The epidermal circadian clock integrates and subverts brain signals to guarantee skin homeostasis.

In mammals, the circadian clock network drives daily rhythms of tissue-specific homeostasis. To dissect daily inter-tissue communication, we constructed a mouse minimal clock network comprising only two nodes: the peripheral epidermal clock and the central brain clock. By transcriptomic and functional characterization of this isolated connection, we identified a gatekeeping function of the peripheral tissue clock with respect to systemic inputs. The epidermal clock concurrently integrates and subverts brain signals to ensure timely execution of epidermal daily physiology. Timely cell-cycle termination in the epidermal stem cell compartment depends upon incorporation of clock-driven signals originating from the brain. In contrast, the epidermal clock corrects or outcompetes potentially disruptive feeding-related signals to ensure the optimal timing of DNA replication. Together, we present an approach for cataloging the systemic dependencies of daily temporal organization in a tissue and identify an essential gate-keeping function of peripheral circadian clocks that guarantees tissue homeostasis.

Brain-muscle communication prevents muscle aging by maintaining daily physiology.

A molecular clock network is crucial for daily physiology and maintaining organismal health. We examined the interactions and importance of intratissue clock networks in muscle tissue maintenance. In arrhythmic mice showing premature aging, we created a basic clock module involving a central and a peripheral (muscle) clock. Reconstituting the brain-muscle clock network is sufficient to preserve fundamental daily homeostatic functions and prevent premature muscle aging. However, achieving whole muscle physiology requires contributions from other peripheral clocks. Mechanistically, the muscle peripheral clock acts as a gatekeeper, selectively suppressing detrimental signals from the central clock while integrating important muscle homeostatic functions. Our research reveals the interplay between the central and peripheral clocks in daily muscle function and underscores the impact of eating patterns on these interactions.

Single-Cell RNA Sequencing Reveals Metabolic Stress-Dependent Activation of Cardiac Macrophages in a Model of Dyslipidemia-Induced Diastolic Dysfunction.

BACKGROUND: Metabolic distress is often associated with heart failure with preserved ejection fraction (HFpEF) and represents a therapeutic challenge. Metabolism-induced systemic inflammation links comorbidities with HFpEF. How metabolic changes affect myocardial inflammation in the context of HFpEF is not known. METHODS: We found that ApoE knockout mice fed a Western diet recapitulate many features of HFpEF. Single-cell RNA sequencing was used for expression analysis of CD45+ cardiac cells to evaluate the involvement of inflammation in diastolic dysfunction. We focused bioinformatics analysis on macrophages, obtaining high-resolution identification of subsets of these cells in the heart, enabling us to study the outcomes of metabolic distress on the cardiac macrophage infiltrate and to identify a macrophage-to-cardiomyocyte regulatory axis. To test whether a clinically relevant sodium glucose cotransporter-2 inhibitor could ameliorate the cardiac immune infiltrate profile in our model, mice were randomized to receive the sodium glucose cotransporter-2 inhibitor dapagliflozin or vehicle for 8 weeks. RESULTS: ApoE knockout mice fed a Western diet presented with reduced diastolic function, reduced exercise tolerance, and increased pulmonary congestion associated with cardiac lipid overload and reduced polyunsaturated fatty acids. The main immune cell types infiltrating the heart included 4 subpopulations of resident and monocyte-derived macrophages, determining a proinflammatory profile exclusively in ApoE knockout- Western diet mice. Lipid overload had a direct effect on inflammatory gene activation in macrophages, mediated through endoplasmic reticulum stress pathways. Investigation of the macrophage-to-cardiomyocyte regulatory axis revealed the potential effects on cardiomyocytes of multiple inflammatory cytokines secreted by macrophages, affecting pathways such as hypertrophy, fibrosis, and autophagy. Finally, we describe an anti-inflammatory effect of sodium glucose cotransporter-2 inhibitor in this model. CONCLUSIONS: Using single-cell RNA sequencing , in a model of diastolic dysfunction driven by hyperlipidemia, we have determined the effects of metabolic distress on cardiac inflammatory cells, in particular on macrophages, and suggest sodium glucose cotransporter-2 inhibitors as potential therapeutic agents for the targeting of a specific phenotype of HFpEF.

