Role of Hypothalamic Melanocortin System in Adaptation of Food Intake to Food Protein Increase in Mice

The hypothalamic melanocortin system—the melanocortin receptor of type 4 (MC4R) and its ligands: α-melanin-stimulating hormone (α-MSH, agonist, inducing hypophagia), and agouti-related protein (AgRP, antagonist, inducing hyperphagia)—is considered to play a central role in the control of food intake. We tested its implication in the mediation of the hunger-curbing effects of protein-enriched diets (PED) in mice. Whereas there was a 20% decrease in food intake in mice fed on the PED, compared to mice fed on an isocaloric starch-enriched diet, there was a paradoxical decrease in expression of the hypothalamic proopiomelanocortin gene, precursor of α-MSH, and increase in expression of the gene encoding AgRP. The hypophagia effect of PED took place in mice with invalidation of either MC4R or POMC, and was even strengthened in mice with ablation of the AgRP-expressing neurons. These data strongly suggest that the hypothalamic melanocortin system does not mediate the hunger-curbing effects induced by changes in the macronutrient composition of food. Rather, the role of this system might be to defend the body against the variations in food intake generated by the nutritional environment

Ghrelin treatment induces rapid and delayed increments of food intake : A heuristic model to explain ghrelin's orexigenic effects

Ghrelin is a stomach-derived peptide hormone with salient roles in the regulation of energy balance and metabolism. Notably, ghrelin is recognized as the most powerful known circulating orexigenic hormone. Here, we systematically investigated the effects of ghrelin on energy homeostasis and found that ghrelin primarily induces a biphasic effect on food intake that has indirect consequences on energy expenditure and nutrient partitioning. We also found that ghrelin-induced biphasic effect on food intake requires the integrity of Agouti-related peptide/neuropeptide Y-producing neurons of the hypothalamic arcuate nucleus, which seem to display a long-lasting activation after a single systemic injection of ghrelin. Finally, we found that different autonomic, hormonal and metabolic satiation signals transiently counteract ghrelin-induced food intake. Based on our observations, we propose a heuristic model to describe how the orexigenic effect of ghrelin and the anorectic food intake-induced rebound sculpt a timely constrain feeding response to ghrelin.Instituto Multidisciplinario de Biología Celula

Insights From Liver-Humanized Mice on Cholesterol Lipoprotein Metabolism and LXR-Agonist Pharmacodynamics in Humans

Background and Aims Genetically modified mice have been used extensively to study human disease. However, the data gained are not always translatable to humans because of major species differences. Liver-humanized mice (LHM) are considered a promising model to study human hepatic and systemic metabolism. Therefore, we aimed to further explore their lipoprotein metabolism and to characterize key hepatic species-related, physiological differences. Approach and Results Fah(-/-), Rag2(-/-), and Il2rg(-/-) knockout mice on the nonobese diabetic (FRGN) background were repopulated with primary human hepatocytes from different donors. Cholesterol lipoprotein profiles of LHM showed a human-like pattern, characterized by a high ratio of low-density lipoprotein to high-density lipoprotein, and dependency on the human donor. This pattern was determined by a higher level of apolipoprotein B100 in circulation, as a result of lower hepatic mRNA editing and low-density lipoprotein receptor expression, and higher levels of circulating proprotein convertase subtilisin/kexin type 9. As a consequence, LHM lipoproteins bind to human aortic proteoglycans in a pattern similar to human lipoproteins. Unexpectedly, cholesteryl ester transfer protein was not required to determine the human-like cholesterol lipoprotein profile. Moreover, LHM treated with GW3965 mimicked the negative lipid outcomes of the first human trial of liver X receptor stimulation (i.e., a dramatic increase of cholesterol and triglycerides in circulation). Innovatively, LHM allowed the characterization of these effects at a molecular level. Conclusions LHM represent an interesting translatable model of human hepatic and lipoprotein metabolism. Because several metabolic parameters displayed donor dependency, LHM may also be used in studies for personalized medicine.Peer reviewe

