Biology subjects

Chang, T. Y.

Publications and source records attributed to Chang, T. Y..

7 recordsLinked to original sources

bioRxiv2026

Time-restricted eating promotes sustained fat loss in Drosophila

While current therapeutics restricting calorie intake, such as GLP-1 agonists, induce fat loss for many people, they are ineffective for others and concerns remain about their long-term effects on health, particularly loss of lean muscle mass. Moreover, many quickly regain fat if they stop treatment. In contrast, time-restricted eating does not restrict calorie intake but instead restricts the time window for eating and prevents obesity in mice and humans. Here we investigated the effects of intermittent Time-Restricted Feeding (iTRF), which extends lifespan and delays markers of aging, on stored fat in Drosophila. Ten days of iTRF caused significant fat loss relative to ad lib diet, an effect that persisted even after return to ad lib diet. Unlike iTRF-induced lifespan extension, iTRF-induced fat loss did not depend on circadian-regulated autophagy. iTRF treated both diet-induced and genetically induced obesity and significantly reduced lipid droplet size in the fat body (adipose tissue). Instead of causing muscle loss, iTRF increased total and muscle-specific protein levels and enhanced flight performance, suggesting a shift in body composition. We found that iTRF evoked fasting-induced hyperactivity, partially mediated by octopamine, the fly ortholog of the human stress hormone norepinephrine. Ablation of octopaminergic neurons (OANs) prevented iTRF-mediated effects: fat loss, increased protein, and enhanced flight performance. Our results suggest that Drosophila iTRF causes rapid, permanent fat loss and increased muscle function through a "fight or flight" response. Understanding the mechanisms driving differences between Drosophila and human responses to TRE could be critical for identifying effective therapeutic targets for obesity.

physiology↗

bioRxiv2026

Directed evolution of the Drosophila microbiome improves intestinal health and extends lifespan

The gut microbiome and its bacterially derived metabolites are known to affect many aspects of the host organisms health, including metabolism, immune response, intestinal inflammation, oxidative stress, and even lifespan. Because pathological changes in the gut microbiome and these functions are associated with aging, many have hypothesized that we could protect against aging by generating beneficial changes to the gut microbiome. Here, we directed evolution outside of the host (ex vivo) and generated a Drosophila gut microbiome resistant to paraquat, a toxin that causes oxidative stress. Compared to a control microbiome, this paraquat-resistant (PQR) microbiome transplanted back into the Drosophila gut endowed the host with multiple health benefits: increased resistance to dietary paraquat, reduced age-related pathologies in the gut, and extended lifespan. We identified the beneficial species of the PQR microbiome as Lactiplantibacillus plantarum and further identified mutations specific to lifespan-extending isolates linked to greater production of acetate. Directly feeding this short-chain fatty acid, acetate, to Drosophila was sufficient to recapitulate an extended lifespan, similar to that induced by gut colonization of PQR bacteria in the gut. These results serve as a proof of principle that increasing the resistance of the microbiome to oxidative stress via directed ex vivo evolution could serve as a therapeutic strategy to protect against aging.

physiology↗

bioRxiv2024

Investigating the consequences of chronic short sleep for metabolism and survival of oxidative stress

In previous work, we found that short sleep caused sensitivity to oxidative stress; here we set out to characterize the physiological state of a diverse group of chronically short-sleeping mutants during hyperoxia as an acute oxidative stress. Using RNA-sequencing analysis, we found that short-sleeping mutants had a normal transcriptional oxidative stress response relative to controls. In both short-sleeping mutants and controls, hyperoxia led to downregulation of glycolytic genes and upregulation of genes involved in fatty acid metabolism, reminiscent of metabolic shifts during sleep. We hypothesized that short-sleeping mutants may be sensitive to hyperoxia because of defects in metabolism. Consistent with this, short-sleeping mutants were sensitive to starvation. Using metabolomics, we identified a pattern of low levels of long chain fatty acids and lysophospholipids in short-sleeping mutants relative to controls during hyperoxia, suggesting a defect in lipid metabolism. Though short-sleeping mutants did not have common defects in many aspects of lipid metabolism (basal fat stores, usage kinetics during hyperoxia, respiration rates, and cuticular hydrocarbon profiles), they were all sensitive to dehydration, suggesting a general defect in cuticular hydrocarbons, which protect against dehydration. To test the bi-directionality of sleep and lipid metabolism, we tested flies with both diet-induced obesity and genetic obesity. Flies with diet-induced obesity had no sleep or oxidative stress phenotype; in contrast, the lipid metabolic mutant, brummer, slept significantly more than controls but was sensitive to oxidative stress. Previously, all short sleepers tested were sensitive and all long sleepers resistant to oxidative stress. brummer mutants, the first exceptions to this rule, lack a key enzyme required to mobilize fat stores, suggesting that a defect in accessing lipid stores can cause sensitivity to oxidative stress. Taken together, we found that short-sleeping mutants have many phenotypes in common: sensitivity to oxidative stress, starvation, dehydration, and defects in lipid metabolites. These results argue against a specific role for sleep as an antioxidant and suggest the possibility that lipid metabolic defects underlie the sensitivity to oxidative stress of short-sleeping mutants.