Impact of Bmal1 Rescue and Time-Restricted Feeding on Liver and Muscle Proteomes During the Active Phase in Mice.

Molecular clocks and daily feeding cycles support metabolism in peripheral tissues. Although the roles of local clocks and feeding are well defined at the transcriptional level, their impact on governing protein abundance in peripheral tissues is unclear. Here, we determine the relative contributions of local molecular clocks and daily feeding cycles on liver and muscle proteomes during the active phase in mice. LC-MS/MS was performed on liver and gastrocnemius muscle harvested 4 h into the dark phase from WT, Bmal1 KO, and dual liver- and muscle-Bmal1-rescued mice under either ad libitum feeding or time-restricted feeding during the dark phase. Feeding-fasting cycles had only minimal effects on levels of liver proteins and few, if any, on the muscle proteome. In contrast, Bmal1 KO altered the abundance of 674 proteins in liver and 80 proteins in muscle. Local rescue of liver and muscle Bmal1 restored ∼50% of proteins in liver and ∼25% in muscle. These included proteins involved in fatty acid oxidation in liver and carbohydrate metabolism in muscle. For liver, proteins involved in de novo lipogenesis were largely dependent on Bmal1 function in other tissues (i.e., the wider clock system). Proteins regulated by BMAL1 in liver and muscle were enriched for secreted proteins. We found that the abundance of fibroblast growth factor 1, a liver secreted protein, requires BMAL1 and that autocrine fibroblast growth factor 1 signaling modulates mitochondrial respiration in hepatocytes. In liver and muscle, BMAL1 is a more potent regulator of dark phase proteomes than daily feeding cycles, highlighting the need to assess protein levels in addition to mRNA when investigating clock mechanisms. The proteome is more extensively regulated by BMAL1 in liver than in muscle, and many metabolic pathways in peripheral tissues are reliant on the function of the clock system as a whole.

Liver and muscle circadian clocks cooperate to support glucose tolerance in mice.

Physiology is regulated by interconnected cell and tissue circadian clocks. Disruption of the rhythms generated by the concerted activity of these clocks is associated with metabolic disease. Here we tested the interactions between clocks in two critical components of organismal metabolism, liver and skeletal muscle, by rescuing clock function either in each organ separately or in both organs simultaneously in otherwise clock-less mice. Experiments showed that individual clocks are partially sufficient for tissue glucose metabolism, yet the connections between both tissue clocks coupled to daily feeding rhythms support systemic glucose tolerance. This synergy relies in part on local transcriptional control of the glucose machinery, feeding-responsive signals such as insulin, and metabolic cycles that connect the muscle and liver. We posit that spatiotemporal mechanisms of muscle and liver play an essential role in the maintenance of systemic glucose homeostasis and that disrupting this diurnal coordination can contribute to metabolic disease.

Atribuciones hacia la timidez y la soledad en niños y niñas de diferentes contextos sociales argentinos / Attributions towards shyness and unsociability in Argentinian children from different social contexts

