Biology subjects

Koyama, T.

Publications and source records attributed to Koyama, T..

24 records · Page 2Linked to original sources

bioRxiv2020

A nutrient-responsive hormonal circuit controls energy and water homeostasis in Drosophila

The regulation of systemic energy balance involves the coordinated activity of specialized organs, which control nutrient uptake, utilization and storage to promote metabolic homeostasis during environmental challenges. The humoral signals that drive such homeostatic programs are largely unidentified. Here we show that three pairs of central neurons in adult Drosophila respond to internal water and nutrient availability by releasing Capa-1 and -2 hormones that signal through the Capa receptor (CapaR) to exert systemic metabolic control. Loss of Capa/CapaR signaling leads to intestinal hypomotility and impaired nutrient absorption, which gradually deplete internal nutrient stores and reduce organismal lifespan. Conversely, hyperactivation of the Capa circuitry stimulates fluid and waste excretion. Furthermore, we demonstrate that Capa/CapaR regulates energy metabolism by modulating the release of the glucagon-like adipokinetic hormone, which governs lipolysis in adipose tissue to stabilize circulating energy levels. Altogether, our results uncover a novel inter-tissue program that plays a central role in coordinating post-prandial responses that are essential to maintain adult viability.

physiology↗

bioRxiv2020

TGF-beta/Activin ligand Myoglianin couples muscle growth to the initiation of metamorphosis

Although the mechanisms that control growth are now well understood, the mechanism by which animals assess their body size remains one of the great puzzles in biology. The final larval instar of holometabolous insects, after which growth stops and metamorphosis begins, is specified by a threshold size. We investigated the mechanism of threshold size assessment in the tobacco hornworm, Manduca sexta. The threshold size was found to change depending on the amount of exposure to poor nutrient conditions whereas hypoxia treatment consistently led to a lower threshold size. Under these various conditions, the mass of the muscles plus integuments was correlated with the threshold size. Furthermore, the expression of myoglianin (myo) increased at the threshold size in both M. sexta and Tribolium castaneum. Knockdown of myo in T. castaneum led to larvae that underwent supernumerary larval molts and stayed in the larval stage permanently even after passing the threshold size. We propose that increasing levels of Myo produced by the growing tissues allow larvae to assess their body size and trigger metamorphosis at the threshold size.

developmental biology↗

bioRxiv2019

Population-specific and transethnic genome-wide analyses reveal distinct and shared genetic risks of coronary artery disease

To elucidate the genetics of coronary artery disease (CAD) in the Japanese population, we conducted a large-scale genome-wide association study (GWAS) of 168,228 Japanese (25,892 cases and 142,336 controls) with genotype imputation using a newly developed reference panel of Japanese haplotypes including 1,782 CAD cases and 3,148 controls. We detected 9 novel disease-susceptibility loci and Japanese-specific rare variants contributing to disease severity and increased cardiovascular mortality. We then conducted a transethnic meta-analysis and discovered 37 additional novel loci. Using the result of the meta-analysis, we derived a polygenic risk score (PRS) for CAD, which outperformed those derived from either Japanese or European GWAS. The PRS prioritized risk factors among various clinical parameters and segregated individuals with increased risk of long-term cardiovascular mortality. Our data improves clinical characterization of CAD genetics and suggests the utility of transethnic meta-analysis for PRS derivation in non-European populations.

genetics↗

bioRxiv2019

Analysis of genes within the schizophrenia-linked 22q11.2 deletion identifies interaction of night owl/LZTR1 and NF1 in GABAergic sleep control

