The biological functions of hedgehog signaling encompass not only its well-defined role in embryonic development and tissue homeostasis, but its dysregulation is further implicated in a variety of human cancers. Previously, the hedgehog pathway has been identified as a differential regulator of white and brown adipocyte differentiation.
Fat-specific hedgehog mutant mice displayed almost complete lipoatrophy of their white fat compartment. Increased glucose uptake in the residual white adipose tissue depots of these mice raised the question whether hedgehog might also have implications on regulating metabolism in mature adipocytes. Therefore, the aim of this thesis was to elucidate the functional role of hedgehog activation in adipocytes. In the work presented here, we show that hedgehog signaling initiates reprogramming of cellular metabolism. A novel signaling axis dependent on the transmembrane receptor Smoothened (Smo) induces increased glucose consumption and metabolic rerouting within minutes of ligand binding, a finding initially uncovered in adipocytes. Upon Smo activation, metabolism is reconfigured to a Warburg-like state via extracellular Ca2+ influx that leads to activation of Camkk2 and, together with its second upstream kinase Lkb1 to subsequent activation of Ampk, a master regulator of cellular energy homeostasis. Thus, this mechanism represents a novel non-canonical hedgehog signaling pathway. Further, this Smo-Ampk axis can be uncoupled from canonical signaling by Smo modulators. We identified cyclopamine, a classic hedgehog antagonist, to be capable of concomitant inhibition of canonical and activation of non-canonical signaling, representing a new class of "selective partial agonists". In addition, the system remains intact in vivo, inducing glucose uptake independently of insulin. ^Intriguingly, activation of the Smo-Ampk axis triggers glucose uptake in muscle and brown adipose tissue specifically. These findings provide fundamental insight into Smo signaling and have substantial implications for the development and design of hedgehog modulators such as cancer therapeutics. Considering the rapidly rising incidence of obesity and related metabolic disorders such as type 2 diabetes currently affecting more than 10% of world's population, and the concomitant need for treatment strategies, these data further provide a new therapeutic avenue for these diseases.