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#metabolism

4 posts4 participants0 posts today
flypapers

📰 "Autophagy-driven Presynaptic Reorganization as a Molecular Signature of Brain Resilience."
biorxiv.org/content/10.1101/20
#Metabolism #Drosophila #Sleep

bioRxiv · Autophagy-driven Presynaptic Reorganization as a Molecular Signature of Brain Resilience.Neural circuits must remain functionally stable while responding flexibly to changing demands, stressors, and aging-related decline. While this balance is thought to be maintained through plasticity programs that integrate molecular, metabolic, and activity-dependent signals to reconfigure synapses structurally and functionally, direct mechanistic models of how such adaptations are orchestrated remain scarce. Here, we show that targeted impairment of autophagy in the Drosophila mushroom body (MB), a key sleep-regulatory and integrative center in the fly brain, triggers a brain-wide remodeling at presynaptic active zones (AZ). Quantitative proteomics revealed a specific upregulation of AZ scaffold proteins (including BRP, RIM, and Unc13A), accompanied by reduced levels of calcium channel subunits and increased Shaker-type potassium channels. These changes occurred largely independent of transcription and highlight a coordinated, excitability-tuning response centered on the AZ. Behaviorally, MB-specific autophagy impairment increased sleep and modestly extended lifespan. These adaptations resembled a previously described resilience program termed PreScale, which promotes restorative sleep homeostasis in response to sleep deprivation and early, still reversible brain aging. Conversely, overexpression of Atg5 in the MB delayed the onset of PreScale. Notably, autophagic disruption confined to MB neurons also caused widespread, non-cell autonomous accumulation of Ref(2)P and ATG8a-positive aggregates across the brain, revealing systemic propagation of proteostatic stress. Together, our findings identify MB autophagy as a key regulator of synaptic architecture and sleep-associated resilience. Such early acting programs may actively preserve circuit function and behavioral output by regulating synaptic plasticity, and define a genetically tractable model for how local stress signals can orchestrate brain-wide adaptation via post-transcriptional synaptic reprogramming. ### Competing Interest Statement The authors have declared no competing interest. European Commission, https://ror.org/00k4n6c32, 101097053 Deutsche Forschungsgemeinschaft, https://ror.org/018mejw64, 447288260
flypapers

📰 "Different ways to die: harnessing variation in Drosophila reveals loss of tolerance and resistance over age and sex-specific association between infection susceptibility and lifespan"
biorxiv.org/content/10.1101/20
#Metabolism #Drosophila #Immunity

bioRxiv · Different ways to die: harnessing variation in Drosophila reveals loss of tolerance and resistance over age and sex-specific association between infection susceptibility and lifespanIt is widely accepted that susceptibility to infection increases with age. The reason often invoked is the dysregulation of the immune system, which is both cause and consequence of ageing. However, we do not all age in the same way, and increased susceptibility may not be solely due to immune dysregulation affecting resistance to infection. There are many possible ways to make a host less tolerant to infection by dysregulating key physiological or metabolic processes. We hypothesised that the increase in susceptibility to infection over age can be linked to both immune ageing and decreased tolerance, and importantly, that it will depend on genotype and sex of the host. We assessed susceptibility to Gram-negative bacterial challenge in both sexes in 22 Drosophila isolines at young and old ages, and leveraged variation between genotypes to investigate how frequently an increase in susceptibility to infection was more associated with a decline in resistance or disease tolerance mechanisms. To achieve this, we assessed pathogen load to report on host immune decline. Strikingly, in most cases, greater infection susceptibility at old age was driven by reduced tolerance, although we also frequently identify cases that suffered bona fide immunosenescence, e.g. impaired resistance. We screened across bacterial pathogens during systemic and oral infections and found sex-specific signatures in survival in young and old individuals, but increased susceptibility with age occurred in both sexes. Pairing infection survival with lifespan data, we find that transcending genotype variation, susceptibility at old age predicts lifespan in males only, regardless of the existence or direction of sex bias in longevity. This work highlights that increased infection susceptibility is an early-arising ageing phenotype that occurs in both sexes, but only predicts lifespan in males, paralleling burgeoning evidence in mammals for male-biased effects of age on infection and its connection with mortality. Our data support a model where infection susceptibility increases with age following the same multiplicative pattern as organismal mortality, with existing failures making new failures more consequential. We propose that the term immunosenescence be used specifically to describe proven dysregulation of immune tissue resistance mechanisms. We argue that to fully understand the drivers of age-related susceptibility to infection, it is essential to consider genotype, sex, and their interaction, as well as the dysregulation of non-immune functions that influence the ability to control pathogens. ### Competing Interest Statement The authors have declared no competing interest. Wellcome Trust, https://ror.org/029chgv08, 210183/Z/18/Z Royal Society, https://ror.org/03wnrjx87, RGS\R1\221328 Fundação para a Ciência e Tecnologia, https://ror.org/00snfqn58, 2023.08149.CEECIND
flypapers

