Brown fat development and function
The long-term research interest of the Tseng laboratory is to understand the regulation of energy homeostasis and use it to develop potential therapeutic approaches for obesity, type 2 diabetes and related diseases. Their current research projects are focused in three general areas:
- The role of developmental signals in the determination of brown versus white adipose cell fate. Excess adipose tissue characterizes 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.
- The identification and characterization of progenitor/stem cells that give rise to different adipose depots. 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.
- The 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.
1. Tseng YH, Kokkotou E, Schulz TJ, Huang TL, Winnay JN, Taniguchi CM, Tran TT, Suzuki R, Espinoza DO, Yamamoto Y, Ahrens MJ, Dudley AT, Norris AW, Kulkarni RN, Kahn CR. New role of bone morphogenetic protein-7 in brown adipogenesis and energy expenditure. Nature 2008; 454: 1000-4. #Corresponding author. PMCID:PMC2745972
2. Zhang H, Schulz TJ, Espinoza DO, Huang TL, Emanuelli B., Kristiansen K, Tseng YH. Crosstalk between insulin and BMP signaling systems in brown adipogenesis. Molecular and Cellular Biology 2010; 30: 4224-33. PMCID: PMC2937545
3. Schulz TJ, Huang TL, Tran TT, Zhang H, Townsend KL, Shadrach J, Cerletti M, McDougall LE, Giorgadze N, Tchkonia T, Schrier D, Falb D, Kirkland JL, Wagers AJ,
4. Tseng YH. Identification of inducible brown adipocyte progenitors residing in skeletal muscle and white fat. Proceedings of National Academy of Science, USA 2011; 108(1):143-8. PMCID: PMC3017184
5. Cypess AM, Zhang H, Schulz TJ, Huang TL, Espinoza DO, Kristiansen K, Unterman TG, Tseng YH. Insulin/IGF-1 regulation of necdin and brown adipocyte differentiation via CREB- and FoxO1-associated pathway. Endocrinology 2011; 152 (10): 3680-9. PMCID: PMC3176640
6. Townsend KL, Suzuki R, Huang TL, Jing E, Schulz TJ, Lee K, Taniguchi CM, Espinoza DO, McDougall LE, He TC, Kokkotou E, Tseng YH. BMP-7 reverses obesity and regulates appetite through a central mTOR pathway. FASEB J 2012; 26(5): 2187-96. PMCID: PMC3336788
7. Schulz TJ, Huang P, Huang TL, Xue R, McDougall LE, Townsend KL, Cypess AM, Mishina Y, Gussoni E, Tseng YH. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature 2013; 495(7441):379-83. PMCID: PMC3623555
8. Townsend KL, An D, Lynes MD, Huang TL, Zhang, H, Goodyear LJ, Tseng YH. Increased mitochondrial activity in BMP7-treated brown adipocytes, due to increased CPT1- and CD36-mediated fatty acid uptake. Antioxidants & Redox Signaling 2013; 19(3): 243-257. PMCID: PMC3623555