Obesity arises from a combination of genetic, environmental, and behavioral factors. However, the processes that regulate white adipose tissue (WAT) expansion at the level of the adipocyte are not well understood. The Hedgehog (HH) pathway plays a conserved role in adipogenesis, inhibiting fat formation in vivo and in vitro, but it has not been shown that mice with reduced HH pathway activity have enhanced adiposity. We report that mice lacking the HH coreceptor BOC displayed age-related overweight and excess WAT. They also displayed alterations in some metabolic parameters but normal food intake. Furthermore, they had an exacerbated response to a high-fat diet, including enhanced weight gain and adipocyte hypertrophy, livers with greater fat accumulation, and elevated expression of genes related to adipogenesis, lipid metabolism, and adipokine production. Cultured Boc-/- mouse embryo fibroblasts showed enhanced adipogenesis relative to Boc+/+ cells, and they expressed reduced levels of HH pathway target genes. Therefore, a loss-of-function mutation in an HH pathway component is associated with WAT accumulation and overweight in mice. Variant alleles of such HH regulators may contribute to WAT accumulation in human individuals with additional genetic or lifestyle-based predisposition to obesity.
Bibliographical noteFunding Information:
This research was supported by National Institutes of Health grant AR-46207 (R.S.K.) and a National Research Foundation of Korea grant funded by the Korea Government (NRF-2011-0017315) (J.-S.K.).
Funding. This research was supported by National Institutes of Health grant AR-46207 (R.S.K.) and a National Research Foundation of Korea grant funded by the Korea Government (NRF-2011-0017315) (J.-S.K.). Duality of Interest. No potential conflicts of interest relevant to this article were reported. Author Contributions. H.-J.L., S.-B.J., A.I.R., H.-J.L., M.-J.K., and S.-H.K. contributed to the experimental design, research, data analysis, and review of the manuscript. R.S.K. and J.-S.K. contributed to experimental design, data analysis, and writing of the manuscript. R.S.K. and J.-S.K. are the guarantors of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. This work was presented as a poster at the International Conference of the Korean Society for Molecular and Cellular Biology, Seoul, Korea, 9–11 October 2013.
© 2015 by the American Diabetes Association.
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism