The melanocortin pathway and energy homeostasis: From discovery to obesity therapy.

BACKGROUND: Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in controlling mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variations influencing the population distribution of body weight. At the end of 2020, the U.S. Food and Drug Administration (FDA) approved setmelanotide, a melanocortin 4 receptor agonist, for use in individuals with severe obesity due to either pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency. SCOPE OF REVIEW: Herein, we chart the melanocortin pathway's history, explore its pharmacology, genetics, and physiology, and describe how a neuropeptidergic circuit became an important druggable obesity target. MAJOR CONCLUSIONS: Unravelling the genetics of the subset of severe obesity has revealed the importance of the melanocortin pathway in appetitive control; coupling this with studying the molecular pharmacology of compounds that bind melanocortin receptors has brought a new obesity drug to the market. This process provides a drug discovery template for complex disorders, which for setmelanotide took 25 years to transform from a single gene into an approved drug

Температурное поле в кристалле иттрий-алюминиевого граната при двухстадийном выращивании

Установлено существование оптимального значения теплопроводности, при котором достигается наиболее равномерное распределение модуля температурного градиента на фронте кристаллизации

Reducing GBA2 activity ameliorates neuropathology in niemann-pick type C mice

The enzyme glucocerebrosidase (GBA) hydrolyses glucosylceramide (GlcCer) in lysosomes. Markedly reduced GBA activity is associated with severe manifestations of Gaucher disease including neurological involvement. Mutations in the GBA gene have recently also been identified as major genetic risk factor for Parkinsonism. Disturbed metabolism of GlcCer may therefore play a role in neuropathology. Besides lysosomal GBA, cells also contain a non-lysosomal glucosylceramidase (GBA2). Given that the two β-glucosidases share substrates, we speculated that over-activity of GBA2 during severe GBA impairment might influence neuropathology. This hypothesis was studied in Niemann-Pick type C (Npc1-/-) mice showing secondary deficiency in GBA in various tissues. Here we report that GBA2 activity is indeed increased in the brain of Npc1-/- mice. We found that GBA2 is particularly abundant in Purkinje cells (PCs), one of the most affected neuronal populations in NPC disease. Inhibiting GBA2 in Npc1-/- mice with a brain-permeable low nanomolar inhibitor significantly improved motor coordination and extended lifespan in the absence of correction in cholesterol and ganglioside abnormalities. This trend was recapitulated, although not to full extent, by introducing a genetic loss of GBA2 in Npc1-/- mice. Our findings point to GBA2 activity as therapeutic target in NPC

A Specific Activity-Based Probe to Monitor Family GH59 Galactosylceramidase, the Enzyme Deficient in Krabbe Disease

Galactosylceramidase (GALC) is the lysosomal β-galactosidase responsible for the hydrolysis of galactosylceramide. Inherited deficiency in GALC causes Krabbe disease, a devastating neurological disorder characterized by accumulation of galactosylceramide and its deacylated counterpart, the toxic sphingoid base galactosylsphingosine (psychosine). We report the design and application of a fluorescently tagged activity-based probe (ABP) for the sensitive and specific labeling of active GALC molecules from various species. The probe consists of a β-galactopyranose-configured cyclophellitol-epoxide core, conferring specificity for GALC, equipped with a BODIPY fluorophore at C6 that allows visualization of active enzyme in cells and tissues. Detection of residual GALC in patient fibroblasts holds great promise for laboratory diagnosis of Krabbe disease. We further describe a procedure for in situ imaging of active GALC in murine brain by intra-cerebroventricular infusion of the ABP. In conclusion, this GALC-specific ABP should find broad applications in diagnosis, drug development, and evaluation of therapy for Krabbe disease

Dual role of striatal astrocytes in behavioral flexibility and metabolism in the context of obesity

