Circadian disruption correlates with a wide range of metabolic and neurological disorders. General control non‐derepressible 2 (GCN2) activation, the primary sensory mechanism of amino acid ...insufficiency, also plays an integral role in maintaining the circadian clock in peripheral tissues such as the liver. The objective of this work is to examine the regulation of the circadian clock via GCN2‐mediated sensing of dietary protein quality. We hypothesized that low protein quality feeding will alter the circadian clock in a GCN2 dependent manner. To test this, wild type (WT) and whole body GCN2 knockout (GCN2KO) mice were housed in total darkness within an environmentally‐controlled indirect calorimetry cabinet and provided a diet either devoid of leucine (LeuD) or amino acid replete (Control) for 8‐days and then killed at 2 circadian time (CT) points 12‐hours apart (CT3, CT15). Following the treatment period, LeuD‐fed GCN2KO mice displayed a 40% reduction in the circadian oscillation of their energy expenditure (p<.001) relative to Controls whereas no such difference was present in their WT counterparts. Measurements of the 12‐hour expression pattern of various circadian oscillatory genes within the liver revealed that GCN2 is necessary for circadian oscillation of Bmal2 mRNA expression independent of diet (p<0.01). Furthermore, LeuD feeding alters the expression pattern of the clock‐controlled genes (CCGs) Ciart, Klf10and Noctby over 5‐, 10‐, and 2‐fold respectively (p<0.05) in a GCN2 dependent manner. Together, these findings demonstrate that dietary protein quality plays a role in the maintenance of circadian rhythms within the liver. Furthermore, GCN2 is required to maintain whole body metabolic rhythms when challenged with a diet of poor protein quality. In observing the alterations in the circadian expression pattern of these CCGs with feeding a low protein quality diet, our findings expand our understanding of the role of dietary amino acid intake and the maintenance of circadian metabolic rhythms within the liver.
Nonshivering thermogenesis in rodents requires macronutrients to fuel the generation of heat during hypothermic conditions. In this study, we examined the role of the nutrient sensing kinase, general ...control nonderepressible 2 (GCN2) in directing adaptive thermogenesis during acute cold exposure in mice. We hypothesized that GCN2 is required for adaptation to acute cold stress via activation of the integrated stress response (ISR) resulting in liver production of FGF21 and increased amino acid transport to support nonshivering thermogenesis. In alignment with our hypothesis, female and male mice lacking GCN2 failed to adequately increase energy expenditure and veered into torpor. Mice administered a small molecule inhibitor of GCN2 were also profoundly intolerant to acute cold stress.
deletion also impeded liver-derived FGF21 but in males only. Within the brown adipose tissue (BAT), acute cold exposure increased ISR activation and its transcriptional execution in males and females. RNA sequencing in BAT identified transcripts that encode actomyosin mechanics and transmembrane transport as requiring GCN2 during cold exposure. These transcripts included class II myosin heavy chain and amino acid transporters, critical for maximal thermogenesis during cold stress. Importantly,
deletion corresponded with higher circulating amino acids and lower intracellular amino acids in the BAT during cold stress. In conclusion, we identify a sex-independent role for GCN2 activation to support adaptive thermogenesis via uptake of amino acids into brown adipose.
This paper details the discovery that GCN2 activation is required in both male and female mice to maintain core body temperature during acute cold exposure. The results point to a novel role for GCN2 in supporting adaptive thermogenesis via amino acid transport and actomyosin mechanics in brown adipose tissue.
Dietary sulfur amino acid restriction (SAAR) improves body composition and metabolic health across several model organisms in part through induction of the integrated stress response (ISR).
We ...investigate the hypothesis that activating transcription factor 4 (ATF4) acts as a converging point in the ISR during SAAR.
Using liver-specific or global gene ablation strategies, in both female and male mice, we address the role of ATF4 during dietary SAAR.