Resumen Las atribuciones de los niños y las niñas hacia los comportamientos de retraimiento social suelen estar determinadas por el entorno sociocultural particular en el que se desarrollan e influyen en la forma en que reaccionan a las conductas de sus pares durante las interacciones sociales. El objetivo de este trabajo fue comparar dichas atribuciones hacia dos subtipos de retraimiento social (timidez y preferencia por la soledad) referidas por niños y niñas de tres contextos diferentes de Mendoza (Argentina): urbano, urbano-marginado y rural. Se llevó a cabo un estudio con 221 niños y niñas abordando jardines de infantes estatales de cada ámbito (urbano: . = 82, Mmeses= 62.33; urbano-marginado: . = 72, Mmeses= 60.47; rural: . = 67, Mmeses= 63.07). Los escolares fueron entrevistados individualmente con una serie de viñetas gráficas con personajes hipotéticos desplegando conductas sociables, tímidas, solitarias y agresivas frente a las cuales respondieron preguntas sobre sus atribuciones y percepciones en distintos aspectos. Las diferentes pruebas no paramétricas realizadas señalaron que el personaje tímido fue percibido con mayor motivación social y menor intencionalidad en su conducta que el personaje solitario en todos los grupos. No se encontraron diferencias entre los contextos en la atribución de consecuencias sociales negativas para estas conductas, aunque el grupo de escolares rurales reportó mayor preferencia afiliativa y compasión por el personaje tímido en comparación con el grupo urbano. Se discuten estos resultados considerando cómo las expectativas de socialización de cada contexto podrían influir en las percepciones de los escolares hacia el retraimiento social.

Abstract Children's attributions towards withdrawn behaviors are usually determined by the particular social milieu in which they develop and tend to influence their behaviors and reactions. The aim of this work was to compare the attributions towards two subtypes of social withdrawal (shyness and unsociability) referred by children from three different contexts in Mendoza, Argentina: urban, urban-marginalized and rural. Participants were 221 kindergarten children from these contexts (urban: n = 82, Mmonths = 62.33; urban-marginalized: n = 72, Mmonths = 60.47; rural: n = 67, Mmonths = 63.07). Children were individually interviewed with a series of graphic vignettes with hypothetical characters displaying shy and unsociable behaviors, and for comparison purposes were also assessed aggressive and socially competent behaviors. After each vignette, children were asked a series of questions designed to assess their attributions toward each behavior in six dimensions: intentionality, social motivation, affiliative preference, social status, negative impact and sympathy. The results of this study showed that young children in the three contexts were able to distinguish social withdrawal from other types of behaviors (i.e., aggressiveness and sociability). Overall, withdrawn behaviors received more positive attributions (greater affiliative preference, better social position and less negative impact) than aggressive behaviors, although they were also perceived negatively in relation to more socially competent behaviors (the latter were attributed greater affiliative preference and best position within the peer group). Furthermore, it was observed that children from the three contexts made clearly distinctions among the different forms of social withdrawal in terms of intentionality and social motivation. Specifically, they reported that compared with unsociable characters, shy ones are more socially motivated and less intentional in their behavior, evocating greater feelings of compassion. However, some peculiarities can be appreciated in each context. The results indicated that children in the urban group reported greater feelings of sympathy for the shy character in relation to the unsociable, which was not evidenced in the other groups. In addition, children from the rural sample showed a greater preference for interact with the hypothetical shy peer than with the unsociable character and this inclination was also greater when compared with the urban sample. Taken together, these results may suggest that different socialization norms and expectations would evoke different meanings and implications to the socially withdrawn manifestations. It might be possible that in urban contexts children's socialization expectations highlight extraversion and self-affirming behaviors which generate more empathetic reactions in front of passive or fearful manifestations as shyness. On the other hand, rural children may prefer peers who display shy behaviors possibly because it is in line with expectations of social cohesion and modesty that are value in this milieu. Nevertheless, no differences were found between shy and unsociable behaviors in any of the contexts in terms of social position and negative impact that they anticipated for the peer group. These results could provide some support for the idea that social withdrawal tends to be globally perceived as benign at an early age, and especially in the rural context, where it is a frequent and valued behavior. Although it is not possible with the limited variables included in this study to know which are the specific contextual aspects that affect some attributions and through what mechanisms they do so, these findings are an important starting point to continue deepening the socialization processes in urban, urban-marginalized and rural young children. This study is also one of the first to evaluate the knowledge and attributions of Argentinean children from different social context toward social withdrawal and provides new evidence on the differences in the cultural meaning and implications of withdrawn behaviors in early childhood.