PRODUCCIÓN CIENTÍFICA: GÉNEROS Y TRANSVERSALIDADES

La propuesta del taller fue dividirlo en cuatro ejes, utilizando distintas preguntas cada una como motivadoras del debate, del intercambio y la construcción de saberes. Cada dos ejes se abre un espacio para preguntas y comentarios. Por otro lado, se invita a los presentes a completar una encuesta por Google forms como actividad inaugural a fin de conocer mejor sobre sus experiencias y trayectorias vinculadas a géneros y transversalidades, los resultados se comparten al finalizar el encuentro. 1º Eje: ¿Cómo aparece la pregunta del género y la diversidad en sus investigaciones? ¿De qué manera la incorporaron? La pregunta del género y la diversidad aparece como una realidad social que urge poner de relevancia en el modelo de producción de conocimiento científico, mientras que su incorporación significó un compromiso fundamentalmente político de ubicarla como categoría que permita la construcción de una ciencia diversa y transversalizada. Se plantea, ante las distintas resistencias que surgen frente a la implementación de la perspectiva de género, la necesidad de una transformación cultural para lograr un trabajo transversal en las facultades, en la investigación y la ciencia, así como la de sumar esta perspectiva como una mirada más desde la cual observar las distintas realidades. 2º Eje: ¿Qué estrategias y experiencias se generan ante las resistencias a la incorporación de la perspectiva de género (diversidad o interseccionalidad)? El rol del estudio y la formación feminista como estrategias ante las resistencias a la incorporación de la perspectiva de género. Además de la relevancia de la participación desde procesos de investigación, del debate y del repensar las formas de comunicar. Surgen varias preguntas para invitar a reflexionar sobre nuestras prácticas y nuestros trabajos de investigación, entre ellas: ¿Alcanza sólo pensar a las mujeres como objeto de estudio? ¿Es necesario que la categoría de género sea la principal para que se convierta en una perspectiva en nuestro trabajo de investigación? Se recuperan distintas situaciones, la necesidad de que se incorporen estos temas en función de una militancia académica y, en términos institucionales, la premura de incorporar seminarios y materias con perspectiva de género y dar lugar al debate a fin de visibilizar la problemática. 3º Eje: ¿Cuáles son los atravesamientos del género en sus prácticas cotidianas e institucionales de investigación? Urge la interseccionalidad, una mirada que suponga ampliar los feminismos hacia la justicia social. Recuperar los espacios colectivos, a fin de que las palabras circulen, y que con ellas se desarmen las jerarquías de poder. Poner en valor el conocimiento situado, socializar los recursos para la enseñanza y la investigación. Así como incorporar la literatura como herramienta para innovar en la enseñanza de textos más academicistas. Se debe transversalizar lo cotidiano, la perspectiva de género debe atravesar las fronteras de la disciplina, de lo académico, de las instituciones, de la vida. Hay que ocupar espacios, fomentar actividades, motivadas en la transformación. 4º Eje: ¿Cómo se reconfiguró el trabajo de investigación, tanto a nivel individual como colectivo, en razón del ASPO (ahora DISPO)? Se presentan miradas diversas de la situación. Se recoge la posibilidad de fortalecer las alianzas, de interrelacionarnos, de encontrarnos en espacios de conversatorios al acortarse las distancias geográficas por lo virtual. Sin embargo, no se pierde de vista la injusta distribución de recursos, entendida desde dos términos. Por un lado, por la falta de delimitación clara de los lugares de trabajo, que principalmente afecta a las mujeres, al no existir límite respecto del cuidado de los demás. Y por el otro, la imposibilidad material de acceso a bibliotecas para llevar adelante la investigación o el estudio, de acceso a internet, a dispositivos electrónicos, etc. Finalmente se presentan los resultados de la encuesta y se abre un espacio para las preguntas y comentarios. Se pregunta a los talleristas acerca de su opinión respecto a la posible compatibilidad y dificultades (o no) de la maternidad y la ciencia. Es planteada la importancia de los respaldos, tanto afectivos como institucionales y laborales durante la maternidad. En este sentido, la construcción de redes de contención laboral y de compañerismo en los diversos espacios compartidos. Se agrega la necesidad de modificar las conductas en nuestras relaciones en cargos de dirección, dado que el cambio no solo viene por interpelar a las instituciones (las que también se ven interpeladas). Además, se revela la urgencia por la implementación de las licencias por paternidad, y de políticas públicas que otorguen mecanismos para que el tiempo de las licencias de maternidad no signifiquen un comienzo desde cero, un reinicio que requiera de un gran esfuerzo para retomar el trabajo de investigación. Como variable para reflexionar se instalan las problemáticas de las familias monoparentales. Por último, surge la pregunta acerca de cuáles son los desafíos de la interseccionalidad en el ámbito de las políticas públicas. En términos de desafíos existe mucho por construir, sin embargo, hay movimientos de importantes magnitudes. Se están gestando grandes transformaciones sociales, y las instituciones públicas se están adaptando, solicitan recomendaciones, opiniones, por ejemplo, a las universidades. Se concluye que la perspectiva de género nos invita a un largo proceso de repensarnos y reconstruirnos, un proceso signado por resistencias, tanto en lo personal, en lo cotidiano como en lo académico. Sin embargo, la transversalización de la cuestión de género en los distintos espacios abre el camino a una transformación social y cultural, y en ello, a la construcción de una ciencia diversa, feminista y colectiva

Hypothalamic AgRP-neurons control peripheral substrate utilization and nutrient partitioning

Obesity-related diseases such as diabetes and dyslipidemia result from metabolic alterations including the defective conversion, storage and utilization of nutrients, but the central mechanisms that regulate this process of nutrient partitioning remain elusive. As positive regulators of feeding behaviour, agouti-related protein (AgRP) producing neurons are indispensible for the hypothalamic integration of energy balance. Here, we demonstrate a role for AgRP-neurons in the control of nutrient partitioning. We report that ablation of AgRP-neurons leads to a change in autonomic output onto liver, muscle and pancreas affecting the relative balance between lipids and carbohydrates metabolism. As a consequence, mice lacking AgRP-neurons become obese and hyperinsulinemic on regular chow but display reduced body weight gain and paradoxical improvement in glucose tolerance on high-fat diet. These results provide a direct demonstration of a role for AgRP-neurons in the coordination of efferent organ activity and nutrient partitioning, providing a mechanistic link between obesity and obesity-related disorders

