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In response to a meal, insulin drives hepatic glycogen synthesis to help regulate systemic glucose homeostasis. The mechanistic target of rapamycin complex 1 (mTORC1) is a well-established insulin target and contributes to the postprandial control of liver lipid metabolism, autophagy, and protein synthesis. However, its role in hepatic glucose metabolism is less understood. Here, we used metabolomics, isotope tracing, and mouse genetics to define a role for liver mTORC1 signaling in the control of postprandial glycolytic intermediates and glycogen deposition. We show that mTORC1 is required for glycogen synthase activity and glycogenesis. Mechanistically, hepatic mTORC1 activity promotes the feeding-dependent induction of Ppp1r3b, a gene encoding a phosphatase important for glycogen synthase activity whose polymorphisms are linked to human diabetes. Reexpression of Ppp1r3b in livers lacking mTORC1 signaling enhances glycogen synthase activity and restores postprandial glycogen content. mTORC1-dependent transcriptional control of Ppp1r3b is facilitated by FOXO1, a well characterized transcriptional regulator involved in the hepatic response to nutrient intake. Collectively, we identify a role for mTORC1 signaling in the transcriptional regulation of Ppp1r3b and the subsequent induction of postprandial hepatic glycogen synthesis., Introduction The liver is a central regulator of systemic glucose metabolism. Dysregulation of postprandial hepatic glucose metabolism contributes to the development of metabolic disorders, such as insulin resistance and type [...]

Circadian rhythms govern glucose homeostasis, and their dysregulation leads to complex metabolic diseases. Gut microbes exhibit diurnal rhythms that influence host circadian networks and metabolic processes, yet underlying mechanisms remain elusive. Here, we showed hierarchical, bidirectional communication among the liver circadian clock, gut microbes, and glucose homeostasis in mice. To assess this relationship, we utilized mice with liver-specific deletion of the core circadian clock gene Bmal1 via Albumin-cre maintained in either conventional or germ-free housing conditions. The liver clock, but not the forebrain clock, required gut microbes to drive glucose clearance and gluconeogenesis. Liver clock dysfunctionality expanded proportions and abundances of oscillating microbial features by 2-fold relative to that in controls. The liver clock was the primary driver of differential and rhythmic hepatic expression of glucose and fatty acid metabolic pathways. Absent the liver clock, gut microbes provided secondary cues that dampened these rhythms, resulting in reduced lipid fuel utilization relative to carbohydrates. All together, the liver clock transduced signals from gut microbes that were necessary for regulating glucose and lipid metabolism and meeting energy demands over 24 hours., Introduction Circadian rhythms are essential to nearly all life, coordinating behavior and compartmentalizing physiological processes that govern energy balance over a 24-hour period (1). Self-sustaining and cell-autonomous, circadian rhythms serve [...]

Temperate zone winters are experiencing greater rates of warming relative to other seasons and latitudinal regions globally. Spring-spawning fishes native to northern environments rely on both increasing temperature and lengthening photoperiod to cue reproduction and may thus be particularly sensitive to rapid warming earlier in the year while day lengths remain short. We investigated the reproductive response of pumpkinseed sunfish (Lepomis gibbosus) to spring warming commencing at a range of day lengths (9-15 hours), corresponding to various calendar days (10 January-22 May). In both the laboratory and field, both male and female fish that experienced early warming while day lengths were A l'echelle planetaire, les hivers dans les regions temperees se rechauffent plus rapidement que les autres saisons et que dans d'autres regions latitudinales. Chez les poissons indigenes des milieux nordiques qui frayent au printemps, l'augmentation des temperatures et l'allongement de la photoperiode sont des signaux qui induisent la reproduction, de sorte que ces poissons pourraient etre particulierement sensibles au rechauffement rapide plus tot dans l'annee, alors que la duree des jours demeure courte. Nous avons examine l'effet sur la reproduction de crapets-soleils (Lepomis gibbosus) du debut du rechauffement printanier a differentes durees du jour (de 9 a 15 heures) correspondant a differentes dates (du 10 janvier au 22 mai). Tant en laboratoire que sur le terrain, chez des poissons males et femelles ayant ete exposes a un rechauffement hatif alors que la longueur du jour etait inferieure a 11 heures, (1) la preparation a la reproduction dans le foie n'avait pas ete initiee avant le debut du developpement des gonades, (2) l'allocation de ressources a la reproduction etait reduite. L'analyse de donnees publiees sur les poissons de regions temperees donne a penser que le developpement du foie precedant le developpement des gonades est repandu dans les guildes thermiques d'eau chaude, temperee et froide, bien que la phenologie precise du developpement du foie par rapport a celui des gonades semble tres variable d'une espece a l'autre. Collectivement, nos resultats indiqueraient que l'attenuation de la preparation a la reproduction serait un mecanisme de modulation de l'efficacite de la reproduction chez les poissons tant d'eau chaude que d'eau temperee en reponse a un rechauffement printanier plus hatif. [Traduit par la Redaction], 1. Introduction At north-temperate latitudes, winters are projected to warm more rapidly than other seasons and regions under a changing global climate (Hoegh-Guldberg et al. 2018). Climate-driven declines in winter [...]

