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San Diego, CA, United States

Microscopy image depicting fat cells (or adipocytes) after differentiation. The cells are stained with Oil Red O, which highlights lipid or fat droplets that accumulate with the fat cells. The metabolic studies described here indicated that fat cells produce these fatty acids, in part, from essential amino acids rather than sugar only. Credit: Metabolic Systems Biology lab, UC San Diego Jacobs School of Engineering Researchers at the University of California, San Diego report new insights into what nutrients fat cells metabolize to make fatty acids. The findings pave the way for understanding potential irregularities in fat cell metabolism that occur in patients with diabetes and obesity and could lead to new treatments for these conditions. The researchers published their findings online in the Nov. 16 issue of Nature Chemical Biology. "This study highlights how specific tissues in our bodies use particular nutrients. By understanding fat cell metabolism at the molecular level, we are laying the groundwork for further research to identify better drug targets for treating diabetes and obesity," said Christian Metallo, a bioengineering professor in the Jacobs School of Engineering at UC San Diego and senior author of the study. Metallo is affiliated with the Institute for Engineering in Medicine, the Moore's Cancer Center, and the CHO Systems Biology Center, all at UC San Diego. In the new study, researchers discovered that as fat cells develop, they change what types of nutrients they metabolize to produce fat and energy. Pre-adipocytes, which are precursors to fat cells, preferentially consume glucose, a simple sugar, to grow and make energy. But when pre-adipocytes become fat cells, researchers found that they metabolize not just glucose, but also branched-chain amino acids, a small set of the essential amino acids for humans. This finding is important because it shows that fat cells play an important role in regulating the body's levels of branched-chain amino acids—which are typically elevated in individuals with diabetes and obesity. "We've taken a step towards understanding why these amino acids are accumulating in the blood of diabetics and those suffering from obesity," said Courtney Green, a bioengineering Ph.D. student at UC San Diego and first author of the study. "The next step is to understand how and why this metabolic pathway becomes impaired in the fat cells of these individuals." Metallo and his team studied the metabolism of fat cells from the pre-adipocyte stage throughout the fat cell differentiation process. They induced pre-adipocytes to differentiate into fat cells and cultured the cells in media containing nutrients enriched with carbon-13 isotopes, a form of carbon atoms that are used as metabolic tracers in cells, animals, and people. Through this method, researchers were able to trace what carbon-based nutrients the cells metabolized and what they produced at different stages of the cell differentiation process. "We are curious about how different cells in our body, such as fat cells, consume and metabolize their surrounding nutrients. A better understanding of how these biochemical pathways are used by cells could help us find new approaches to treat diseases such as cancer or diabetes," said Metallo. More information: Courtney R Green et al. Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis, Nature Chemical Biology (2015). DOI: 10.1038/nchembio.1961


Li G.,University of Sichuan | Xu F.,Sun Yat Sen University | Zhu J.,Institute for Engineering in Medicine | Krawczyk M.,Institute for Engineering in Medicine | And 27 more authors.
Journal of Biological Chemistry | Year: 2015

PAX6 is a master regulatory gene involved in neuronal cell fate specification. It also plays a critical role in early eye field and subsequent limbal stem cell (LSC) determination during eye development. Defects in Pax6 cause aniridia and LSC deficiency in humans and the Sey (Small eye) phenotype in mice (Massé, K., Bhamra, S., Eason, R., Dale, N., and Jones, E. A. (2007) Nature 449, 1058-1062). However, how PAX6 specifies LSC and corneal fates during eye development is not well understood. Here, we show that PAX6 is expressed in the primitive eye cup and later in corneal tissue progenitors in early embryonic development. In contrast, p63 expression commences after that of PAX6 in ocular adnexal and skin tissue progenitors and later in LSCs. Using an in vitro feeder-free culture system, we show that PAX6 knockdown in LSCs led to up-regulation of skin epidermis-specific keratins concomitant with differentiation to a skin fate. Using gene expression analysis, we identified the involvement of Notch, Wnt, and TGF-β signaling pathways in LSC fate determination. Thus, loss of PAX6 converts LSCs to epidermal stem cells, as demonstrated by a switch in the keratin gene expression profile and by the appearance of congenital dermoid tissue. © 2015, American Society for Biochemistry and Molecular Biology Inc. All rights reserved. Source

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