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

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

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

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

Investigations on therapeutic glucocerebrosidases through paired detection with fluorescent activity-based probes

Deficiency of glucocerebrosidase (GBA) causes Gaucher disease (GD). In the common non-neuronopathic GD type I variant, glucosylceramide accumulates primarily in the lysosomes of visceral macrophages. Supplementing storage cells with lacking enzyme is accomplished via chronic intravenous administration of recombinant GBA containing mannose-terminated N-linked glycans, mediating the selective uptake by macrophages expressing mannose-binding lectin(s). Two recombinant GBA preparations with distinct N-linked glycans are registered in Europe for treatment of type I GD: imiglucerase (Genzyme), contains predominantly Man(3) glycans, and velaglucerase (Shire PLC) Man(9) glycans. Activity-based probes (ABPs) enable fluorescent labeling of recombinant GBA preparations through their covalent attachment to the catalytic nucleophile E340 of GBA. We comparatively studied binding and uptake of ABP-labeled imiglucerase and velaglucerase in isolated dendritic cells, cultured human macrophages and living mice, through simultaneous detection of different GBAs by paired measurements. Uptake of ABP-labeled rGBAs by dendritic cells was comparable, as well as the bio-distribution following equimolar intravenous administration to mice. ABP-labeled rGBAs were recovered largely in liver, white-blood cells, bone marrow and spleen. Lungs, brain and skin, affected tissues in severe GD types II and III, were only poorly supplemented. Small, but significant differences were noted in binding and uptake of rGBAs in cultured human macrophages, in the absence and presence of mannan. Mannan-competed binding and uptake were largest for velaglucerase, when determined with single enzymes or as equimolar mixtures of both enzymes. Vice versa, imiglucerase showed more prominent binding and uptake not competed by mannan. Uptake of recombinant GBAs by cultured macrophages seems to involve multiple receptors, including several mannose-binding lectins. Differences among cells from different donors (n = 12) were noted, but the same trends were always observed. Our study suggests that further insight in targeting and efficacy of enzyme therapy of individual Gaucher patients could be obtained by the use of recombinant GBA, trace-labeled with an ABP, preferably equipped with an infrared fluorophore or other reporter tag suitable for in vivo imagin

Binding of ABP-labeled imiglucerase to macrophages.

<p>(<b>a</b>) Time-dependent binding of green β-epoxide ABP <b>5</b>-labeled imiglucerase to macrophages at 18°C. (<b>b</b>) Dose dependence of binding of green β-epoxide ABP <b>5</b>-labeled imiglucerase to macrophages at 18°C. (<b>c</b>) Binding of mixtures of green ABP <b>5</b>− and red ABP <b>6</b>-labeled imiglucerase. (<b>d</b>) Quantification of <b>c</b>: cell-bound green ABP <b>5</b>-imiglucerase at 18°C related to input (<i>green closed square</i>); cell-bound red ABP <b>6</b>-imiglucerase at 18°C related to input (<i>red closed circle</i>). Data are average of duplicate experiments, ± SD. Effect of mannan on binding of ABP-labeled rGBAs. (<b>e</b>) Binding of 10−2,500 nM imiglucerase and velaglucerase at 18°C in the presence and absence of mannan (10 μg μL⁻¹) shown for human monocyte-derived macrophages from one random donor (<i>Donor III</i>). From <i>top</i> to <i>bottom</i>: unlabeled (<i>apo</i>) imiglucerase post-labeled with green ABP <b>5</b>; <i>apo</i> velaglucerase post-labeled with red ABP <b>6</b>; pre-labeled green ABP <b>5</b> imiglucerase and pre-labeled red ABP <b>6</b>-velaglucerase. Fluorescence was calibrated with 50 fmol equimolar ABP <b>5</b>− and <b>6</b>-labeled imi present on each SDS-PAGE gel (<i>asterisk</i>). (<b>f</b>) Quantification of <b>e</b>; see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0170268#pone.0170268.s003" target="_blank">S3 Fig</a> for binding data of <i>n</i> = 12 donors. (<b>f</b>) Binding of equimolar 10−2,500 nM imiglucerase and velaglucerase at 18°C in the presence and absence of mannan (10 μg μL⁻¹) shown for human monocyte-derived macrophages from one donor with green ABP <b>5</b>-labeled imiglucerase and red ABP <b>6</b>-labeled velaglucerase. Fluorescence was calibrated with 50 fmol equimolar ABP <b>5</b>− and <b>6</b>-labeled imi present on each SDS-PAGE gel (<i>asterisk</i>). (<b>h</b>) Quantification of <b>g</b>; see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0170268#pone.0170268.s004" target="_blank">S4 Fig</a> for binding data of <i>n</i> = 12 donors.</p

Binding parameters.

<p>Binding parameters.</p

Uptake of ABP-labeled rGBAs by dendritic cells.

<p>(<b>a</b>) ABP <b>5</b>− and <b>6</b>-labeled imiglucerase and velaglucerase. (<b>b</b>) Arbitrary units of fluorescence (AU) quantified per fmol ABP-labeling of imiglucerase (<i>open columns</i>) and velaglucerase (<i>closed columns</i>). (<b>c</b>) CSLM micrographs of fixed murine bone marrow-derived immature dendritic cells after 30 min uptake of green ABP <b>5</b>-labeled imi and red ABP <b>6</b>-labeled vela in absence (<i>top row</i>) and presence of 1 μg/μL mannan (<i>bottom row</i>). Nuclei in blue (Draq5 staining). Micrographs were merged with bright-field microscopic image. Scale-bar represents 25 μm. (<b>d</b>) Uptake of equimolar mixture of green ABP <b>5</b>-labeled imi and red ABP <b>6</b>-labeled vela without and with 1 μg/μL mannan (<i>left</i> and <i>right column</i>, respectively), analyzed when fixed. Equal green and red fluorescence yields yellow overlay. Scale-bar represents 25 μm. (<b>e</b>) Dynamic endocytosis of equimolar mixture of ABP <b>5</b>-labeled imi and ABP <b>6</b>-labeled vela as registered in living cells (<i>left column</i>). Arrows show shift in red ABP <b>6</b> and green ABP <b>5</b>-labeled rGBA visualized at different time-point. <i>Right column</i>: identical experiment but with fixed cells prior to fluorescence acquisition. Asterisk depicts nucleus, scale-bar represents 7.5 μm. (<b>f</b>) Dynamic uptake of ABP-labeled rGBA, visualized by primary 75-minute pulse of red ABP <b>6</b>-labeled imi followed by washing and secondary 75-minute pulse of green ABP <b>5</b>-labeled imi. Asterisk depicts nucleus, scale-bar represents 25 μm.</p