Fluoxetine, a commonly prescribed selective serotonin reuptake inhibitor antidepressant, has been shown to increase hepatic lipid accumulation, a key factor in the development of nonalcoholic fatty liver disease. Interestingly, fluoxetine has also been reported to increase peripheral serotonin synthesis. As emerging evidence suggests that serotonin may be involved in the development of nonalcoholic fatty liver disease, we sought to determine if fluoxetine-induced hepatic lipid accumulation is mediated via altered serotonin production. Fluoxetine treatment increased lipid accumulation in association with increased mRNA expression of tryptophan hydroxylase 1 (Tphl, serotonin biosynthetic enzyme) and intracellular serotonin content. Serotonin alone had a similar effect to increase lipid accumulation. Moreover, blocking serotonin synthesis reversed the fluoxetine- induced increases in lipid accumulation. Collectively, these data suggest that fluoxetine-induced lipid accumulation can be mediated, in part, by elevated serotonin production. These results suggest a potential therapeutic target to ameliorate the adverse metabolic effects of fluoxetine exposure. Key words: selective serotonin reuptake inhibitor, Fluoxetine, steatosis, nonalcoholic fatty liver disease, de novo lipogenesis, serotonin, metabolic disorder. On a montre que la fluoxetine, un antidepresseur inhibiteur selectif de la recapture de serotonine prescrit couramment, entraine une augmentation de l'accumulation de lipides hepatiques, facteur cle dans l'apparition d'une steatose hepatique non alcoolique. Il est interessant de noter que l'on a aussi rapporte que la fluoxetine entraine une augmentation de la synthese peripherique de serotonine. Comme des donnees emergentes laissent entrevoir que la serotonine pourrait jouer un role dans l'apparition de la steatose hepatique non alcoolique, nous avons cherche a etablir si l'accumulation de lipides engendree par la fluoxetine est mediee par l'intermediaire de la production de serotonine. L'administration de fluoxetine entraine une augmentation de l'accumulation de lipides en association avec une augmentation de l'expression en ARNm de la tryptophane hydroxylase 1 (Tphl, une enzyme de la synthese biologique de serotonine) et des taux de serotonine intracellulaires. La serotonine seule avait un effet similaire sur l'augmentation de l'accumulation de lipides. En outre, l'inhibition de la synthese de serotonine permettait d'inverser les augmentations de l'accumulation de lipides engendrees par la fluoxetine. Collectivement, ces donnees laissent entendre que l'augmentation de la production de serotonine pourrait participer a la mediation de l'accumulation de lipides engendree par la fluoxetine. Ces resultats laissent entrevoir qu'il pourrait s'agir d'une cible therapeutique eventuelle en vue d'attenuer les effets indesirables metaboliques de l'exposition a la fluoxetine. [Traduit par la Redaction] Mots-cles : inhibiteur selectif de la recapture de serotonine, fluoxetine, steatose, steatose hepatique non alcoolique, lipogenese de novo, serotonine, trouble metabolique., Introduction In Canada, it has been reported that 11.3% of people aged 15 and older had symptoms consistent with depression, with approximately one-third of individuals taking antidepressants to manage symptoms [...]

The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment.sup.1-3. These enduring dormant DTCs are seeds of future metastases, and the mechanisms that switch them from dormancy to outgrowth require definition. Because cancer dormancy provides a unique therapeutic window for preventing metastatic disease, a comprehensive understanding of the distribution, composition and dynamics of reservoirs of dormant DTCs is imperative. Here we show that different tissue-specific microenvironments restrain or allow the progression of breast cancer in the liver--a frequent site of metastasis.sup.4 that is often associated with a poor prognosis.sup.5. Using mouse models, we show that there is a selective increase in natural killer (NK) cells in the dormant milieu. Adjuvant interleukin-15-based immunotherapy ensures an abundant pool of NK cells that sustains dormancy through interferon-[gamma] signalling, thereby preventing hepatic metastases and prolonging survival. Exit from dormancy follows a marked contraction of the NK cell compartment and the concurrent accumulation of activated hepatic stellate cells (aHSCs). Our proteomics studies on liver co-cultures implicate the aHSC-secreted chemokine CXCL12 in the induction of NK cell quiescence through its cognate receptor CXCR4. CXCL12 expression and aHSC abundance are closely correlated in patients with liver metastases. Our data identify the interplay between NK cells and aHSCs as a master switch of cancer dormancy, and suggest that therapies aimed at normalizing the NK cell pool might succeed in preventing metastatic outgrowth. Liver-resident natural killer (NK) cells sustain the dormancy of disseminated breast cancer cells, and a decrease in NK cells and increase in activated hepatic stellate cells is associated with the formation of liver metastases., Author(s): Ana Luísa Correia [sup.1] [sup.2] [sup.3] , Joao C. Guimaraes [sup.4] [sup.11] , Priska Auf der Maur [sup.1] [sup.3] , Duvini De Silva [sup.1] [sup.2] [sup.11] , Marcel P. [...]