The human 22q11.2 chromosomal deletion is one of the strongest identified genetic risk factors for schizophrenia. Although the deletion spans a number of genes, the contribution of each of these to the 22q11.2 deletion syndrome (DS) is not known. To investigate the effect of individual genes within this interval on the pathophysiology associated with the deletion, we analyzed their role in sleep, a behavior affected in virtually all psychiatric disorders, including the 22q11.2 DS. We identified the gene LZTR1 (night owl, nowl) as a regulator of sleep in Drosophila. Neuronal loss of nowl causes short and fragmented sleep, especially during the night. In humans, LZTR1 has been associated with Ras-dependent neurological diseases also caused by Neurofibromin-1 (Nf1) deficiency. We show that Nf1 loss leads to a night-time sleep phenotype nearly identical to that of nowl loss, and that nowl negatively regulates Ras and interacts with Nf1 in sleep regulation. We also show that nowl is required for metabolic homeostasis, suggesting that LZTR1 may contribute to the genetic susceptibility to obesity associated with the 22q11.2 DS. Furthermore, knockdown of nowl or Nf1 in GABA-responsive sleep-promoting neurons elicits the sleep-fragmentation phenotype, and this defect can be rescued by increased GABAA receptor signaling, indicating that Nowl promotes sleep by decreasing the excitability of GABA-responsive wake-driving neurons. Our results suggest that nowl/LZTR1 may be a conserved regulator of GABA signaling and sleep that contributes to the 22q11.2 DS.

animal behavior and cognition↗

bioRxiv2018

Risk of hypoglycemia induced by pivalate-conjugated antibiotics in young children: a population-based retrospective study in Japan

Infection is a common cause for an outpatient visit for young children. Pivalate-conjugated antibiotics (PCAs) are often used for these patients in Japan. However, a few case reports have shown that PCAs can provoke hypoglycemia in children, but no larger study has shown that PCAs increase the risk of hypoglycemia. The current study was performed as a retrospective review of children aged 1 month to 5 years old with at least once prescription of PCAs or other beta-lactam antibiotics from January 2011 to December 2013, using a medical and pharmacy claims database. Hypoglycemia was defined based on the International Statistical Classification of Diseases and Related Health Problems 10th Revision code or prescription of 10% or 20% glucose injection, and the incidence of hypoglycemic events was investigated. Logistic regression analysis was performed to examine the risk of hypoglycemia with PCAs compared with control antibiotics. The study cohort contained 179,594 eligible patients (male: 52.2%, mean age: 3.2 years). The numbers of prescriptions were 454,153 and 417,287 for PCAs and control antibiotics, respectively. Multivariate analysis showed that PCAs were associated with hypoglycemia (adjusted OR 1.18, 95% CI 1.12 to 1.24, P < 0.01), and the risk of hypoglycemia was also significantly increased with use of PCAs for [≤]7 days (adjusted OR 1.17, 95% CI 1.11 to 1.24, P < 0.01). These results suggest that prescription of PCAs to young children should be avoided, even for a short time period.

pharmacology and toxicology↗

bioRxiv2018

Torso-like is a component of the hemolymph and regulates the insulin signalling pathway in Drosophila

In Drosophila key developmental transitions are governed by the steroid hormone ecdysone. A number of neuropeptide-activated signalling pathways control ecdysone production in response to environmental signals, including the insulin signalling pathway, which regulates ecdysone production in response to nutrition. Here, we find that the Membrane Attack Complex/Perforin-like protein Torso-like, best characterised for its role in activating the Torso receptor tyrosine kinase in early embryo patterning, also regulates the insulin signalling pathway in Drosophila. We previously reported that the small body size and developmental delay phenotypes of torso-like null mutants resemble those observed when insulin signalling is reduced. Here we report that, in addition to growth defects, torso-like mutants also display metabolic and nutritional plasticity phenotypes characteristic of mutants with impaired insulin signalling. We further find that in the absence of torso-like the expression of insulin-like peptides is increased, as is their accumulation in the insulin-producing cells. Finally, we show that Torso-like is a component of the hemolymph and that it is required in the prothoracic gland to control developmental timing and body size. Taken together, our data suggest that the secretion of Torso-like from the prothoracic gland influences the activity of insulin signalling throughout the body in Drosophila.\n\nARTICLE SUMMARYIn many animals distinct developmental transitions are crucial for the coordinated progression from the juvenile stage to adulthood. In Drosophila, the transition from an immature larva into a reproductively mature adult is controlled by the steroid hormone ecdysone. Several neuropeptide-activated signalling pathways, including the insulin signalling pathway, regulate ecdysone production in response to environmental cues. Here we find that the perforin-like protein Torso-like regulates the insulin signalling pathway. We show that Torso-like is secreted into circulation where it acts to influence insulin-like peptide activity, revealing a novel mechanism for the regulation of insulin signalling in Drosophila.

developmental biology↗