TP53-mediated clonal hematopoiesis confers increased risk for incident atherosclerotic disease.

Somatic mutations in blood indicative of clonal hematopoiesis of indeterminate potential (CHIP) are associated with an increased risk of hematologic malignancy, coronary artery disease, and all-cause mortality. Here we analyze the relation between CHIP status and incident peripheral artery disease (PAD) and atherosclerosis, using whole-exome sequencing and clinical data from the UK Biobank and Mass General Brigham Biobank. CHIP associated with incident PAD and atherosclerotic disease across multiple beds, with increased risk among individuals with CHIP driven by mutation in DNA Damage Repair (DDR) genes such as TP53 and PPM1D. To model the effects of DDR-induced CHIP on atherosclerosis, we used a competitive bone marrow transplantation strategy, and generated atherosclerosis-prone Ldlr-/- chimeric mice carrying 20% p53-deficient hematopoietic cells. The chimeric mice were analyzed 13-weeks post-grafting and showed increased aortic plaque size and accumulation of macrophages within the plaque, driven by increased proliferation of p53-deficient plaque macrophages. In summary, our findings highlight the role of CHIP as a broad driver of atherosclerosis across the entire arterial system beyond the coronary arteries, and provide genetic and experimental support for a direct causal contribution of TP53-mutant CHIP to atherosclerosis.

Dietary essential amino acids for the treatment of heart failure with reduced ejection fraction.

AIMS: Heart failure with reduced ejection fraction (HFrEF) is a leading cause of mortality worldwide, requiring novel therapeutic and lifestyle interventions. Metabolic alterations and energy production deficit are hallmarks and thereby promising therapeutic targets for this complex clinical syndrome. We aim to study the molecular mechanisms and effects on cardiac function in rodents with HFrEF of a designer diet in which free essential amino acids-in specifically designed percentages-substituted for protein. METHODS AND RESULTS: Wild-type mice were subjected to transverse aortic constriction (TAC) to induce left ventricle (LV) pressure overload or sham surgery. Whole-body glucose homeostasis was studied with glucose tolerance test, while myocardial dysfunction and fibrosis were measured with echocardiogram and histological analysis. Mitochondrial bioenergetics and morphology were investigated with oxygen consumption rate measurement and electron microscopy evaluation. Circulating and cardiac non-targeted metabolite profiles were analyzed by ultrahigh performance liquid chromatography-tandem mass spectroscopy, while RNA-sequencing was used to identify signalling pathways mainly affected. The amino acid-substituted diet shows remarkable preventive and therapeutic effects. This dietary approach corrects the whole-body glucose metabolism and restores the unbalanced metabolic substrate usage-by improving mitochondrial fuel oxidation-in the failing heart. In particular, biochemical, molecular, and genetic approaches suggest that renormalization of branched-chain amino acid oxidation in cardiac tissue, which is suppressed in HFrEF, plays a relevant role. Beyond the changes of systemic metabolism, cell-autonomous processes may explain at least in part the diet's cardioprotective impact. CONCLUSION: Collectively, these results suggest that manipulation of dietary amino acids, and especially essential amino acids, is a potential adjuvant therapeutic strategy to treat systolic dysfunction and HFrEF in humans.

The central clock suffices to drive the majority of circulatory metabolic rhythms.

Life on Earth anticipates recurring 24-hour environmental cycles via genetically encoded molecular clocks active in all mammalian organs. Communication between these clocks controls circadian homeostasis. Intertissue communication is mediated, in part, by temporal coordination of metabolism. Here, we characterize the extent to which clocks in different organs control systemic metabolic rhythms, an area that remains largely unexplored. We analyzed the metabolome of serum from mice with tissue-specific expression of the clock gene Bmal1. Having functional hepatic and muscle clocks can only drive a minority (13%) of systemic metabolic rhythms. Conversely, limiting Bmal1 expression to the central pacemaker in the brain restores rhythms to 57% of circulatory metabolites. Rhythmic feeding imposed on clockless mice resulted in a similar rescue, indicating that the central clock mainly regulates metabolic rhythms via behavior. These findings explicate the circadian communication between tissues and highlight the importance of the central clock in governing those signals.

