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Changes in available nutrients are inevitable events for most living organisms. Upon nutritional stress, several signaling pathways cooperate to change the transcription program through chromatin regulation to rewire cellular metabolism. In budding yeast, histone H3 threonine 11 phosphorylation (H3pT11) acts as a marker of low glucose stress and regulates the transcription of nutritional stress-responsive genes. Understanding how this histone modification ‘senses’ external glucose changes remains elusive. Here, we show that Tda1, the yeast ortholog of human Nuak1, is a direct kinase for H3pT11 upon low glucose stress. Yeast AMP-activated protein kinase (AMPK) directly phosphorylates Tda1 to govern Tda1 activity, while CK2 regulates Tda1 nuclear localization. Collectively, AMPK and CK2 signaling converge on histone kinase Tda1 to link external low glucose stress to chromatin regulation.

Cellular recycling via autophagy-associated proteins is a key catabolic pathway critical to invasive fungal pathogen growth and virulence in the nutrient-limited host environment. Protein kinase A (PKA) is vital for the growth and virulence of numerous fungal pathogens. However, the underlying basis for its regulation of pathogenesis remains poorly understood in any species. Our Aspergillus fumigatus PKA-dependent whole proteome and phosphoproteome studies employing advanced mass spectroscopic approaches identified numerous previously undefined PKA-regulated proteins in catabolic pathways. Here, we demonstrate reciprocal inhibition of autophagy and PKA activity, and identify 16 autophagy-associated proteins as likely novel PKA-regulated effectors. We characterize the novel PKA-phosphoregulated sorting nexin Atg20, and demonstrate its importance for growth, cell wall stress response, and virulence of A. fumigatus in a murine infection model. Additionally, we identify physical and functional interaction of Atg20 with previously characterized sorting nexin Atg24. Furthermore, we demonstrate the importance of additional uncharacterized PKA-regulated putative autophagy-associated proteins to hyphal growth. Our data presented here indicate that PKA regulates the autophagy pathway much more extensively than previously known, including targeting of novel effector proteins with fungal-specific functions important for invasive disease.

Initially described as lytic bodies due to their degradative and recycling functions, lysosomes play a critical role in metabolic adaptation to nutrient availability. More recently, the contribution of lysosomal proteins to cell signaling has been established, and lysosomes have emerged as signaling hubs that regulate diverse cellular processes, including cell proliferation and cell fate. Deciphering these signaling pathways has revealed an extensive crosstalk between the lysosomal and cell cycle machineries that is only beginning to be understood. Recent studies also indicate that a number of lysosomal proteins are involved in the regulation of embryonic and adult stem cell fate and identity. In this review, we will focus on the role of the lysosome as a signaling platform with an emphasis on its function in integrating nutrient sensing with proliferation and cell cycle progression, as well as in stemness-related features, such as self-renewal and quiescence.

