Koji Sato

Bio: Koji Sato is an academic researcher from University of Tokyo. The author has contributed to research in topics: Olfactory receptor & Medicine. The author has an hindex of 19, co-authored 44 publications receiving 4195 citations. Previous affiliations of Koji Sato include University of Minnesota & Hokkaido University.

Insect olfactory receptors are heteromeric ligand-gated ion channels

Abstract: In many organisms, from worms to humans, olfactory cues are detected by large families of seven transmembrane-spanning receptors, which have until now been classified as G protein-coupled receptors. Insects, however, have evolved a surprisingly simple and efficient sense of smell in which the odorant receptors require a second component — the ion-channel-forming chaperone protein Or83b — for correct function. In the first of two related papers, Sato et al. show that these heteromeric receptors form ligand-gated cation channels that are not dependent on G protein-coupled second messengers, and speculate that other seven transmembrane-spanning proteins may show similar ion channel activity. Wicher et al. show that, in addition to direct channel activation, ligand binding to odorant receptors causes G protein-coupled channel activation. This work has implications for the search for insect odorant receptor inhibitors for possible use in controlling host seeking behaviour of disease carrying insects such as the mosquito. Olfactory cues are detected by large families of seven transmembrane-spanning receptors, which have until now been classified as G-protein-coupled receptors. In insects, these odorant receptors require a second protein (Or83b) for correct function. These heteromeric receptors form ligand-gated cation channels that are not dependent on G protein-coupled second messengers and it is speculated that seven other transmembrane-spanning proteins may show similar ion channel activity. In insects, each olfactory sensory neuron expresses between one and three ligand-binding members of the olfactory receptor (OR) gene family, along with the highly conserved and broadly expressed Or83b co-receptor1,2,3,4,5,6,7,8,9. The functional insect OR consists of a heteromeric complex of unknown stoichiometry but comprising at least one variable odorant-binding subunit and one constant Or83b family subunit10,11,12,13,14,15,16. Insect ORs lack homology to G-protein-coupled chemosensory receptors in vertebrates17 and possess a distinct seven-transmembrane topology with the amino terminus located intracellularly10,18. Here we provide evidence that heteromeric insect ORs comprise a new class of ligand-activated non-selective cation channels. Heterologous cells expressing silkmoth, fruitfly or mosquito heteromeric OR complexes showed extracellular Ca2+influx and cation-non-selective ion conductance on stimulation with odorant. Odour-evoked OR currents are independent of known G-protein-coupled second messenger pathways. The fast response kinetics and OR-subunit-dependent K+ ion selectivity of the insect OR complex support the hypothesis that the complex between OR and Or83b itself confers channel activity. Direct evidence for odorant-gated channels was obtained by outside-out patch-clamp recording of Xenopus oocyte and HEK293T cell membranes expressing insect OR complexes. The ligand-gated ion channel formed by an insect OR complex seems to be the basis for a unique strategy that insects have acquired to respond to the olfactory environment.

Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1.

Abstract: Adiponectin is an anti-diabetic adipokine. Its receptors possess a seven-transmembrane topology with the amino terminus located intracellularly, which is the opposite of G-protein-coupled receptors. Here we provide evidence that adiponectin induces extracellular Ca(2+) influx by adiponectin receptor 1 (AdipoR1), which was necessary for subsequent activation of Ca(2+)/calmodulin-dependent protein kinase kinase beta (CaMKKbeta), AMPK and SIRT1, increased expression and decreased acetylation of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), and increased mitochondria in myocytes. Moreover, muscle-specific disruption of AdipoR1 suppressed the adiponectin-mediated increase in intracellular Ca(2+) concentration, and decreased the activation of CaMKK, AMPK and SIRT1 by adiponectin. Suppression of AdipoR1 also resulted in decreased PGC-1alpha expression and deacetylation, decreased mitochondrial content and enzymes, decreased oxidative type I myofibres, and decreased oxidative stress-detoxifying enzymes in skeletal muscle, which were associated with insulin resistance and decreased exercise endurance. Decreased levels of adiponectin and AdipoR1 in obesity may have causal roles in mitochondrial dysfunction and insulin resistance seen in diabetes.