Brain circuits involved in metabolic control and reward-associated behaviors are potent drivers of feeding behavior and are both dramatically altered in obesity, a multifactorial disease resulting from genetic and environmental factors. In both mice and human, exposure to calorie-dense food has been associated with increased astrocyte reactivity and pro-inflammatory response in the brain. Although our understanding of how astrocytes regulate brain circuits has recently flourish, whether and how striatal astrocytes contribute in regulating food-related behaviors and whole-body metabolism is still unknown. In this study, we show that exposure to enriched food leads to profound changes in neuronal activity and synchrony. Chemogenetic manipulation of astrocytes activity in the dorsal striatum was sufficient to restore the cognitive defect in flexible behaviors induced by obesity, while manipulation of astrocyte in the nucleus accumbens led to acute change in whole-body substrate utilization and energy expenditure. Altogether, this work reveals a yet unappreciated role for striatal astrocyte as a direct operator of reward-driven behavior and metabolic control

Evolving trends in the management of acute appendicitis during COVID-19 waves. The ACIE appy II study

Background: In 2020, ACIE Appy study showed that COVID-19 pandemic heavily affected the management of patients with acute appendicitis (AA) worldwide, with an increased rate of non-operative management (NOM) strategies and a trend toward open surgery due to concern of virus transmission by laparoscopy and controversial recommendations on this issue. The aim of this study was to survey again the same group of surgeons to assess if any difference in management attitudes of AA had occurred in the later stages of the outbreak. Methods: From August 15 to September 30, 2021, an online questionnaire was sent to all 709 participants of the ACIE Appy study. The questionnaire included questions on personal protective equipment (PPE), local policies and screening for SARS-CoV-2 infection, NOM, surgical approach and disease presentations in 2021. The results were compared with the results from the previous study. Results: A total of 476 answers were collected (response rate 67.1%). Screening policies were significatively improved with most patients screened regardless of symptoms (89.5% vs. 37.4%) with PCR and antigenic test as the preferred test (74.1% vs. 26.3%). More patients tested positive before surgery and commercial systems were the preferred ones to filter smoke plumes during laparoscopy. Laparoscopic appendicectomy was the first option in the treatment of AA, with a declined use of NOM. Conclusion: Management of AA has improved in the last waves of pandemic. Increased evidence regarding SARS-COV-2 infection along with a timely healthcare systems response has been translated into tailored attitudes and a better care for patients with AA worldwide

Proyecto, investigación e innovación en urbanismo, arquitectura y diseño industrial

Actas de congresoLas VII Jornadas de Investigación “Encuentro y Reflexión” y I Jornadas de Investigación de becarios y doctorandos. Proyecto, investigación e innovación en Urbanismo, Arquitectura y Diseño Industrial se centraron en cuatro ejes: el proyecto; la dimensión tecnológica y la gestión; la dimensión social y cultural y la enseñanza en Arquitectura, Urbanismo y Diseño Industrial, sustentados en las líneas prioritarias de investigación definidas epistemológicamente en el Consejo Asesor de Ciencia y Tecnología de esta Universidad Nacional de Córdoba. Con el objetivo de afianzar continuidad, formación y transferencia de métodos, metodología y recursos se incorporó becarios y doctorandos de los Institutos de investigación. La Comisión Honoraria la integraron las tres Secretarias de Investigación de la Facultad, arquitectas Marta Polo, quien fundó y María del Carmen Franchello y Nora Gutiérrez Crespo quienes continuaron la tradición de la buena práctica del debate en la cotidianeidad de la propia Facultad. Los textos que conforman las VII Jornadas son los avances y resultados de las investigaciones realizadas en el bienio 2016-2018.Fil: Novello, María Alejandra. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; ArgentinaFil: Repiso, Luciana. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; ArgentinaFil: Mir, Guillermo. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; ArgentinaFil: Brizuela, Natalia. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; ArgentinaFil: Herrera, Fernanda. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; ArgentinaFil: Períes, Lucas. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; ArgentinaFil: Romo, Claudia. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; ArgentinaFil: Gordillo, Natalia. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; ArgentinaFil: Andrade, Elena Beatriz. Universidad Nacional de Córdoba. Facultad de Arquitectura, Urbanismo y Diseño; Argentin