Young hands, old books: : Drawings by children in a fourteenth-century manuscript, LJS MS. 361

This article scrutinises three marginal drawings in LJS 361, Kislak Center for Special Collections, Rare Books and Manuscripts, University of Pennsylvania Libraries. It first considers the provenance of the manuscript, questioning how it got into the hands of children. Then, it combines developmental psychology with close examination of the material evidence to develop a list of criteria to attribute the drawings to children. There is consideration of the features that help us estimate the age of the artists, and which indicate that one drawing was a collaborative effort between two children. A potential relationship is identified between the doodles and the subject matter of the text, prompting questions about pre-modern child education and literacy. Finally, the article considers the implications of this finding in both codicology and social history since these marginal illustrations demonstrate that children were active in the material life of medieval books

The skeleton of the staghorn coral Acropora millepora: molecular and structural characterization

15 pagesInternational audienceThe scleractinian coral Acropora millepora is one of the most studied species from the Great Barrier Reef. This species has been used to understand evolutionary, immune and developmental processes in cnidarians. It has also been subject of several ecological studies in order to elucidate reef responses to environmental changes such as temperature rise and ocean acidification (OA). In these contexts, several nucleic acid resources were made available. When combined to a recent proteomic analysis of the coral skeletal organic matrix (SOM), they enabled the identification of several skeletal matrix proteins, making A. millepora into an emerging model for biomineralization studies. Here we describe the skeletal microstructure of A. millepora skeleton, together with a functional and biochemical characterization of its occluded SOM that focuses on the protein and saccharidic moieties. The skeletal matrix proteins show a large range of isoelectric points, compositional patterns and signatures. Besides secreted proteins, there are a significant number of proteins with membrane attachment sites such as transmembrane domains and GPI anchors as well as proteins with integrin binding sites. These features show that the skeletal proteins must have strong adhesion properties in order to function in the calcifying space. Moreover this data suggest a molecular connection between the calcifying epithelium and the skeletal tissue during biocalcification. In terms of sugar moieties, the enrichment of the SOM in arabinose is striking, and the monosaccharide composition exhibits the same signature as that of mucus of acroporid corals. Finally, we observe that the interaction of the acetic acid soluble SOM on the morphology of in vitro grown CaCO3 crystals is very pronounced when compared with the calcifying matrices of some mollusks. In light of these results, we wish to commend Acropora millepora as a model for biocalcification studies in scleractinians, from molecular and structural viewpoints

Biomineralisation by earthworms: an investigation into the stability and distribution of amorphous calcium carbonate

Background Many biominerals form from amorphous calcium carbonate (ACC), but this phase is highly unstable when synthesised in its pure form inorganically. Several species of earthworm secrete calcium carbonate granules which contain highly stable ACC. We analysed the milky fluid from which granules form and solid granules for amino acid (by liquid chromatography) and functional group (by Fourier transform infrared (FTIR) spectroscopy) compositions. Granule elemental composition was determined using inductively coupled plasma-optical emission spectroscopy (ICP-OES) and electron microprobe analysis (EMPA). Mass of ACC present in solid granules was quantified using FTIR and compared to granule elemental and amino acid compositions. Bulk analysis of granules was of powdered bulk material. Spatially resolved analysis was of thin sections of granules using synchrotron-based μ-FTIR and EMPA electron microprobe analysis. Results The milky fluid from which granules form is amino acid-rich (≤ 136 ± 3 nmol mg−1 (n = 3; ± std dev) per individual amino acid); the CaCO3 phase present is ACC. Even four years after production, granules contain ACC. No correlation exists between mass of ACC present and granule elemental composition. Granule amino acid concentrations correlate well with ACC content (r ≥ 0.7, p ≤ 0.05) consistent with a role for amino acids (or the proteins they make up) in ACC stabilisation. Intra-granule variation in ACC (RSD = 16%) and amino acid concentration (RSD = 22–35%) was high for granules produced by the same earthworm. Maps of ACC distribution produced using synchrotron-based μ-FTIR mapping of granule thin sections and the relative intensity of the ν2: ν4 peak ratio, cluster analysis and component regression using ACC and calcite standards showed similar spatial distributions of likely ACC-rich and calcite-rich areas. We could not identify organic peaks in the μ-FTIR spectra and thus could not determine whether ACC-rich domains also had relatively high amino acid concentrations. No correlation exists between ACC distribution and elemental concentrations determined by EMPA. Conclusions ACC present in earthworm CaCO3 granules is highly stable. Our results suggest a role for amino acids (or proteins) in this stability. We see no evidence for stabilisation of ACC by incorporation of inorganic components