Metre-long cell-laden microfibres exhibit tissue morphologies and functions

Abstract: Artificial reconstruction of fibre-shaped cellular constructs could greatly contribute to tissue assembly in vitro. Here we show that, by using a microfluidic device with double-coaxial laminar flow, metre-long core-shell hydrogel microfibres encapsulating ECM proteins and differentiated cells or somatic stem cells can be fabricated, and that the microfibres reconstitute intrinsic morphologies and functions of living tissues. We also show that these functional fibres can be assembled, by weaving and reeling, into macroscopic cellular structures with various spatial patterns. Moreover, fibres encapsulating primary pancreatic islet cells and transplanted through a microcatheter into the subrenal capsular space of diabetic mice normalized blood glucose concentrations for about two weeks. These microfibres may find use as templates for the reconstruction of fibre-shaped functional tissues that mimic muscle fibres, blood vessels or nerve networks in vivo.

Sex-specific peptides from exocrine glands stimulate mouse vomeronasal sensory neurons

Abstract: The discovery that sex hormones can be secreted from the eyes is something new in the world of sexual communication. A male-specific peptide secreted from the extraorbital lachrymal gland is transferred to the female's pheromone-sensing organ during physical contact such as facial grooming. It stimulates specific pheromone receptor neurons and elicits an electrical response. The ‘male’ peptide is a member of a previously unrecognized large multigene family of secreted peptides. A female signal, yet to be identified, acts in a similar way, suggesting that these pheromones operate via specific courtship behaviour to ensure sex recognition and discrimination. In mammals, social and reproductive behaviours are modulated by pheromones, which are chemical signals that convey information about sex and strain1,2. The vomeronasal organ, located at the base of the nasal septum, is responsible for mediating pheromone information in mice3,4,5,6,7,8,9. Two classes of putative pheromone receptor gene families, V1R and V2R, are expressed by vomeronasal sensory neurons in mutually segregated epithelial zones of the vomeronasal organ10,11,12,13,14. Although numerous studies have suggested that pheromones originate from urine15,16,17,18, direct recordings of behaving mice have shown that neuronal firing in the vomeronasal system is modulated by physical contact with the facial area19. Here we identify a male-specific 7-kDa peptide secreted from the extraorbital lacrimal gland. This peptide, which we named exocrine gland-secreting peptide 1 (ESP1), is encoded by a gene from a previously unrecognized large family clustered in proximity to the class I major histocompatibility complex (MHC) region. ESP1 is secreted from the eyes and is transferred to the female vomeronasal organ, where it stimulates V2R-expressing vomeronasal sensory neurons and elicits an electrical response. Our results indicate that mice respond to sex-specific peptides released from exocrine glands through the vomeronasal system during direct contact.

The male mouse pheromone ESP1 enhances female sexual receptive behaviour through a specific vomeronasal receptor

Abstract: Various social behaviours in mice are regulated by chemical signals called pheromones that act through the vomeronasal system. Exocrine gland-secreting peptide 1 (ESP1) is a 7-kDa peptide that is released into male tear fluids and stimulates vomeronasal sensory neurons in female mice. Here, we describe the molecular and neural mechanisms that are involved in the decoding of ESP1 signals in the vomeronasal system, which leads to behavioural output in female mice. ESP1 is recognized by a specific vomeronasal receptor, V2Rp5, and the ligand-receptor interaction results in sex-specific signal transmission to the amygdaloid and hypothalamic nuclei via the accessory olfactory bulb. Consequently, ESP1 enhances female sexual receptive behaviour upon male mounting (lordosis), allowing successful copulation. In V2Rp5-deficient mice, ESP1 induces neither neural activation nor sexual behaviour. These findings show that ESP1 is a crucial male pheromone that regulates female reproductive behaviour through a specific receptor in the mouse vomeronasal system.