Young Argentine Children's Attributions about Hypothetical Socially Withdrawn Peers.

This study assessed young children's attributions about different subtypes of hypothetical socially withdrawn peers. Participants were N = 114 (56% boys, Mage= 60.53 months, SD = 7.58) children attending urban public kindergartens in Mendoza, Argentina. Children were presented with vignettes describing hypothetical shy, unsociable, aggressive, and socially competent peers, and were asked a series of questions to assess their attributions toward each behavior. The results indicated that Argentine children characterized hypothetical unsociable peers as behaving with greater intentionality and lesser social motivations than shy children. No differences were found between the unsociable and shy hypothetical peers regarding the attributions of sympathy, affiliative preference, negative impact and social standing in the class. These findings provide some of the first evidence about Argentine children understanding of social withdrawal. Results are discussed in terms of the possible cultural meanings and implications of these behaviors.

Creencias parentales sobre el retraimiento social en la edad preescolar / Parental beliefs about social withdrawal in preschool age

Antecedentes: Las creencias parentales, entiéndase sus ideas, conocimientos, valores y atribuciones, son primordiales en el estudio de las relaciones entre padres e hijos. Son procesos cognitivos y afectivos que inciden en las estrategias para promover conductas sociales aceptables o para modificar aquellas no deseables. Objetivo general: Explorar las creencias de los padres y las madres sobre los comportamientos de retraimiento social de sus hijos/as en la ciudad de Mendoza, Argentina. Método: Se optó por una metodología cualitativa, utilizando el enfoque de la Teoría Fundamentada. El muestreo fue no probabilístico e intencional y participaron padres y madres de cinco niños/as de cuatro años que asistían a instituciones educativas de gestión estatal. Se utilizó la entrevista enfocada como instrumento de recolección de datos. Resultados: Categorías emergentes: atribuciones causales internas y externas, atribuciones causales del desarrollo cognitivo y/o socioemocional, estrategias parentales de socialización y caracterizadas por control excesivo y sobreprotección. Conclusiones: Las creencias parentales proveen un marco de referencia que guían las interacciones de sus hijos/as y determinan las oportunidades que les brindan para su desarrollo socioemocional. Palabras clave: creencias parentales; retraimiento social; desarrollo socioemocional; preescolar.

Background: Parental beliefs, namely parents' ideas, knowledge, values, and attributions, are essential in the study of relationships between parents and children. They consist of cognitive and affective processes that influence strategies to promote acceptable social behaviors or to modify those considered undesirable. General Objective: To explore fathers' and mothers' beliefs about their children's social withdrawal behaviors in the city of Mendoza, Argentina. Method: A qualitative methodology and a grounded theory approach were chosen. A non-probability purposive sampling was used. Fathers and mothers of five four-year-old children who attended public educational institutions participated in the study. The focused interview was used as a data collection instrument. Results: Emerging categories: internal and external causal attributions, causal attributions of cognitive and/or social-emotional development, parental socialization strategies characterized by excessive control and overprotection. Conclusions: Parental beliefs provide a frame of reference that guides children's interactions and determines the opportunities parents offer their children for their social-emotional development. Keywords: parental beliefs; social withdrawal; social-emotional development; preschool.

Dietary palmitic acid promotes a prometastatic memory via Schwann cells.

