Wnt Signaling Activation in Adipose Progenitors Promotes Insulin-Independent Muscle Glucose Uptake

Zeve, Daniel; Seo, Jin Ho; Suh, Jae Myoung; Stenesen, Drew; Tang, Wei; Berglund, Eric D.; Wan, Yihong; Williams, Linda; Lim, Ajin; Martinez, Myrna J.; McKay, Renée M.; Millay, Douglas P.; Olson, Eric N.; Graff, Jonathan M.

doi:10.1016/j.cmet.2012.03.010

Cited by 66 publications

(92 citation statements)

References 44 publications

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“…Wnt signaling blocks mammalian adipogenesis in vitro (42), and, in mice, activation of the canonical Wnt pathway in adipocytes by ectopic expression of Wnt10b, a Wnt ligand, inhibits obesity (43,44). Furthermore, autonomous activation of the Wnt pathway in adipose progenitors with constitutively active β-catenin expression decreases fat mass (45). Therefore, the reduced fat mass in Dcg > wg larvae indicates that autonomous Wg signaling activity in the fat body serves as a regulator of fat mass.…”

Section: Discussionmentioning

confidence: 99%

Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila

Lee

Bassel‐Duby

Olson

2014

Proc. Natl. Acad. Sci. U.S.A.

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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.O besity is a systemic disorder caused by an energy imbalance in which energy input exceeds energy utilization, resulting in accumulation of excess body fat. Muscle plays a central role in systemic energy homeostasis by consuming nutrients and signaling in an endocrine manner to other tissues (1-3). Thus, there has been intense interest in identifying secreted factors from muscle that modulate the function of adipose tissue.Previously, we reported that cardiac deletion of MED13, a subunit of the Mediator complex, increases susceptibility to obesity in mice whereas cardiac overexpression of MED13 confers a lean phenotype (4), revealing an unforeseen function of the heart as a systemic regulator of energy homeostasis. The Mediator is a conserved multisubunit complex that mediates the interaction between RNA polymerase II and transcription factors and therefore governs transcription in all eukaryotes (5). MED13 and MED12 are among four subunits of the auxiliary kinase module, which confers additional regulatory functions to the Mediator complex (6). Expression profiling of yeast mutants or gene-depleted Drosophila cell lines revealed a close correlation between the gene-expression programs controlled by MED13 and MED12, suggesting their concerted actions in gene regulation (7,8).Drosophila provides a powerful model system for the genetic analysis of obesity (9-11). The processes that regulate energy homeostasis, such as energy storage and mobilization of fat in adipose tissue of the fat bo...

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Section: Discussionmentioning

confidence: 99%

Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila

Lee

Bassel‐Duby

Olson

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Studies on developmental signaling cascades have also highlighted the notion that developmental forces are important to adipose development and to regional distinctions. This can be illustrated by the WNT pathway, which regulates adipose tissue formation in a spatially significant manner (Longo et al, 2004;Zeve et al, 2012). In relation to gene changes, fat-storing cells derived from subcutaneous progenitors accumulate more lipid and express higher levels of PPARγ and C/EBPα upon differentiation compared with visceral progenitor cells (Baglioni et al, 2012;Tchkonia et al, 2002).…”

Section: Reviewmentioning

confidence: 99%

“…Notably, these mutants displayed essentially a complete loss of subcutaneous adipose tissue accompanied by a lineage change in the subcutaneous adipose stem cells. Of note, the secretome of WNT mutant stem cells was altered and the cells produced high levels of a glucose-lowering hormone, glucodyne, which had many actions similar to insulin but functioned through distinct mechanisms (Zeve et al, 2012).…”

Section: Reviewmentioning

confidence: 99%

The developmental origins of adipose tissue

et al. 2013

Self Cite

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Adipose tissue is formed at stereotypic times and locations in a diverse array of organisms. Once formed, the tissue is dynamic, responding to homeostatic and external cues and capable of a 15-fold expansion. The formation and maintenance of adipose tissue is essential to many biological processes and when perturbed leads to significant diseases. Despite this basic and clinical significance, understanding of the developmental biology of adipose tissue has languished. In this Review, we highlight recent efforts to unveil adipose developmental cues, adipose stem cell biology and the regulators of adipose tissue homeostasis and dynamism.

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“…Furthermore, activation of the Wnt/␤-catenin pathway in vivo promotes a decrease in the plasma glucose level, which modulates the localization and expression of GLUT4 in adipocytes and increases glucose uptake in these cells (56). It has also been proposed that these pathways could have an important role in the control of energy intake and food behavior, modulating the energy balance throughout the body (57).…”

Section: Wnt Signaling Stimulates Glucose Utilization In Neuronsmentioning

confidence: 99%

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Cisternas

Salazar

Silva-Álvarez

et al. 2016

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinThe Wnt signaling pathway is critical for a number of functions in the central nervous system, including regulation of the synaptic cleft structure and neuroprotection against injury. Deregulation of Wnt signaling has been associated with several brain pathologies, including Alzheimer's disease. In recent years, it has been suggested that the Wnt pathway might act as a central integrator of metabolic signals from peripheral organs to the brain, which would represent a new role for Wnt signaling in cell metabolism. Energy metabolism is critical for normal neuronal function, which mainly depends on glucose utilization. Brain energy metabolism is important in almost all neurological disorders, to which a decrease in the capacity of the brain to utilize glucose has been linked. However, little is known about the relationship between Wnt signaling and neuronal glucose metabolism in the cellular context. In the present study, we found that acute treatment with the Wnt3a ligand induced a large increase in glucose uptake, without changes in the expression or localization of glucose transporter type 3. In addition, we observed that Wnt3a treatment increased the activation of the metabolic sensor Akt. Moreover, we observed an increase in the activity of hexokinase and in the glycolytic rate, and both processes were dependent on activation of the Akt pathway. Furthermore, we did not observe changes in the activity of glucose-6-phosphate dehydrogenase or in the pentose phosphate pathway. The effect of Wnt3a was independent of both the transcription of Wnt target genes and synaptic effects of Wnt3a. Together, our results suggest that Wnt signaling stimulates glucose utilization in cortical neurons through glycolysis to satisfy the high energy demand of these cells.

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Wnt Signaling Activation in Adipose Progenitors Promotes Insulin-Independent Muscle Glucose Uptake

Cited by 66 publications

References 44 publications

Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila

Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila

The developmental origins of adipose tissue

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

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