Bitter taste is an aversive taste because it is unconsciously associated with toxic compounds. However, a considerable variability in bitter sensitivity exists in those who have the genetic polymorphism for bitter taste receptors (TAS2Rs). Besides the oral cavity, TAS2Rs are present in many body tissues, including the gastrointestinal tract; therefore, they are crucial players both in the gustatory/hedonic system and in the homeostatic system, triggering numerous biological responses, including adipogenesis, carcinogenesis, or immunity. Bitter-tasting compounds are widely distributed in plant and animal foods and belong to many chemical classes. In this study, the evidence was reviewed on bitter peptides, considering the food sources, their formation in food under different processing and storage conditions and in the gastrointestinal tract during digestion, as well as their biological activities. Bitterness associated with peptides is due to the presence of hydrophobic amino acids in the C-terminus. The current literature mainly explores the enzymes and hydrolysis conditions, with the aim of reducing the formation of bitter peptides in hydrolysate preparation or food. Few studies highlight the bioactivity (namely, antihypertensive, antidiabetic, antioxidant, or immunity boosting), besides the bitterness. However, encapsulation of bitter peptides has been tentatively used to develop antihypertensive and antidiabetic supplements. In the era of personalized nutrition and precision medicine, the evidence available suggests the opportunity to use bitter bioactive peptides as functional ingredients in food. Such types of food may modulate a plethora of physiological mechanisms by targeting TAS2Rs in the gastrointestinal tract, thus modulating appetite sensations or gastrointestinal motility and discomfort according to individual nutritional needs and goals. More studies are needed to optimize the technological strategies to target TAS2Rs by bitter bioactive peptides, improve their stability in food, and validate the biological efficacy through well-designed in vivo studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cells continuously fine-tune signaling pathway proteins to match nutrient and stress levels in their local environment by modifying intracellular proteins with O-linked N-acetylglucosamine (O-GlcNAc) sugars, an essential process for cell survival and growth. The small size of these monosaccharide modifications poses a challenge for functional determination, but the chemistry and biology communities have together created a collection of precision tools to study these dynamic sugars. This review presents the major themes by which O-GlcNAc influences signaling pathway proteins, including G-protein coupled receptors, growth factor signaling, mitogen-activated protein kinase (MAPK) pathways, lipid sensing, and cytokine signaling pathways. Along the way, we describe in detail key chemical biology tools that have been developed and applied to determine specific O-GlcNAc roles in these pathways. These tools include metabolic labeling, O-GlcNAc-enhancing RNA aptamers, fluorescent biosensors, proximity labeling tools, nanobody targeting tools, O-GlcNAc cycling inhibitors, light-activated systems, chemoenzymatic labeling, and nutrient reporter assays. An emergent feature of this signaling pathway meta-analysis is the intricate interplay between O-GlcNAc modifications across different signaling systems, underscoring the importance of O-GlcNAc in regulating cellular processes. We highlight the significance of O-GlcNAc in signaling and the role of chemical and biochemical tools in unraveling distinct glycobiological regulatory mechanisms. Collectively, our field has determined effective strategies to probe O-GlcNAc roles in biology. At the same time, this survey of what we do not yet know presents a clear roadmap for the field to use these powerful chemical tools to explore cross-pathway O-GlcNAc interactions in signaling and other major biological pathways., Competing Interests: Conflict of interest The authors declare no potential conflict of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The gastrointestinal (GI) tract in both vertebrates and invertebrates is now recognized as a major source of signals modulating, via gut-peptide hormones, the metabolic activities of peripheral organs, and carbo-lipid balance. Key advances in the understanding of metabolic functions of gut-peptide hormones and their mediated interorgan communication have been made using Drosophila as a model organism, given its powerful genetic tools and conserved metabolic regulation. Here, we summarize recent studies exploring peptide hormones that are involved in the communication between the midgut and other peripheral organs/tissues during feeding conditions. We also highlight the emerging impacts of fly gut-peptide hormones on stress sensing and carbo-lipid metabolism in various disease models, such as energy overload, pathogen infection, and tumor progression. Due to the functional similarity of intestine and its derived peptide hormones between Drosophila and mammals, it can be anticipated that findings obtained in the fly system will have important implications for the understanding of human physiology and pathology.

TARGET OF RAPAMYCIN (TOR) kinase has been recognised as a key developmental regulator in both plants and animals. Despite their distinct developmental programmes, all eukaryotes studied possess a functional TOR kinase, which integrates environmental and nutrient signals to direct growth and development. This is particularly important in plants, as they are sessile and must sense and respond to external signals to coordinate multicellular growth appropriately. Thus, the investigation of TOR is essential for plant developmental studies in the context of the resources available for growth. Recently, links have been shown between TOR and plant development from embryogenesis through to senescence, however more investigation is crucial to fully elucidate TOR function in each developmental process.

