While high-caloric diet impairs insulin response to cause hyperglycemia, whether and how counter-regulatory hormones are modulated by high-caloric diet is largely unknown. We find that enhanced response of Drosophila adipokinetic hormone (AKH, the glucagon homolog) in the fat body is essential for hyperglycemia associated with a chronic high-sugar diet. We show that the activin type I receptor Baboon (Babo) autonomously increases AKH signaling without affecting insulin signaling in the fat body via, at least, increase of Akh receptor (AkhR) expression. Further, we demonstrate that Activin-β (Actβ), an activin ligand predominantly produced in the enteroendocrine cells (EEs) of the midgut, is up-regulated by chronic high-sugar diet and signals through Babo to promote AKH action in the fat body, leading to hyperglycemia. Importantly, activin signaling in mouse primary hepatocytes also increases glucagon response and glucagon-induced glucose production, indicating a conserved role for activin in enhancing AKH/glucagon signaling and glycemic control.

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...

Endoreplication, known as endocycle, is a variant of the cell cycle that differs from mitosis and occurs in specific tissues of different organisms. Endoreplicating cells generally undergo multiple rounds of genome replication without chromosome segregation. Previous studies demonstrated that Drosophila fizzy-related protein (Fzr) and its mammalian homolog Cdh1 function as key regulators of endoreplication entrance by activating the anaphase-promoting complex/cyclosome to initiate the ubiquitination and subsequent degradation of cell cycle factors such as Cyclin B (CycB). However, the molecular mechanism underlying Fzr-mediated endoreplication is not completely understood. In this study, we demonstrated that the transcription factor Myc acts downstream of Fzr during endoreplication in Drosophila salivary gland. Mechanistically, Fzr interacts with chromatin-associated histone H2B to enhance H2B ubiquitination in the Myc promoter and promotes Myc transcription. In addition to negatively regulating CycB transcription, the Fzr-ubiquitinated H2B (H2Bub)-Myc signaling cascade also positively regulates the transcription of the MCM6 gene that is involved in DNA replication by directly binding to specific motifs within their promoters. We further found that the Fzr-H2Bub-Myc signaling cascade regulating endoreplication progression is conserved between insects and mammalian cells. Altogether, our work uncovers a novel transcriptional cascade that is involved in Fzr-mediated endoreplication.