Activin signaling mediates muscle-to-adipose communication in a mitochondria dysfunction-associated obesity model

Abstract

Mitochondrial dysfunction has been associated with obesity and metabolic disorders. However, whether mitochondrial perturbation in a single tissue influences mitochondrial function and metabolic status of another distal tissue remains largely unknown. We analyzed the nonautonomous role of muscular mitochondrial dysfunction in Drosophila. Surprisingly, impaired muscle mitochondrial function via complex I perturbation results in simultaneous mitochondrial dysfunction in the fat body (the fly adipose tissue) and subsequent triglyceride accumulation, the major characteristic of obesity. RNA-sequencing (RNA-seq) analysis, in the context of muscle mitochondrial dysfunction, revealed that target genes of the TGF-β signaling pathway were induced in the fat body. Strikingly, expression of the TGF-β family ligand, Activin-β (Actβ), was dramatically increased in the muscles by NF-κB/Relish (Rel) signaling in response to mitochondrial perturbation, and decreasing Actβ expression in mitochondrial-perturbed muscles rescued both the fat body mitochondrial dysfunction and obesity phenotypes. Thus, perturbation of muscle mitochondrial activity regulates mitochondrial function in the fat body nonautonomously via modulation of Activin signaling.mitochondrial synchrony | Activin-β | complex I perturbation | NF-κB/Relish | lipid metabolism I ndividual organs in a multicellular organism, besides performing their respective roles, must communicate with other organs to maintain systemic homeostasis. The central nervous system (CNS) in particular integrates information regarding the status of peripheral metabolic processes via hormonal signaling and directs energy homeostasis and feeding behavior (1). In addition, metabolic changes in a peripheral organ can affect the physiology of other peripheral organs (2, 3). The skeletal muscle system, which is newly recognized as playing endocrine-related roles, produces myokines after exercise to target other metabolic organs (liver, adipose tissue, pancreas, gut, and bone) and modulates systemic energy homeostasis (4).Mitochondria are semiautonomous organelles that integrate multiple physiological signals. Growing evidence indicates that mitochondrial alterations in one organ leads to abnormalities in biological processes in distal organs through hormonal signaling (5, 6). In addition to exercise, which induces mitochondrial activity and improves muscle performance, mitochondrial perturbationassociated muscle injury is also sufficient to modulate functions of other organs and change systemic outcomes via myokine production. For example, in mammals, mitochondrial dysfunction due to disruption of autophagic function in skeletal muscles results in elevated production of muscular FGF21 that triggers browning of white adipose tissue and increases lipid mobilization (7). Further, in Drosophila, mild mitochondrial distress in adult muscles delays aging via an increase of muscular ImpL2 production and remote suppression of insulin signaling in the fat body and brain (8). Despite these examples, molecula...

Mitochondrial retrograde signaling in the nervous system

“…In Drosophila , mild inhibition of complex I activity in muscle causes increased expression and secretion of ImpL2 (an ortholog of human insulin‐like growth factor‐binding protein 7, IGFBP7), which systemically inhibits insulin receptor pathway activity and increases lifespan . Muscle‐specific mitochondrial dysfunction in Drosophila results in a TGF‐β‐mediated retrograde response in adipose tissue as a result of increased systemic levels of the TGF‐β ligand Activin‐β secreted from muscle tissue .…”

Endocrine Regulation of Energy Balance by Drosophila TGF‐β/Activins

“…A recent study has illustrated how Actβ mediates synchronized mitochondrial dysfunction between larval muscle and fat body. As mentioned above, larval muscles with impaired mitochondrial complex I produce Actβ to activate Babo signaling and simultaneously suppress mitochondrial activity in the fat body . It is not likely that Actβ impairs mitochondrial activity via down‐regulation of general mitochondrial genes because complex I perturbation in larval muscles, which correlates with elevated Actβ production, actually up‐regulates the expression of more than half of mitochondrial genes.…”

“…Specifically, intracellular Babo signaling promotes lipid mobilization and decreases TAG content in the larval fat body . Even though modulation of activin signaling in the fat body exhibits changes in mitochondrial function and lipid β‐oxidation rate that contribute to lipid mobilization, the molecular mechanisms by which activin signaling regulates lipid metabolism are still unknown. Nevertheless, enhanced activin signaling and impaired lipid homeostasis in the fat body is associated with larval muscle dysfunction, suggesting a muscle‐to‐fat‐body interorgan communication modulated by activins.…”

“…Activin/Babo signaling in the fat body is highly associated with mitochondrial activity, including ATP production, O 2 consumption, as well as β‐oxidation . A recent study has illustrated how Actβ mediates synchronized mitochondrial dysfunction between larval muscle and fat body.…”

“…As endocrine factors controlling systemic energy homeostasis, fly activins are also regulated by nutrient status as well as stress signaling. For example, Actβ induction in larval muscles is regulated by mitochondrial unfolded protein responses (UPR mt ) . Complex I perturbation in muscle results in reactive oxygen species (ROS) generation and activates Relish (Rel), one of the UPR mt transcriptional factors mounting protective transcriptional responses, to enhance Actβ expression .…”