ObjectivePro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1–5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency.MethodsWe studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial. We annotated the functional status of 369 published MC4R variants.ResultsIn cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants. Wild-type rodents appear more sensitive to Setmelanotide when compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond. In a 28-day Phase 1b clinical trial, Setmelanotide led to weight loss in obese MC4R variant carriers. Patients with POMC defects upstream of MC4R show significantly more weight loss with Setmelanotide than MC4R deficient patients or obese controls.ConclusionsSetmelanotide led to weight loss in obese people with MC4R deficiency; however, further studies are justified to establish whether Setmelanotide can elicit clinically meaningful weight loss in a subset of the MC4R deficient obese population.

Ecomorphological patterns of the fish assemblage from the upper Paraná River floodplain, Brazil, were described and evaluated according to trophic (guilds), spatial (habitats) and phylogenetic (taxonomic distances) structures. The samples were obtained through the Long Term Research Project (LTER-CNPq/UEM/NUPELIA) in August and October 2001. Thirty-five species were analyzed from thirty-one morphological variables. Strong significant correlations (Mantel test) between morphology and trophic guilds and between morphology and taxonomy were found, while morphology and habitat revealed a weak correlation. However, the partial Mantel test showed that the correlations between morphology and trophic guilds persist even when the effect of taxonomy is discounted. The ecomorphological pattern shown by the Principal Component Analysis separated species according to locomotion structures used in feeding. At one extreme there are the piscivores and insectivores that exploit lentic habitats and have compressed bodies and well developed anal fins, while at the other there are detritivores and invertivores that exploit lotic and semi-lotic habitats and have depressed bodies and well developed pectoral, pelvic and caudal fins. Canonical Discriminant Analysis using ecomorphological variables successfully predicted 94.5% of the trophic guild ecomorphotypes, but only 57.1% of the habitat ecomorphotypes. These data indicate that the fish assemblage of the upper Paraná River floodplain is structured ecomorphologically mainly according to trophic structure rather than habitat.Este trabalho objetivou descrever e avaliar os padrões ecomorfológicos da assembleia de peixes da planície de inundação do alto rio Paraná, Brasil, analisando os efeitos das estruturas trófica (guildas), espacial (tipos de habitats) e filogenética (distância taxonômica). Trinta e cinco espécies foram analisadas a partir de 31 variáveis morfológicas obtidas de espécimes coletados em agosto e outubro de 2001 no âmbito do Projeto Ecológico de Longa Duração (PELD-CNPq/UEM/NUPELIA). O teste de Mantel revelou que há correlação significativa das distâncias morfológicas com guildas tróficas e distâncias taxonômicas, enquanto com os tipos de habitats a correlação se mostrou fraca. Contudo, o teste de Mantel parcial demonstrou que a correlação da morfologia com as guildas tróficas independe da filogenia. O padrão de diversificação ecomorfológica apresentado pela Análise de Componentes Principais revelou um gradiente ecomorfológico relacionado à locomoção associada à ecologia trófica. Em um extremo estão espécies de piscívoros e insetívoros que exploram preferencialmente habitats lênticos com corpos comprimidos e nadadeiras anais desenvolvidas, enquanto no outro extremo estão os detritívoros e invertívoros que exploram preferencialmente habitats lóticos e semi-lóticos e apresentam corpos deprimidos e nadadeiras peitorais, pélvicas e caudais desenvolvidas. A Análise Discriminante Canônica realizada com os índices ecomorfológicos previu com sucesso 94,5% dos ecomorfotipos rel...

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SummaryHypothalamic melanocortin neurons play a pivotal role in weight regulation. Here, we examined the contribution of Semaphorin 3 (SEMA3) signaling to the development of these circuits. In genetic studies, we found 40 rare variants in SEMA3A-G and their receptors (PLXNA1-4; NRP1-2) in 573 severely obese individuals; variants disrupted secretion and/or signaling through multiple molecular mechanisms. Rare variants in this set of genes were significantly enriched in 982 severely obese cases compared to 4,449 controls. In a zebrafish mutagenesis screen, deletion of 7 genes in this pathway led to increased somatic growth and/or adiposity demonstrating that disruption of Semaphorin 3 signaling perturbs energy homeostasis. In mice, deletion of the Neuropilin-2 receptor in Pro-opiomelanocortin neurons disrupted their projections from the arcuate to the paraventricular nucleus, reduced energy expenditure, and caused weight gain. Cumulatively, these studies demonstrate that SEMA3-mediated signaling drives the development of hypothalamic melanocortin circuits involved in energy homeostasis.

This article evaluates the effect of hot air drying on the physicochemical characteristics, color, concentration of bioactive compounds and antioxidant activity of agroindustrial residue of acerola, which was hot air dried under different conditions of temperature (60, 70 and 80C) and air velocity (4, 5 and 6 m/s), taking up the residue in natura as the control group. The experimental dimensionless moisture content as a function of drying time of acerola residue is also presented and discussed. The retention values of total phenolic (26-31%), carotenoids (50-61%), anthocyanins (23-36%), proanthocyanidins (21%), ascorbic acid (40-70%) and the antioxidant activity measured by 2,2-diphenyl-1-picrylhydrazyl method (20%) were calculated and discussed. Considering the concentration of bioactive compounds detected in the final product, as well as the microbiological stability achieved by the substantial moisture reduction, it can be concluded that the dried acerola residue is an important source of bioactive compounds with appropriate characteristics to be utilized as a health-relevant food ingredient. PRACTICAL APPLICATIONSBrazil is one of the largest agricultural producers in the world. In recent years, the processing industry has developed and as a consequence, the generation of residues has also increased. The search for answers to this technological challenge was the motivation of this research, which evaluated the drying process as means for obtaining a natural functional powder from acerola residue. The data shown would provide the scientific rationale for a better exploitation of this tropical fruit residue.

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