Physical exercise is essential for the amelioration of insulin resistance (IR). The mechanisms in charge of improved IR, regulated by exercise, are insufficiently studied. Previous research revealed that Sirtuin 6 (SIRT6)--mediated insulin signaling acts a crucial element in hepatic IR. The objective of our research was to determine the effects of exercise on SIRT6-mediated insulin signaling in liver of IR rats. Forty male Sprague Dawley rats were randomly assigned to four groups (n = 10 rats each): control rats fed with standard chow (Lean group); sedentary rats fed with a high-fat diet (HFD-SED); rats fed with HFD and submitted to 8 week chronic swimming exercise training (HFD-CE); and rats fed HFD and submitted to one acute swimming exercise training (HFD-AE). HFD feeding lead to increased body weight, accumulation of hepatic triglyceride and serum free fatty acids, and enhanced gluconeogenesis. Besides, HFD feeding decreased body insulin sensitivity. Hepatic USP10 and SIRT6 protein levels decreased under obese status. Both chronic and acute exercise intervention alleviated physiological and metabolic status, increased hepatic USP10 and SIRT6 levels, improved insulin signaling transduction, and inhibited gluconeogenesis. These results showed that exercise intervention regulated SIRT6-mediated insulin signaling, which contributes to our understanding of the molecular mechanisms behind IR, in that a regular exercise can mitigate the effects of IR. Key words: exercise, insulin resistance, SIRT6, insulin signaling transduction, gluconeogenesis. L'exercice physique est essentiel pour permettre d'attenuer la resistance a l'insuline. Les modes d'action en jeu dans l'attenuation de la resistance a l'insuline par un exercice physique regule ont ete trop peu etudies. Des recherches anterieures ont revele que la voie de signalisation de l'insuline mediee par SIRT6 est une caracteristique cruciale de l'ischemie-reperfusion (IR) hepatique. Notre recherche portait sur les effets de l'exercice physique sur la voie de signalisation de l'insuline mediee par SIRT6 dans le foie de rat soumis a une IR. Nous avons reparti aleatoirement 40 rats Sprague Dawley males dans quatre groupes (n = 10 rats chacun) : rats temoins avec administration d'une moulee standard (groupe maigre); rats sedentaires avec administration d'un regime alimentaire a haute teneur en matieres grasses (RHMG-SED); rats avec administration d'un RHMG et d'un entrainement physique a long terme (nage sur 8 semaines--RHMG-ELT) et avec exercice physique a court terme (nage ponctuelle--RHMD-ECT). L'administration d'un RHMG menait a une augmentation de la masse corporelle, a l'accumulation de triglycerides dans le foie et d'acides gras libres dans le serum, ainsi qu'a une augmentation de la gluconeogenese. Par ailleurs, l'administration du RHMG entrainait une diminution de la sensibilite de l'organisme a l'insuline. Les taux hepatiques d'USP10 et de SIRT6 en proteines diminuaient a l'etat obese. Tant a long terme qu'a court terme, l'administration de l'exercice physique permettait d'ameliorer l'etat physiologique et metabolique, d'augmenter les taux hepatiques d'USP10 et de SIRT6, d'ameliorer la transduction dans les voies de signalisation de l'insuline, ainsi que d'inhiber la gluconeogenese. Ces consequences revelaient que l'administration d'un exercice physique entraine une regulation de la voie de signalisation de l'insuline mediee par SIRT6, ce qui permet d'obtenir des progres notables dans l'accomplissement des modes d'action moleculaires latents, ce qui liait l'administration d'un exercice physique a l'attenuation des effets de l'IR. Mots-cles : exercice physique, resistance a l'insuline, SIRT6, transduction dans les voies de signalisation de l'insuline, gluconeogenese., Introduction Insulin primarily controls blood glucose via promoting glucose ingestion in insulin-sensitive tissue containing skeletal muscle, adipose tissues, and liver. It also suppresses glucose production in related tissues and organ. [...]