Hedgehog Signaling - a mediator between liver and adipose tissue

Background For many years the understanding and research of Hedgehog (Hh) signaling was limited to embryogenesis and cancer development. However, the functions of Hh in adult organs in control of metabolism and maintenance of homeostasis become more important as Hh is implied in many metabolic disorders such as non-alcoholic fatty liver disease (NAFLD). Active Hh signaling could be detected in mature hepatocytes and is linked to fatty acid metabolism. Previous experiments have also shown morphologic changes in adipose tissue in consequence of Hh inactivation in the liver. The crosstalk of liver and adipose tissue is a complex process for which the role of hepatic Hh signaling has not been investigated yet.

Methods Primary hepatocytes, serum and the different types of adipose tissue – visceral, subcutaneous and brown – were isolated from mice with specific inactivation of Hh signaling in hepatocytes. Morphologic and biochemical characterization of adipose tissue was conducted with immunohistochemistry including analysis of adipocyte size as well as qPCR. A fibroblast growth factor 21 (FGF21) ELISA was performed.

Results Mice with an inactivation of Hh signaling in hepatocytes show a distinct phenotype. Weight of all types of adipose tissue is increased in both sexes. Additionally a changed distribution of cell size can be detected. On the gene expression level, inactivation of Hh signaling was associated with an increased expression of brown and beige adipocyte markers and decrease in the expression of a marker associated with lipogenesis. Immunohistochemistry reveals UCP-1-positive cell clusters in visceral and subcutaneous adipose tissue, indicating a browning effect. As a signal molecule, which is responsible for the observed peripheral communication of the liver with the AT, we found FGF21 as a potential candidate as it is accumulated in the culture supernatant of hepatocytes of transgenic knockout mice compared to the wild type in vitro.

Conclusion Hepatocyte-specific inactivation of Hh leads to extrahepatic phenotypic and metabolic changes in the adipose tissue of mice, resulting in the emergence of brown adipocytes in subcutaneous and, more intensely, in visceral adipose tissue. The results reveal a novel and interesting aspect of how morphogenic pathways control metabolism through inter-organ communication. The effects of hepatic Hh could be mediated by FGF21 as a downstream target, which in turn activates adipocyte browning.

Publication History

Article published online:
04 January 2021