We show that ATF4 is dispensable in the chronic induction of the hepatokine fibroblast growth factor 21 while being essential for the sustained production of endogenous hydrogen sulfide. We also affirm that biological sex, independent of ATF4 status, is a determinant of the response to dietary SAAR.
Our results suggest that auxiliary components of the ISR, which are independent of ATF4, are critical for SAAR-mediated improvements in metabolic health in mice.
Resumen
Este artículo examina el trabajo de los maestros en la Honduras pos‐golpe mientras navegan a través del primer año de reformas al sector educativo, el cual intenta privatizar y descentralizar ...el sistema de educación pública del país. Desde el golpe de estado de junio de 2009, los maestros hondureños han sido líderes del movimiento de resistencia contra el golpe que ahora desafía el actual estatus quo y propone ‘refundar’ el estado. A pesar de que los maestros hondureños están en desacuerdo con estas reformas y otros aspectos de la práctica gubernamental pos‐golpe, en el fondo ellos son los agentes del estado responsables por implementar estas nuevas políticas educativas. Basándome en mi investigación etnográfica en el Departamento de Valle, ubicado en el sur, yo exploro la naturaleza contradictoria del trabajo de agentes del estado vista desde la perspectiva de las políticas educativas y de cómo la legislación realmente se pone en práctica.
This article examines the work of schoolteachers in postcoup Honduras as they navigate through the first year of reforms to the education sector. The aim of the reforms is to privatize and decentralize the country's national public education system. Since the June 2009 coup, Honduran schoolteachers have been leaders of the anti‐coup resistance movement that now challenges the current status quo and proposes to “re‐found” the state. Although Honduran schoolteachers disagree with the reforms and other aspects of post‐coup governance, they are ultimately the state agents responsible for implementing these new education policies. Based on ethnographic fieldwork in the southern Department of Valle, this research explores the contradictory nature of the work of state agents through the lens of education policies, and examines how legislation is put into practice.
Highlights • Surgical intervention is necessary in patients that are unstable or in the presence of probable bowel wall compromise. • Medical management of PI includes antibiotics, elemental diet and ...oxygen therapy. • We propose a management algorithm for the treatment of PI based on clinical, laboratory and radiological findings.
This article examines how teachers in post‐coup Honduras reluctantly complied with legislation with which they disagreed. New laws passed after the June 2009 military coup decentralized and ...privatized government funding by requiring that teachers solicit money for school infrastructure projects from municipal governments and private companies instead of from the Ministry of Education. This article demonstrates how teachers drew on their situated knowledge of state procedures and reluctantly engaged in clientelist relations with coup‐supporting politicians, who most teachers despised given their own involvement in the anti‐coup resistance movement. Anthropologists and others often emphasize the “top‐down” nature of how neoliberalism gets imposed and how state policies get implemented. In the case of public education policies in post‐coup Honduras, however, the same individuals responsible for implementing neoliberal legislation also actively protested against neoliberalism and the patronage of rich politicians in general. The analysis of teachers’ simultaneous critique of and engagement with clientelism is illuminative of how state agents in other contexts may end up implementing legislation with which they disagree. While not denying the global scope of neoliberal policies, this article advances scholarly knowledge of how frontline state agents implement state policies.
