Biology subjects

Wat, L. W.

Publications and source records attributed to Wat, L. W..

7 recordsLinked to original sources

bioRxiv2024

Insulin/insulin-like growth factor signaling pathway promotes higher fat storage in Drosophila females

In Drosophila, adult females store more fat than males. While the mechanisms that restrict body fat in males are becoming clearer, less is known about how females achieve higher fat storage. Here, we perform a detailed investigation of the mechanisms that promote higher fat storage in females. We show greater intake of dietary sugar supports higher fat storage due to female-biased remodeling of the fat body lipidome. Dietary sugar stimulates a female-specific increase in Drosophila insulin-like peptide 3 (Dilp3), which acts together with greater peripheral insulin sensitivity to augment insulin/insulin-like growth factor signaling pathway (IIS) activity in adult females. Indeed, Dilp3 overexpression prevented the female-biased decrease in body fat after removal of dietary sugar. Given that adult-specific IIS inhibition caused a female-biased decrease in body fat, our data reveal IIS as a key determinant of female fat storage.

physiology↗

bioRxiv2024

Neuronal lipid droplets play a conserved and sex-biased role in maintaining whole-body energy homeostasis

ABSTRACTLipids are essential for neuron development and physiology. Yet, the central hubs that coordinate lipid supply and demand in neurons remain unclear. Here, we combine invertebrate and vertebrate models to establish the presence and functional significance of neuronal lipid droplets (LD) in vivo. We find that LD are normally present in neurons in a non-uniform distribution across the brain, and demonstrate triglyceride metabolism enzymes and lipid droplet-associated proteins control neuronal LD formation through both canonical and recently-discovered pathways. Appropriate LD regulation in neurons has conserved and male-biased effects on whole-body energy homeostasis across flies and mice, specifically neurons that couple environmental cues with energy homeostasis. Mechanistically, LD-derived lipids support neuron function by providing phospholipids to sustain mitochondrial and endoplasmic reticulum homeostasis. Together, our work identifies a conserved role for LD as the organelle that coordinates lipid management in neurons, with implications for our understanding of mechanisms that preserve neuronal lipid homeostasis and function in health and disease. HIGHLIGHTSO_LILipid droplets (LD) normally form in neurons across species Neuronal LD are regulated by a conserved gene network C_LIO_LINeuronal LD regulation plays a conserved and sex-biased role in maintaining energy homeostasis C_LIO_LILD regulation supports ER and mitochondrial function in hunger-activated neurons C_LI GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/613929v1_ufig1.gif" ALT="Figure 1"> View larger version (54K): org.highwire.dtl.DTLVardef@1936e92org.highwire.dtl.DTLVardef@40478aorg.highwire.dtl.DTLVardef@18d5faorg.highwire.dtl.DTLVardef@882ee9_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

A PTER-dependent pathway of taurine metabolism linked to energy balance

Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in biosynthesis of taurine from cysteine as well as the downstream derivatization of taurine into secondary taurine metabolites4,5. One such taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by diverse physiologic perturbations that alter taurine and/or acetate flux, including endurance exercise7, nutritional taurine supplementation8, and alcohol consumption6,9. While taurine N-acetyltransferase activity has been previously detected in mammalian cells6,7, the molecular identity of this enzyme, and the physiologic relevance of N-acetyltaurine, have remained unknown. Here we show that the orphan body mass index-associated enzyme PTER (phosphotriesterase-related)10 is the principal mammalian taurine N-acetyltransferase/hydrolase. In vitro, recombinant PTER catalyzes bidirectional taurine N-acetylation with free acetate as well as the reverse N-acetyltaurine hydrolysis reaction. Genetic ablation of PTER in mice results in complete loss of tissue taurine N-acetyltransferase/hydrolysis activities and systemic elevation of N-acetyltaurine levels. Upon stimuli that increase taurine levels, PTER-KO mice exhibit lower body weight, reduced adiposity, and improved glucose homeostasis. These phenotypes are recapitulated by administration of N-acetyltaurine to wild-type mice. Lastly, the anorexigenic and anti-obesity effects of N-acetyltaurine require functional GFRAL receptors. Together, these data uncover enzymatic control of a previously enigmatic pathway of secondary taurine metabolism linked to energy balance.

