TY - JOUR
T1 - Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila
AU - Lee, Ji Hoon
AU - Bassel-Duby, Rhonda
AU - Olson, Eric N.
PY - 2014/7/1
Y1 - 2014/7/1
N2 - Obesity develops in response to an imbalance of energy homeostasis and whole-body metabolism. Muscle plays a central role in the control of energy homeostasis through consumption of energy and signaling to adipose tissue. We reported previously that MED13, a subunit of the Mediator complex, acts in the heart to control obesity in mice. To further explore the generality and mechanistic basis of this observation, we investigated the potential influence of MED13 expression in heart and muscle on the susceptibility of Drosophila to obesity. Here, we show that heart/muscle-specific knockdown of MED13 or MED12, another Mediator subunit, increases susceptibility to obesity in adult flies. To identify possible muscle-secreted obesity regulators, we performed an RNAi-based genetic screen of 150 genes that encode secreted proteins and found that Wingless inhibition also caused obesity. Consistent with these findings, muscle-specific inhibition of Armadillo, the downstream transcriptional effector of the Wingless pathway, also evoked an obese phenotype in flies. Epistasis experiments further demonstrated that Wingless functions downstream of MED13 within a muscle-regulatory pathway. Together, these findings reveal an intertissue signaling system in which Wingless acts as an effector of MED13 in heart and muscle and suggest that Wingless-mediated cross-talk between striated muscle and adipose tissue controls obesity in Drosophila. This signaling system appears to represent an ancestral mechanism for the control of systemic energy homeostasis.
AB - Obesity develops in response to an imbalance of energy homeostasis and whole-body metabolism. Muscle plays a central role in the control of energy homeostasis through consumption of energy and signaling to adipose tissue. We reported previously that MED13, a subunit of the Mediator complex, acts in the heart to control obesity in mice. To further explore the generality and mechanistic basis of this observation, we investigated the potential influence of MED13 expression in heart and muscle on the susceptibility of Drosophila to obesity. Here, we show that heart/muscle-specific knockdown of MED13 or MED12, another Mediator subunit, increases susceptibility to obesity in adult flies. To identify possible muscle-secreted obesity regulators, we performed an RNAi-based genetic screen of 150 genes that encode secreted proteins and found that Wingless inhibition also caused obesity. Consistent with these findings, muscle-specific inhibition of Armadillo, the downstream transcriptional effector of the Wingless pathway, also evoked an obese phenotype in flies. Epistasis experiments further demonstrated that Wingless functions downstream of MED13 within a muscle-regulatory pathway. Together, these findings reveal an intertissue signaling system in which Wingless acts as an effector of MED13 in heart and muscle and suggest that Wingless-mediated cross-talk between striated muscle and adipose tissue controls obesity in Drosophila. This signaling system appears to represent an ancestral mechanism for the control of systemic energy homeostasis.
KW - Kohtalo
KW - Metabolic syndrome
KW - Myokines
KW - Skuld
UR - http://www.scopus.com/inward/record.url?scp=84903719295&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84903719295&partnerID=8YFLogxK
U2 - 10.1073/pnas.1409427111
DO - 10.1073/pnas.1409427111
M3 - Article
C2 - 24979807
AN - SCOPUS:84903719295
SN - 0027-8424
VL - 111
SP - 9491
EP - 9496
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 26
ER -