📰 "Convolvulus pluricaulis mediates its pharmacological effects via sod1, rdl, glut1, GABA-B-R1 and CG6293 orthologs in Drosophila melanogaster"
biorxiv.org/content/10.1101/20
#DrosophilaMelanogaster
#Drosophila #Metabolism #Behaviour #Adult

bioRxiv · Convolvulus pluricaulis mediates its pharmacological effects via sod1, rdl, glut1, GABA-B-R1 and CG6293 orthologs in Drosophila melanogasterConvolvulus pluricaulis, commonly known as Shankhpushpi, has been extensively used in the management of disorders of the nervous system, including depression and anxiety. The plant extract has also been demonstrated to function as an antioxidant. However, the molecular effectors underlying the beneficial effects of Shankpushpi are yet to be identified. In this study, we have utilized the fruit fly Drosophila melanogaster to identify the metabolic and molecular targets that mediate the beneficial effects of dietary Shankpushpi intake. Metabolomic analysis revealed changes in Ascorbic acid, glucose, and Adenosine monophosphate in the head tissue of fruit flies that were fed Shankpushpi for 20 days. Subsequent gene expression analysis revealed significant changes in expression of glut 1 (Glucose transporter 1), CG6293 (Ascorbate transporter), rdl (Resistant to dieldrin), GABA-B-R1 (GABA-B receptor subtype 1) and sod 1 (Superoxide dismutase 1) in the head tissue of adult flies that were exposed to different doses of Shankpushpi. Consistent with the expression data, knockdown of sod 1, glut1, GABA-B-R1, and CG6293 but not sod 2 abolished the Shankpushpi-mediated resistance to paraquat-induced oxidative stress. To uncover downstream effectors that are responsible for the antidepressant and anxiolytic effects of Shankpushpi, we examined the effects of dietary intake of Shankpushpi in a stress-induced model of depression. Administration of Shankpushpi during development alleviated depression-like behavior in Drosophila. Wild-type adult flies that were fed Shankpushpi accumulated high levels of Ascorbate in the head tissue, and knockdown of Ascorbate transporter abolished the antidepressant activity of Shankpushpi in the stress-induced model. Thus, indicating that Shankpushpi-induced antidepressant effects are associated with increased Ascorbate transport. Taken together, our analysis using Drosophila melanogaster as a model has uncovered five conserved downstream effectors responsible for the antioxidant activity and one conserved effector responsible for the antidepressant activity of Convolvulus pluricaulis. ### Competing Interest Statement The authors have declared no competing interest. Wellcome Trust/DBT India Alliance, https://ror.org/04reqzt68, IA/I(S)/17/1/503085]
flypapers