biochemistry↗

bioRxiv2023

Rapid and accurate deorphanization of ligand-receptor pairs using AlphaFold

Secreted proteins play crucial roles in paracrine and endocrine signaling; however, identifying novel ligand-receptor interactions remains challenging. Here, we benchmarked AlphaFold as a screening approach to identify extracellular ligand-binding pairs using a structural library of single-pass transmembrane receptors. Key to the approach is the optimization of AlphaFold input and output for screening ligands against receptors to predict the most probable ligand-receptor interactions. Importantly, the predictions were performed on ligand-receptor pairs not used for AlphaFold training. We demonstrate high discriminatory power and a success rate of close to 90 % for known ligand-receptor pairs and 50 % for a diverse set of experimentally validated interactions. These results demonstrate proof-of-concept of a rapid and accurate screening platform to predict high-confidence cell-surface receptors for a diverse set of ligands by structural binding prediction, with potentially wide applicability for the understanding of cell-cell communication.

biochemistry↗

bioRxiv2021

Sex determination gene transformer regulates the male-female difference in Drosophila fat storage via the Adipokinetic hormone pathway

Sex differences in whole-body fat storage exist in many species. For example, Drosophila females store more fat than males. Yet, the mechanisms underlying this sex difference in fat storage remain incompletely understood. Here, we identify a key role for sex determination gene transformer (tra) in regulating the male-female difference in fat storage. Normally, a functional Tra protein is present only in females, where it promotes female sexual development. We show that loss of Tra in females reduced whole-body fat storage, whereas gain of Tra in males augmented fat storage. Tras role in promoting fat storage was largely due to its function in neurons, specifically the Adipokinetic hormone (Akh)-producing cells (APCs). Our analysis of Akh pathway regulation revealed a male bias in APC activity and Akh pathway function, where this sex-biased regulation influenced the sex difference in fat storage by limiting triglyceride accumulation in males. Importantly, Tra loss in females increased Akh pathway activity, and genetically manipulating the Akh pathway rescued Tra-dependent effects on fat storage. This identifies sex-specific regulation of Akh as one mechanism underlying the male-female difference in whole-body triglyceride levels, and provides important insight into the conserved mechanisms underlying sexual dimorphism in whole-body fat storage.

physiology↗

bioRxiv2021

A low sugar diet enhances Drosophila body size in males and females via sex-specific mechanisms

In Drosophila, changes to dietary protein elicit different body size responses between the sexes. Whether this sex difference in nutrient-dependent body size regulation extends to other nutrients, such as dietary sugar, remains unclear. Here, we show that reducing dietary sugar enhanced body size in Drosophila male and female larvae. Indeed, the largest body size was found in larvae reared in a diet without added sugar. Despite the equivalent body size effects of a low sugar diet between males and females, we detected sex-specific changes to the insulin/insulin-like growth factor (IIS) and target of rapamycin (TOR) signaling pathways. Further, we show that the metabolic changes observed in larvae reared on a low sugar diet differ between the sexes. Thus, despite identical phenotypic responses to dietary sugar in males and females, distinct changes to cell signaling pathways and whole-body metabolism were associated with the increased body size in each sex. This highlights the importance of including both sexes in all mechanistic studies on larval growth, as males and females may use different molecular and metabolic mechanisms to achieve similar phenotypic outcomes.

physiology↗

bioRxiv2020

Female-specific upregulation of insulin pathway activity mediates the sex difference in Drosophila body size plasticity

Nutrient-dependent body size plasticity differs between the sexes in most species, including mammals. Previous work in Drosophila showed that body size plasticity was higher in females, yet the mechanisms underlying the sex difference in body size plasticity remain unclear. Here, we discover that a protein-rich diet augments body size in females and not males because of a female-specific increase in activity of the conserved insulin/insulin-like growth factor signaling pathway (IIS). This increased IIS activity was triggered by a diet-induced increase in stunted, and required Drosophila insulin-like peptide 2, illuminating new sex-specific roles for these genes. Importantly, we show that sex determination gene transformer regulates the diet-induced increase in stunted and IIS activity, and mediates the sex difference in body size plasticity. This identifies one sex-specific mechanism underlying the nutrient-dependent regulation of IIS activity and body size plasticity, providing vital insight into conserved mechanisms that mediate sex differences in phenotypic plasticity.

physiology↗