The Arcuate Nucleus: A Site of Fast Negative Feedback for Corticosterone Secretion in Male Rats

Variations in circulating corticosterone (Cort) are driven by the paraventricular nucleus of the hypothalamus (PVN), mainly via the sympathetic autonomic nervous system (ANS) directly stimulating Cort release from the adrenal gland and via corticotropin-releasing hormone targeting the adenohypophysis to release adrenocorticotropic hormone (ACTH). Cort feeds back through glucocorticoid receptors (GRs). Here we show in male Wistar rats that PVN neurons projecting to the adrenal gland do not express GRs, leaving the question of how the ANS in the PVN gets information about circulating Cort levels to control the adrenal. Since the arcuate nucleus (ARC) shows a less restrictive blood-brain barrier, expresses GRs, and projects to the PVN, we investigated whether the ARC can detect and produce fast adjustments of circulating Cort. In low Cort conditions (morning), local microdialysis in the ARC with type I GR antagonist produced a fast and sustained increase of Cort. This was not observed with a type II antagonist. At the circadian peak levels of Cort (afternoon), a type II GR antagonist, but not a type I antagonist, increased Cort levels but not ACTH levels. Antagonist infusions in the PVN did not modify circulating Cort levels, demonstrating the specificity of the ARC to give Cort negative feedback. Furthermore, type I and II GR agonists in the ARC prevented the increase of Cort after stress, demonstrating the role of the ARC as sensor to modulate Cort release. Our findings show that the ARC may be essential to sense blood levels of Cort and adapt Cort secretion depending on such conditions as stress or time of da

Gaucher disease and Fabry disease: New markers and insights in pathophysiology for two distinct glycosphingolipidoses

Gaucher disease (GD) and Fabry disease (FD) are two relatively common inherited glycosphingolipidoses caused by deficiencies in the lysosomal glycosidases glucocerebrosidase and alpha-galactosidase A, respectively. For both diseases enzyme supplementation is presently used as therapy. Cells and tissues of GD and FD patients are uniformly deficient in enzyme activity, but the two diseases markedly differ in cell types showing lysosomal accumulation of the glycosphingolipid substrates glucosylceramide and globotriaosylceramide, respectively. The clinical manifestation of Gaucher disease and Fabry disease is consequently entirely different and the response to enzyme therapy is only impressive in the case of GD patients. This review compares both glycosphingolipid storage disorders with respect to similarities and differences. Presented is an update on insights regarding pathophysiological mechanisms as well as recently available biochemical markers and diagnostic tools for both disorders. Special attention is paid to sphingoid bases of the primary storage lipids in both diseases. The value of elevated glucosylsphingosine in Gaucher disease and globotriaosylsphingosine in Fabry disease for diagnosis and monitoring of disease is discussed as well as the possible contribution of the sphingoid bases to (patho)physiology. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology. (C) 2013 Elsevier B.V. All rights reserve

Tanycytes control hypothalamic liraglutide uptake and its anti-obesity actions

International audienceLiraglutide, an anti-diabetic drug and agonist of the glucagon-like peptide one receptor (GLP1R), has recentlybeen approved to treat obesity in individuals with or without type 2 diabetes. Despite its extensive metabolicbenefits, the mechanism and site of action of liraglutide remain unclear. Here, we demonstrate that liraglutideis shuttled to target cells in the mouse hypothalamus by specialized ependymoglial cells called tanycytes,bypassing the blood-brain barrier. Selectively silencing GLP1R in tanycytes or inhibiting tanycytic transcytosisby botulinum neurotoxin expression not only hampers liraglutide transport into the brain and its activationof target hypothalamic neurons, but also blocks its anti-obesity effects on food intake, body weight and fatmass, and fatty acid oxidation. Collectively, these striking data indicate that the liraglutide-induced activationof hypothalamic neurons and its downstream metabolic effects are mediated by its tanycytic transport intothe mediobasal hypothalamus, strengthening the notion of tanycytes as key regulators of metabolic homeostasis