📰 "Tumour-driven lipid accumulation in oenocytes reflects systemic lipid alterations"
biorxiv.org/content/10.1101/20
#Metabolism #Drosophila #Larva

bioRxiv · Tumour-driven lipid accumulation in oenocytes reflects systemic lipid alterationsCancer cachexia is a multifactorial syndrome characterized by systemic metabolic dysfunction, including liver steatosis. In this study, we examined the role of larval oenocytes - hepatocyte-like cells, in a Drosophila model of cancer cachexia. We found that oenocytes in tumour-bearing larvae accumulate lipid droplets in response to tumour-secreted signals, Gbb and ImpL2. This lipid accumulation reflects systemic changes in lipid metabolism, responding to lipid metabolism manipulations in either the fat body or the muscle. Disrupting lipid synthesis (via FASN1 and DGAT1), storage (via Lsd2), or trafficking (via apolipoproteins) in these tissues significantly modulated lipid droplet accumulation in oenocytes. Moreover, oenocyte-specific knockdown of FASN1 reduced their lipid content and non-autonomously affected lipid droplet size in the fat body, suggesting cross-regulatory interactions between these tissues. Cachectic oenocytes also exhibited altered signaling profiles, characterized by reduced PI3K and elevated Wnt and Ecdysone activity. Enhancing PI3K signaling through Akt overexpression restored oenocyte size and reduced lipid levels; however, these changes did not significantly improve muscle integrity. Together, our data suggests that dynamic exchange of lipids occur between the fat body, oenocytes and the muscle during cancer cachexia. While the fat body and muscle lipid pools are key regulators of muscle integrity, oenocytes - despite their metabolic responsiveness, do not appear to play an active role in preserving muscle function during cachexia.
flypapers

📰 "Metabolic control of enteroendocrine cell fate through a redox state sensor CtBP"
biorxiv.org/content/10.1101/20
#Drosophila #Metabolism #Genomics #Larva

bioRxiv · Metabolic control of enteroendocrine cell fate through a redox state sensor CtBPEnteroendocrine (EE) cells monitor the intestinal nutrient composition and consequently control organismal physiology through hormonal signaling. In addition to the immediate effects on hormone secretion, nutrients influence EE cell abundance by affecting the determination and maintenance of cell fate. EE cells are known to import and respond to dietary sugars, but how the sugar-induced changes in the intracellular metabolic state are sensed to control the immediate and long-term responses of EE cells, remains poorly understood. We report that the NADH binding transcriptional cofactor C-terminal binding protein (CtBP) acts at the interface between nutrient sensing and fate regulation of Drosophila larval EE cells, thus controlling organismal energy metabolism and survival on a high sugar diet. CtBP dimerization in EE cells is regulated through the redox balance of nicotinamide cofactors controlled by glycolysis and pentose phosphate pathway, allowing EE cells sense their internal metabolic state in response to sugar catabolism. CtBP interacts with the EE cell fate determining transcription factor Prospero through a conserved binding motif and binds to genomic targets controlling EE cell fate and size, such as components of Notch and insulin/mTOR pathways. Collectively, our findings uncover a modality where changes in intracellular redox state serve as an instructive signal to control EE cell function to globally control organismal homeostasis. ### Competing Interest Statement Valentin Cracan is listed as an inventor on a patent application on the therapeutic uses of LbNOX and TPNOX (US patent application US20190017034A1). Academy of Finland, https://ror.org/05k73zm37, 312439, 332695 Novo Nordisk Foundation, https://ror.org/04txyc737, NNF18OC0034406, NNF19OC0057478, NNF22OC0078419 Sigrid Jusélius Foundation, https://ror.org/00ckakm23, N/A Finnish Cultural Foundation, 00160858 Magnus Ehrnrooth Foundation National Institute of General Medical Sciences, R35GM142495
RDN

A mouse study finds that electrical activity in brain synapses leads to metabolism of triglycerides in the synapses to support brain energetics. Blocking this lipid metabolism leads to torpor.

Summary: medicalxpress.com/news/2025-07

Original paper: nature.com/articles/s42255-025

Medical Xpress · Triglycerides may play an important role in brain metabolismBy Weill Cornell Medical College
#Science#Biology#Bioenergetics
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