Fatty acid uptake and altered metabolism constitute hallmarks of metastasis1,2, yet evidence of the underlying biology, as well as whether all dietary fatty acids are prometastatic, is lacking. Here we show that dietary palmitic acid (PA), but not oleic acid or linoleic acid, promotes metastasis in oral carcinomas and melanoma in mice. Tumours from mice that were fed a short-term palm-oil-rich diet (PA), or tumour cells that were briefly exposed to PA in vitro, remained highly metastatic even after being serially transplanted (without further exposure to high levels of PA). This PA-induced prometastatic memory requires the fatty acid transporter CD36 and is associated with the stable deposition of histone H3 lysine 4 trimethylation by the methyltransferase Set1A (as part of the COMPASS complex (Set1A/COMPASS)). Bulk, single-cell and positional RNA-sequencing analyses indicate that genes with this prometastatic memory predominantly relate to a neural signature that stimulates intratumoural Schwann cells and innervation, two parameters that are strongly correlated with metastasis but are aetiologically poorly understood3,4. Mechanistically, tumour-associated Schwann cells secrete a specialized proregenerative extracellular matrix, the ablation of which inhibits metastasis initiation. Both the PA-induced memory of this proneural signature and its long-term boost in metastasis require the transcription factor EGR2 and the glial-cell-stimulating peptide galanin. In summary, we provide evidence that a dietary metabolite induces stable transcriptional and chromatin changes that lead to a long-term stimulation of metastasis, and that this is related to a proregenerative state of tumour-activated Schwann cells.

Integration of feeding behavior by the liver circadian clock reveals network dependency of metabolic rhythms.

The mammalian circadian clock, expressed throughout the brain and body, controls daily metabolic homeostasis. Clock function in peripheral tissues is required, but not sufficient, for this task. Because of the lack of specialized animal models, it is unclear how tissue clocks interact with extrinsic signals to drive molecular oscillations. Here, we isolated the interaction between feeding and the liver clock by reconstituting Bmal1 exclusively in hepatocytes (Liver-RE), in otherwise clock-less mice, and controlling timing of food intake. We found that the cooperative action of BMAL1 and the transcription factor CEBPB regulates daily liver metabolic transcriptional programs. Functionally, the liver clock and feeding rhythm are sufficient to drive temporal carbohydrate homeostasis. By contrast, liver rhythms tied to redox and lipid metabolism required communication with the skeletal muscle clock, demonstrating peripheral clock cross-talk. Our results highlight how the inner workings of the clock system rely on communicating signals to maintain daily metabolism.

Ketogenesis impact on liver metabolism revealed by proteomics of lysine ß-hydroxybutyrylation.

Ketone bodies are bioactive metabolites that function as energy substrates, signaling molecules, and regulators of histone modifications. ß-hydroxybutyrate (ß-OHB) is utilized in lysine ß-hydroxybutyrylation (Kbhb) of histones, and associates with starvation-responsive genes, effectively coupling ketogenic metabolism with gene expression. The emerging diversity of the lysine acylation landscape prompted us to investigate the full proteomic impact of Kbhb. Global protein Kbhb is induced in a tissue-specific manner by a variety of interventions that evoke ß-OHB. Mass spectrometry analysis of the ß-hydroxybutyrylome in mouse liver revealed 891 sites of Kbhb within 267 proteins enriched for fatty acid, amino acid, detoxification, and one-carbon metabolic pathways. Kbhb inhibits S-adenosyl-L-homocysteine hydrolase (AHCY), a rate-limiting enzyme of the methionine cycle, in parallel with altered metabolite levels. Our results illuminate the role of Kbhb in hepatic metabolism under ketogenic conditions and demonstrate a functional consequence of this modification on a central metabolic enzyme.

Expanding the link between circadian rhythms and redox metabolism of epigenetic control.