physiology↗

bioRxiv2024

Inhibiting the cholesterol storage enzyme ACAT1/SOAT1 in aging Apolipoprotein E4 mice alter their brains inflammatory profiles

Aging and Apolipoprotein E4 (APOE4) are the two most significant risk factors for late-onset Alzheimers disease (LOAD). Compared to APOE3, APOE4 disrupts cholesterol homeostasis, increases cholesteryl esters (CEs), and exacerbates neuroinflammation in brain cells including microglia. Targeting CEs and neuroinflammation could be a novel strategy to ameliorate APOE4 dependent phenotypes. Toll-like receptor 4 (TLR4) is a key player in inflammation, its regulation is associated with cholesterol content of lipid rafts in cell membranes. We previously demonstrated that in normal microglia expressing APOE3, inhibiting the cholesterol storage enzyme acylCoA:cholesterol acyltransferase 1 (ACAT1/SOAT1) reduces CEs, dampened neuroinflammation via modulating the fate of TLR4. We also showed that treating myelin debris-loaded normal microglia with ACAT inhibitor F12511 reduced cellular CEs and activated ABC transporter 1 (ABCA1) for cholesterol efflux. In this study, we found that treating primary microglia expressing APOE4 with F12511 also reduces CEs, activated ABCA1, and dampened LPS dependent NFkB activation. In vivo, a two-week injections of nanoparticle F12511, which consists of DSPE-PEG2000, phosphatidylcholine, and F12511, to aged female APOE4 mice reduced TLR4 protein content and decreased proinflammatory cytokines including IL-1{beta} in APOE4 mice brains. Overall, our work suggests nanoparticle F12511 is a novel agent to ameliorate LOAD.

biochemistry↗

bioRxiv2023

Stealth liposomes encapsulating a potent ACAT1/SOAT1 inhibitor F12511: pharmacokinetic, biodistribution and toxicity studies in wild-type mice, and efficacy studies in triple transgenic Alzheimer Disease mice.

Cholesterol is essential to cellular function and is stored as cholesteryl esters (CEs). CEs biosynthesis is responsible by the enzymes acyl-CoA: cholesterol acyltransferase 1 and 2 (ACAT1 and ACAT2), with ACAT1 as the primary isoenzyme in most cells in humans. ACATs are targets for atherosclerosis therapies and may also be promising targets for treating Alzheimers Disease (AD). F12511 is a high-affinity ACAT1 inhibitor that has passed phase 1 safety tests for anti-atherosclerosis. Previously, we had developed a nanoparticle system to encapsulate a large concentration of F12511 into a stealth liposome (DSPE-PEG2000 with egg phosphatidylcholine). Here, we injected the nanoparticle encapsulated F12511 (nanoparticle F) intravenously (IV) to wild-type (WT) mice and performed HPLC/MS/MS analysis and ACAT enzyme activity measurement. The results demonstrated that F12511 was present within the mouse brain after a single IV but did not over-accumulate in the brain or other tissues after repeated IVs. Histological examination showed that F12511 did not cause overt neurological or systemic toxicity. We then showed that 2-week IV delivery of nanoparticle F to aging 3xTg AD mice ameliorated amyloidopathy, reduced hyperphosphorylated tau and non-phosphorylated tau, and reduced neuroinflammation. This work lays the foundation with nanoparticle F as a possible therapy for AD and other neurodegenerative diseases.

