Identification and characterization of progenitor/stem cells that give rise to different adipose depots
The adipose tissue arises from the multipotent stem cells of mesodermal origin. When triggered by appropriate developmental cues, these cells become committed to the adipocytes lineage. It has been suggested that different fat depots located in different anatomical locations of the body may derive from distinct developmental origins. Recently, we have identified and isolated a subpopulation of adipogenic progenitors (Sca-1+/CD45-/Mac1-; referred to as Sca-1+ progenitor cells, ScaPCs) residing in murine brown fat, white fat, and skeletal muscle. ScaPCs derived from different tissues possess unique molecular expression signatures and adipogenic capacities. Importantly, while the ScaPCs from interscapular BAT are constitutively committed brown fat progenitors, Sca-1+ cells from skeletal muscle and subcutaneous white fat are highly inducible to differentiate into brown-like adipocytes upon stimulation with BMP7. ScaPCs from obesity-resistant mice exhibit markedly higher thermogenic capacity compared to cells isolated from obesity-prone mice. Currently, ongoing studies in Dr. Tseng’s lab are to further define these progenitors by single cell analysis, microRNA profiling and in vivo fate mapping.
Integration of central and peripheral controls on whole body energy homeostasis
The maintenance of energy balance involves coordinated changes in energy intake and expenditure, and these two limbs of energy balance are physiologically linked. The central nervous system receives diverse inputs to coordinate appetite and energy expenditure, and is therefore the key control center for body weight. Despite recent advances in defining the neuronal circuits for appetite regulation, factors that regulate feeding via these pathways have not yet been fully elucidated. TGF-β/ BMP are known to regulate neuronal development. Recently, this signaling system has been demonstrated to be involved in the regulation of food intake and energy homeostasis in lower organisms, such as C. elegans and Drosophila. However, whether a similar pathway in the regulation of energy balance exists in mammals is currently unknown. Recently, Dr. Tseng and her colleagues have discovered that in addition to its role in brown adipocyte development, central BMP7 signaling appears to play a critical role in regulation of food intake. Studies in Dr. Tseng’s lab are currently dissecting the molecular and neuronal mechanisms that underlie the anorectic effect of BMP7. Ultimately, we hope this combined knowledge will allow us to integrate central and peripheral controls of energy homeostasis and aid in identifying specific targets for therapy of obesity and diabetes.