Nutrient uptake is essential for cellular life and the capacity to perceive extracellular nutrients is critical for coordinating their uptake and metabolism. Commensal fungal pathogens, e.g., Candida albicans, have evolved in close association with human hosts and are well-adapted to using diverse nutrients found in discrete host niches. Human cells that cannot synthesize all amino acids require the uptake of the “essential amino acids” to remain viable. Consistently, high levels of amino acids circulate in the blood. Host proteins are rich sources of amino acids but their use depends on proteases to cleave them into smaller peptides and free amino acids. C. albicans responds to extracellular amino acids by pleiotropically enhancing their uptake and derive energy from their catabolism to power opportunistic virulent growth. Studies using Saccharomyces cerevisiae have established paradigms to understand metabolic processes in C. albicans; however, fundamental differences exist. The advent of CRISPR/Cas9-based methods facilitate genetic analysis in C. albicans, and state-of-the-art molecular biological techniques are being applied to directly examine growth requirements in vivo and in situ in infected hosts. The combination of divergent approaches can illuminate the biological roles of individual cellular components. Here we discuss recent findings regarding nutrient sensing with a focus on amino acid uptake and metabolism, processes that underlie the virulence of C. albicans.

Background: D-3-hydroxybutyrate (D-3-OHB) is a ketone body that serves as an alternative nutritional fuel but also as an important signaling metabolite. Oral ketone supplements containing D/L-3-OHB are becoming a popular approach to achieve ketosis.Aim: To explore the gut-derived effects of ketone supplements.Methods: Eight healthy lean male volunteers were investigated on 2 separate occasions:An acetaminophen test was performed to evaluate gastric emptying and blood samples were obtained consecutively throughout the study period.Results: We show that oral consumption of D/L-3-OHB stimulates cholecystokinin release (P = 0.02), elevates insulin (P = 0.03) and C-peptide (P < 0.001) concentrations, and slows gastric emptying (P = 0.01) compared with matched intravenous D/L-3-OHB administration. Measures of appetite and plasma concentrations of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were unaffected by interventions.Conclusion: Our findings show that D/L-3-OHB exert incretin effects and indicate luminal sensing in the gut endothelium. This adds to our understanding of ketones as signaling metabolites and displays the important difference between physiological ketosis and oral ketone supplements. [ABSTRACT FROM AUTHOR]

Many membrane receptors are regulated by nutrients. However, how these nutrients control a single receptor remains unknown, even in the case of the well-studied calcium-sensing receptor CaSR, which is regulated by multiple factors, including ions and amino acids. Here, we developed an innovative cell-free Förster resonance energy transfer (FRET)-based conformational CaSR biosensor to clarify the main conformational changes associated with activation. By allowing a perfect control of ambient nutrients, this assay revealed that Ca2+ alone fully stabilizes the active conformation, while amino acids behave as pure positive allosteric modulators. Based on the identification of Ca2+ activation sites, we propose a molecular basis for how these different ligands cooperate to control CaSR activation. Our results provide important information on CaSR function and improve our understanding of the effects of genetic mutations responsible for human diseases. They also provide insights into how a receptor can integrate signals from various nutrients to better adapt to the cell response. [ABSTRACT FROM AUTHOR]

Target of rapamycin (TOR) is a protein kinase that coordinates metabolism with nutrient and energy availability in eukaryotes. TOR and its primary interactors, RAPTOR and LST8, have been remarkably evolutionarily static since they arose in the unicellular last common ancestor of plants, fungi, and animals, but the upstream regulatory mechanisms and downstream effectors of TOR signaling have evolved considerable diversity in these separate lineages. Here, I focus on the roles of exaptation and adaptation in the evolution of novel signaling axes in the TOR network in multicellular eukaryotes, concentrating especially on amino acid sensing, cell-cell signaling, and cell differentiation. The protein kinase TOR is an evolutionary "TORtoise" that has not significantly evolved since the last eukaryotic common ancestor. Here, I discuss recent studies illuminating how signaling networks upstream and downstream of TOR have evolved through exaptation and adaptation to coordinate metabolism in diverse eukaryotic lineages. [ABSTRACT FROM AUTHOR]

