Brown adipocyte differentiation is regulated by hedgehog signaling during development

Authors: CHEN, MIAO-HSUEH - Children'S Nutrition Research Center (CNRC); NOSAVANH, LAGINA - Children'S Nutrition Research Center (CNRC)

Submitted to: Endocrine Society Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 5/15/2012
Publication Date: 6/23/2012
Citation: Chen, M., Nosavanh, L. 2012. Brown adipocyte differentiation is regulated by hedgehog signaling during development [abstract]. Proceedings of the 94th Annual Meeting and Expo of the Endocrine Society, Session: Adipose Tissue Development and Inflammation, June 23–26, 2012, Houston, Texas. # OR20-3.

Interpretive Summary:

Technical Abstract: During development, brown fat tissue arises from mesenchymal precursor cells under the control of signaling networks that are not yet well understood. The Hedgehog (Hh) signaling pathway is one of the major signaling pathways that regulate mesenchymal cell fate. However, whether the Hh pathway controls the formation of brown fat is not clear. To investigate the role of the Hh pathway in brown fat development, we selectively activated the Hh pathway in fat tissue by mating the constitutively active M2 allele of Smo (SmoM2) to aP2-Cre transgenic mice, which express the Cre recombinase in many embryonic tissues, including brown fat tissue. Phenotypic analyses indicate that aP2-Cre/SmoM2 mice die at birth, with multiple tissue defects including polydactyly and open neural tubes, the two classic phenotypes associated with Hh pathway gain-of-function. Most importantly, our analyses showed that the amount of brown fat in these mutants is significantly reduced, suggesting that the Hh pathway can negatively regulate brown fat development. To confirm our in vivo observations and to establish that Hh signaling can directly control brown preadipocyte differentiation, we isolated and immortalized brown preadipocytes from E16.5 wild-type embryos. We first examined whether the Hh pathway components are present in these brown preadipocytes. Our results indicate that Smo and the downstream transcription factors Gli2 and Gli3 are present in these cells and localize to the primary cilium, the Hh signaling center, upon exogenous Hh stimulation. Furthermore, we found that the primary cilium, which is responsible for the activation and processing of the Gli transcription factors, is only present in brown preadipocytes but not in fully differentiated brown adipocytes. Finally, our studies indicate that applying Shh ligand together with adipogenic induction media can inhibit the differentiation of these brown preadipocytes. Specifically, Hh treatment resulted in significantly less accumulation of lipid droplets and in the down-regulation of the expression of pro-adipogenic genes. Taken together, our studies support an inhibitory role for Hh signaling in brown fat development.