neuroscience↗

bioRxiv2023

C. elegans SMOC-1 interacts with both BMP and glypican to regulate BMP signaling

ABSTRACTSSecreted modular calcium binding (SMOC) proteins are conserved matricellular proteins found in organisms from C. elegans to humans. SMOC homologs characteristically contain one or two extracellular calcium (EC) binding domain(s) and one or two thyroglobulin type-1 (TY) domain(s). SMOC proteins in Drosophila and Xenopus have been found to interact with cell surface heparan sulfate protein glycans (HSPGs) to exert both positive and negative influences on the conserved bone morphogenetic protein (BMP) signaling pathway. In this study, we used a combination of biochemical, structural modeling, and molecular genetic approaches to dissect the functions of the sole SMOC protein in C. elegans. We showed that SMOC-1 binds LON-2/glypican, as well as the mature domain of DBL-1/BMP. Moreover, SMOC-1 can simultaneously bind LON-2/glypican and DBL-1/BMP. The interaction between SMOC-1 and LON-2/glypican is mediated by the EC domain of SMOC-1, while the interaction between SMOC-1 and DBL-1/BMP involves full-length SMOC-1. We further showed that while SMOC-1(EC) is sufficient to promote BMP signaling when overexpressed, both the EC and TY domains are required for SMOC-1 function at the endogenous locus. Finally, when overexpressed, SMOC-1 can promote BMP signaling in the absence of LON-2/glypican. Taken together, our findings led to a model where SMOC-1 functions both negatively in a LON-2-dependent manner and positively in a LON-2-independent manner to regulate BMP signaling. Our work provides a mechanistic basis for how the evolutionarily conserved SMOC proteins regulate BMP signaling.

developmental biology↗

bioRxiv2022

ACAT1/SOAT1 Blockade Suppresses LPS-Mediated Neuroinflammation by Modulating the Fate of Toll-Like Receptor 4 in Microglia

BackgroundCholesterol is essential for growth and maintenance of mammalian cells. It is stored as cholesteryl esters by the enzymes acyl-CoA:cholesterol acyltransferases 1 & 2 (ACAT 1 & 2) (Sterol O-acyltransferase 1 & 2; SOATs in GenBank). ACAT1 blockade (A1B) in macrophages ameliorates various pro-inflammatory responses elicited by lipopolysaccharides (LPS) or by cholesterol loading. In mouse and human brains, Acat1 expression dominates over Acat2 and Acat1 is elevated in many neurodegenerative diseases and in acute neuroinflammation. However, the possible effects of ACAT1 blockade in neuroinflammation, regulated by mediators such as Toll-Like Receptor 4 (TLR4), has not been studied. MethodsWe conducted LPS-induced acute neuroinflammation experiments in control vs myeloid specific or neuron specific Acat1 knockout (KO) mice. Furthermore, we evaluated LPS-induced neuroinflammation in the microglial cell line N9 with or without pre-treatment of the small molecule ACAT1-specific inhibitor K-604. Biochemical and microscopy assays were used to monitor inflammatory responses and the fate of TLR4. ResultsIn vivo studies revealed that Acat1 inactivation in myeloid cell lineage, but not in neurons, markedly attenuated LPS-induced activation of various pro-inflammatory response genes in hippocampus and cortex. Studies in cell culture showed that pre-incubating cells with K-604 significantly ameliorated the pro-inflammatory responses induced by LPS. In cells acutely treated with LPS (for 30 min), pre-incubation with K-604 significantly increased the endocytosis of TLR4, the major transmembrane signaling receptor that mediates LPS-dependent acute neuroinflammation. In cells chronically treated with LPS (for 24-48 hrs), pre-incubation with K-604 significantly decreased the total TLR4 protein content, presumably due to enhanced trafficking of TLR4 to the lysosomes for degradation. For ex vivo evidence, we isolated microglia from adult mice, and found that in mice without LPS stimulation, myeloid Acat1 inactivation altered cellular distribution of TLR4; in mice with LPS stimulation, myeloid Acat1 inactivation decreased the cellular content of TLR4. ConclusionBlocking ACAT1 in mouse microglia alters the fate of TLR4 and suppresses its ability to participate in pro-inflammatory signaling cascade in response to LPS.

neuroscience↗