1a.Objectives (from AD-416):
Objective 1: No longer applies.
Objective 2: No longer applies
Objective 3: Gain knowledge regarding the impact of nutrition on the Hedgehog signaling pathway.
1b.Approach (from AD-416):
Children's Nutrition Research Center scientists will further investigate mutant animal models with adipose tissue-specific inactivation of Hedgehog pathway components.
This year we completed our studies on the role of Hedgehog (Hh) signaling in brown fat development. Specifically, we showed that activating the Hh signaling pathway prevents immature brown fat cells from becoming mature brown fat cells. We showed this both in tissue culture experiments using an embryonic brown fat cell line we generated in the previous year and in animals using genetically engineered mice. Furthermore, our studies indicated that Hh signaling inhibits brown fat development by activating one of its downstream target genes, COUP-TFII. Finally, by performing gene expression microarray assays, we uncovered an array of novel genes involved in embryonic brown fat development. We also observed that the Hh pathway inhibits white fat development after birth in mice. Specifically, we generated mice with globally elevated Hh pathway activity. These mice appeared normal at birth; however, their body size and weights were lower than those of wild-type mice two weeks after birth, and the mice died within four weeks. The white fat in these mutant mice was significantly smaller, indicating that high Hh pathway activity likely also prevents white fat development. We are currently performing additional studies to analyze the white fat tissue of these mutant mice.
Identifying genes regulated by the Hedgehog pathway during brown fat development. Because of its unique ability to burn calories to generate heat, brown fat could potentially be utilized to counteract weight gain. Brown fat is generated during development by an array of genes whose identities are largely unknown. In Houston, Texas, Children's Nutrition Research Center scientists have performed studies regarding the link between Hh signaling and brown fat formation and have identified a group of genes whose expression is regulated by the Hh pathway during brown fat development. Understanding the roles of these novel genes in the regulation of brown fat development will significantly advance our knowledge of adipose tissue biology and may provide new therapeutic targets for counteracting obesity.