Circadian rhythms play a central role in physiological and metabolic processes. This is mostly achieved through rhythmic regulation of myriad genes via dynamic epigenome changes. Accumulating evidence indicates that oxidative stress and redox balance are under circadian control and feedback on the clock system. Circadian perturbations induce oxidative stress accumulation and disturb redox balance. Along with these changes, epigenomic landscape changes are a remarkable hallmark of clock disruption. This review aims to summarize evidence supporting the link between the circadian clock and redox metabolism, focusing on possible connections through epigenetic mechanisms.

S-adenosyl-l-homocysteine hydrolase links methionine metabolism to the circadian clock and chromatin remodeling.

Circadian gene expression driven by transcription activators CLOCK and BMAL1 is intimately associated with dynamic chromatin remodeling. However, how cellular metabolism directs circadian chromatin remodeling is virtually unexplored. We report that the S-adenosylhomocysteine (SAH) hydrolyzing enzyme adenosylhomocysteinase (AHCY) cyclically associates to CLOCK-BMAL1 at chromatin sites and promotes circadian transcriptional activity. SAH is a potent feedback inhibitor of S-adenosylmethionine (SAM)-dependent methyltransferases, and timely hydrolysis of SAH by AHCY is critical to sustain methylation reactions. We show that AHCY is essential for cyclic H3K4 trimethylation, genome-wide recruitment of BMAL1 to chromatin, and subsequent circadian transcription. Depletion or targeted pharmacological inhibition of AHCY in mammalian cells markedly decreases the amplitude of circadian gene expression. In mice, pharmacological inhibition of AHCY in the hypothalamus alters circadian locomotor activity and rhythmic transcription within the suprachiasmatic nucleus. These results reveal a previously unappreciated connection between cellular metabolism, chromatin dynamics, and circadian regulation.

Manipulation of Dietary Amino Acids Prevents and Reverses Obesity in Mice Through Multiple Mechanisms That Modulate Energy Homeostasis.

Reduced activation of energy metabolism increases adiposity in humans and other mammals. Thus, exploring dietary and molecular mechanisms able to improve energy metabolism is of paramount medical importance because such mechanisms can be leveraged as a therapy for obesity and related disorders. Here, we show that a designer protein-deprived diet enriched in free essential amino acids can 1) promote the brown fat thermogenic program and fatty acid oxidation, 2) stimulate uncoupling protein 1 (UCP1)-independent respiration in subcutaneous white fat, 3) change the gut microbiota composition, and 4) prevent and reverse obesity and dysregulated glucose homeostasis in multiple mouse models, prolonging the healthy life span. These effects are independent of unbalanced amino acid ratio, energy consumption, and intestinal calorie absorption. A brown fat-specific activation of the mechanistic target of rapamycin complex 1 seems involved in the diet-induced beneficial effects, as also strengthened by in vitro experiments. Hence, our results suggest that brown and white fat may be targets of specific amino acids to control UCP1-dependent and -independent thermogenesis, thereby contributing to the improvement of metabolic health.

A non-pharmacological therapeutic approach in the gut triggers distal metabolic rewiring capable of ameliorating diet-induced dysfunctions encompassed by metabolic syndrome.

Metabolic syndrome has increased at a worrisome level. Lifestyle changes are not sufficient to prevent and improve the adverse effects of obesity, thus novel interventions are necessary. The aim of this study was to investigate the use and metabolic outcomes of a non-pharmacological intervention in a high-fat diet (HFD) fed mouse model, capable of recapitulating key aspects of metabolic syndrome. We show that Policaptil Gel Retard has remarkable, beneficial effects on metabolic dysfunction caused by consumption of HFD. We describe the mechanism by which such effects are obtained, highlighting the fact that the amelioration of metabolic function observed upon Policaptil Gel Retard administration is profound and of systemic nature, despite being originated by sequestering, therefore non-pharmacological events elicited in the gut lumen.

Personalized medicine and circadian rhythms: Opportunities for modern society.

Circadian rhythms govern physiology and metabolism, leading to controlled homeostasis. We discuss the impact of circadian rhythms on society and the challenges for the imminent future of personalized medicine.