Dietary interventions such as sulfur amino acid restriction (SAAR) target multiple drivers of aging, and show promise for preventing or delaying the onset of chronic diseases. SAAR promotes metabolic ...health and longevity in laboratory animals. The effects of SAAR on proteostasis remain relatively unexplored. We previously reported that SAAR promotes mitochondrial proteostatic maintenance, despite suppression of global protein synthesis, in two peripheral tissues, the liver and skeletal muscle. However, the brain, a tissue vulnerable to age-related neurodegenerative diseases due to the loss of proteostasis, has not been thoroughly studied. Therefore, we sought to reveal proteostatic responses in the brains of mice fed SAAR for 35 days. Here, we demonstrate that male C57Bl/6J mice fed two levels of SAAR maintained rates of protein synthesis in all sub-cellular fractions of the pre-frontal cortex. In comparison, rates of skeletal muscle protein synthesis in SAAR fed mice were slower than control-fed mice. To gain mechanistic insight, we examined several key nutrient/energy sensitive signaling proteins: AMP-activated protein kinase (AMPK), eukaryotic initiation factor 2 (eIF2), and ribosomal protein S6 (rpS6). SAAR had minimal to modest effects on the total abundance and phosphorylation of these proteins in both tissues. Our results indicate that the pre-frontal cortex in brain is resistant to perturbations in protein synthesis in mice fed SAAR, unlike skeletal muscle, which had a reduction in global protein synthesis. The results from this study demonstrate that proteostatic control in brain is of higher priority than skeletal muscle during dietary SAAR.
In this article, I explore some challenges and strategies for anthropologist expert witnesses working on cases where home‐country governments depict an overall more positive situation than what the ...applicants claim. Drawing upon an anonymized Honduran asylum case, I discuss the utility of state theory for debunking fallacious home‐government sources that downplay dangerous situations while exaggerating state achievements, suggesting ways to illuminate the inherent political motivations of government reports. Honduran asylum applicants flee from gang violence, political violence, and gendered violence, now more than a decade after the June 2009 military coup that ruptured already fragile public institutions. While official Honduran government reports claim that the state is alleviating such problems by creating new programs and laws, ethnographic evidence from anthropologists working with anticoup social movements suggests that the state's security apparatus often exacerbates violence, and that the mere act of passing legislation does little in practice to protect vulnerable Hondurans.
This article examines how teachers in post‐coup Honduras approached implementing neoliberal school finance reforms with which they disagreed. The laws in question decentralize national public ...education and demand that teachers secure funding for basic school infrastructure and academic programs from private businesses. I show how teachers reluctantly engaged aspects of this legislation, but for their own reasons, and suggest that their partial compliance is illuminative of how teachers in other contexts may approach policy implementation.
Este artículo examina cómo los maestros en la Honduras pos‐golpe implementaron reformas educativas neoliberales con las cuales estaban en desacuerdo. Las leyes intentan descentralizar el sistema de educación pública, exigiendo que los maestros gestionen fondos del sector privado para mantener sus centros educativos. Demuestro cómo los maestros manejaron esta legislación de manera renuente y con fines propios. Argumento que su cumplimiento revela cómo los maestros llegan a implementar políticas con las cuales estén en desacuerdo.
Dietary sulfur amino acid restriction (SAAR) protects against diet-induced obesity, extends healthspan, and coincides with an overall reduction in hepatic protein synthesis. To explore the ...underpinnings of SAAR-induced slowed growth and its impact on liver metabolism and proteostasis, we resolved changes in hepatic mRNA and protein abundances and compared synthesis rates of individual liver proteins. To achieve this, adult male mice were provided deuterium-labeled drinking water while freely consuming either a regular-fat or high-fat diet that was SAA restricted. Livers from these mice and their respective dietary controls were used to conduct transcriptomic, proteomic, and kinetic proteomic analyses. We found that remodeling of the transcriptome by SAAR was largely agnostic to dietary fat content. Shared signatures included activation of the integrated stress response alongside alterations in metabolic processes impacting lipids, fatty acids, and amino acids. Changes to the proteome correlated poorly with the transcriptome, and yet, functional clustering of kinetic proteomic changes in the liver during SAAR revealed that the management of fatty acids and amino acids were altered to support central metabolism and redox balance. Dietary SAAR also strongly influenced the synthesis rates of ribosomal proteins and ribosome-interacting proteins regardless of dietary fat. Taken together, dietary SAAR alters the transcriptome and proteome in the liver to safely manage increased fatty acid flux and energy use and couples this with targeted changes in the ribo-interactome to support proteostasis and slowed growth.
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