Adipokines in inflammation and metabolic disease

Abstract: The worldwide epidemic of obesity has brought considerable attention to research aimed at understanding the biology of adipocytes (fat cells) and the events occurring in adipose tissue (fat) and in the bodies of obese individuals. Accumulating evidence indicates that obesity causes chronic low-grade inflammation and that this contributes to systemic metabolic dysfunction that is associated with obesity-linked disorders. Adipose tissue functions as a key endocrine organ by releasing multiple bioactive substances, known as adipose-derived secreted factors or adipokines, that have pro-inflammatory or anti-inflammatory activities. Dysregulated production or secretion of these adipokines owing to adipose tissue dysfunction can contribute to the pathogenesis of obesity-linked complications. In this Review, we focus on the role of adipokines in inflammatory responses and discuss their potential as regulators of metabolic function.

The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD)

Abstract: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent and represents a growing challenge in terms of prevention and treatment. Despite its high prevalence, only a small minority of affected patients develops inflammation and subsequently fibrosis and chronic liver disease, while most of them only exhibit simple steatosis. In this context, the full understanding of the mechanisms underlying the development of NAFLD and non-alcoholic steatohepatitis (NASH) is of extreme importance; despite advances in this field, knowledge on the pathogenesis of NAFLD is still incomplete. The 'two-hit' hypothesis is now obsolete, as it is inadequate to explain the several molecular and metabolic changes that take place in NAFLD. The "multiple hit" hypothesis considers multiple insults acting together on genetically predisposed subjects to induce NAFLD and provides a more accurate explanation of NAFLD pathogenesis. Such hits include insulin resistance, hormones secreted from the adipose tissue, nutritional factors, gut microbiota and genetic and epigenetic factors. In this article, we review the factors that form this hypothesis.

Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. [Erratum: 2004 Sept. 23, v. 431, no. 7007, p. 485.]

Abstract: Elucidating the signalling mechanisms by which obesity leads to impaired insulin action is critical in the development of therapeutic strategies for the treatment of diabetes. Recently, mice deficient for S6 Kinase 1 (S6K1), an effector of the mammalian target of rapamycin (mTOR) that acts to integrate nutrient and insulin signals, were shown to be hypoinsulinaemic, glucose intolerant and have reduced β-cell mass. However, S6K1-deficient mice maintain normal glucose levels during fasting, suggesting hypersensitivity to insulin, raising the question of their metabolic fate as a function of age and diet. Here, we report that S6K1-deficient mice are protected against obesity owing to enhanced β-oxidation. However on a high fat diet, levels of glucose and free fatty acids still rise in S6K1-deficient mice, resulting in insulin receptor desensitization. Nevertheless, S6K1-deficient mice remain sensitive to insulin owing to the apparent loss of a negative feedback loop from S6K1 to insulin receptor substrate 1 (IRS1), which blunts S307 and S636/S639 phosphorylation; sites involved in insulin resistance. Moreover, wild-type mice on a high fat diet as well as K/K Ay and ob/ob (also known as Lep/Lep) micetwo genetic models of obesityhave markedly elevated S6K1 activity and, unlike S6K1-deficient mice, increased phosphorylation of IRS1 S307 and S636/S639. Thus under conditions of nutrient satiation S6K1 negatively regulates insulin signalling.

Odorant Reception in Insects: Roles of Receptors, Binding Proteins, and Degrading Enzymes

Abstract: Our knowledge of the molecular basis of odorant reception in insects has grown exponentially over the past decade. Odorant receptors (ORs) from moths, fruit flies, mosquitoes, and the honey bees have been deorphanized, odorant-degrading enzymes (ODEs) have been isolated, and the functions of odorant-binding proteins (OBPs) have been unveiled. OBPs contribute to the sensitivity of the olfactory system by transporting odorants through the sensillar lymph, but there are competing hypotheses on how they act at the end of the journey. A few ODEs that have been demonstrated to degrade odorants rapidly may act in signal inactivation alone or in combination with other molecular traps. Although ORs in Drosophila melanogaster respond to multiple odorants and seem to work in combinatorial code involving both periphery and antennal lobes, reception of sex pheromones by moth ORs suggests that their labeled lines rely heavily on selectivity at the periphery.