Recent research has shown expression of clock genes in peripheral tissue explants, targeting multiple pathways leading to the entrainment of circadian rhythms. Temporal variations are not solely regulated by photoperiod, but factors such as maternal feed availability can entrain fetal circadian clock. Currently, a paucity of information exists for clock gene expression and short-term temporal transcript abundance in the bovine placenta, which is essential for proper offspring development. Therefore, the objective of this study was to determine the effect of early to mid-gestational nutrient restriction on clock genes, angiogenic factors, and nutrient sensing genes mRNA transcript abundance in placental explants during a 24 h period. Placentomes from adequately fed and nutrient restricted heifers were collected via Cesarean section at day 180 of gestation; separated into caruncular and cotyledonary tissue and placed in culture media for a 24 h period. The mRNA transcript abundance of clock genes (ARNTL , CRY1 , and PER2), angiogenic factors (HIF1A and VEGFA), and nutrient sensing genes (NAMPT and NR3C1) was determined every 4 h. Clock genes were expressed in caruncular and cotyledonary explant tissue. The caruncular explant transcript abundance of the clock genes was not influenced by time (P > 0.05); while ARNTL abundance decreased over time in the cotyledon explant (P < 0.05). A main effect of time was observed for HIF1A , VEGFA , and NR3C1 in the caruncular tissue (P < 0.05). Although, angiogenic factors and nutrient sensing genes in cotyledonary tissue displayed evident temporal variation in transcript abundance (P < 0.05). Nutrient restriction did not alter (P > 0.15) mRNA transcript abundance of clock genes, angiogenic factors, or nutrient sensing genes in either caruncular or cotyledonary tissue. Interestingly, these data may indicate limited transmission and synchronization of maternal and fetal temporal variations in transcript abundance. These findings demonstrate that multiple timepoint collections are needed in future studies due to the innate existence of temporal oscillations observed in the bovine placenta. • Clock genes (ARNTL, CRY1 and PER2) are expressed in bovine placental explants. • HIF1A, VEGFA, NAMPT , and NR3C1 displayed temporal variation in the cotyledon. • Caruncle gene expression showed a limited temporal variation. • Early gestational nutrient restriction did not affect placenta rhythmicity. [ABSTRACT FROM AUTHOR]

In response to nutrient limitation, many animals, including Caenorhabditis elegans, slow or arrest their development. This process requires mechanisms that sense essential nutrients and induce appropriate responses. When faced with nutrient limitation, C. elegans can induce both short and long‐term survival strategies, including larval arrest, decreased developmental rate, and dauer formation. To select the most advantageous strategy, information from many different sensors must be integrated into signaling pathways, including target of rapamycin (TOR) and insulin, that regulate developmental progression. Here, how nutrient information is sensed and integrated into developmental decisions that determine developmental rate and progression in C. elegans is reviewed. [ABSTRACT FROM AUTHOR]

TARGET OF RAPAMYCIN (TOR) kinase has been recognised as a key developmental regulator in both plants and animals. Despite their distinct developmental programmes, all eukaryotes studied possess a functional TOR kinase, which integrates environmental and nutrient signals to direct growth and development. This is particularly important in plants, as they are sessile and must sense and respond to external signals to coordinate multicellular growth appropriately. Thus, the investigation of TOR is essential for plant developmental studies in the context of the resources available for growth. Recently, links have been shown between TOR and plant development from embryogenesis through to senescence, however more investigation is crucial to fully elucidate TOR function in each developmental process. [ABSTRACT FROM AUTHOR]

Leucine (Leu) and its metabolite β-hydroxy- β-methylbutyrate (HMB) stimulate mechanistic target of rapamycin (mTOR) complex 1 (mTORC1)-dependent protein synthesis in the skeletal muscle of neonatal pigs. This study aimed to determine whether HMB and Leu utilize common nutrient-sensing mechanisms to activate mTORC1. In study 1, neonatal pigs were fed one of five diets for 24 h: low protein (LP), high protein (HP), or LP supplemented with 4 (LP+HMB4), 40 (LP+HMB40), or 80 (LP+HMB80) μmol HMB·kg body wt1·day1. In study 2, neonatal pigs were fed for 24 h: LP, LP supplemented with Leu (LP+Leu), or HP diets delivering 9, 18, and 18 mmol Leu·kg body wt1·day1, respectively. The upstream signaling molecules that regulate mTORC1 activity were analyzed. mTOR phosphorylation on Ser2448 and Ser2481 was greater in LP+HMB40, LP+HMB80, and LP+Leu than in LP and greater in HP than in HMB-supplemented groups (P < 0.05), whereas HP and LP+Leu were similar. Rheb-mTOR complex formation was lower in LP than in HP (P < 0.05), with no enhancement by HMB or Leu supplementation. The Sestrin2-GATOR2 complex was more abundant in LP than in HP and was reduced by Leu (P < 0.05) but not HMB supplementation. RagA-mTOR and RagC-mTOR complexes were higher in LP+Leu and HP than in LP and HMB groups (P < 0.05). There were no treatment differences in RagB-SH3BP4, Vps34- LRS, and RagD-LRS complex abundances. Phosphorylation of Erk1/2 and TSC2, but not AMPK, was lower in LP than HP (P < 0.05) and unaffected by HMB or Leu supplementation. Our results demonstrate that HMB stimulates mTORC1 activation in neonatal muscle independent of the leucine-sensing pathway mediated by Sestrin2 and the Rag proteins. [ABSTRACT FROM AUTHOR]

Dietary restriction (DR) under laboratory conditions generally extends life span and delays ageing across species as diverse as yeast, nematode worms, flies and mice, and is underpinned by taxonomically conserved physiological pathways, notably the insulin‐like signalling pathway (IIS). Despite growing excitement about the links between DR/IIS and ageing within biogerontology, our understanding of why the DR response and associated pathways evolved under natural selection remains controversial and limited.Here, we provide a brief overview of current understanding of the relationship between DR and IIS and ageing from modern biogerontology and go on to summarize the evidence that the IIS pathway integrates a range of important environmental cues including photoperiod, temperature and humidity, as well as nutrition.We go on to discuss the main existing evolutionary explanations for DR and argue that they are not mutually exclusive and are too nutrition‐focussed to fully explain the evolutionary origin of the IIS pathway. In the wild, environmental cues and pressures are dynamic and multivariate, and physiological pathways capable of integrating multiple predictive cues could be strongly favoured by natural selection.We hypothesize that the IIS and related pathways, such as mTOR, evolved to detect and integrate a wide range of environmental cues (not just diet) that are predictive of important selective pressures in the wild. Available evidence suggests the pathway is capable of triggering a range of phenotypic responses, depending on the cues provided, ranging from profound physiological remodelling (e.g. diapause, aestivation, hibernation) associated with promoting survival through challenging environments, to more subtle responses to acute, fine‐scale variation in the environment which may allow individuals to better match their level of reproductive investment to their conditions.We argue that the IIS pathway underpins important adaptive phenotypic plastic responses to a wide range of environmental inputs, of which diet is just one. A multi‐disciplinary approach combining perspectives and methods from biogerontology, cell biology, ecology and evolutionary biology will be essential to develop our understanding of the evolutionary origins of this pathway and the way natural selection and the environment have shaped variation in the IIS pathway's response to different environmental cues. A free Plain Language Summary can be found within the Supporting Information of this article. [ABSTRACT FROM AUTHOR]

Introns are ubiquitous in eukaryotic transcripts. They are often viewed as junk RNA but the huge energetic burden of transcribing, removing, and degrading them suggests a significant evolutionary advantage. Ostensibly, an intron functions within the host pre-mRNA to regulate its splicing, transport, and degradation. However, recent studies have revealed an entirely new class of trans -acting functions where the presence of intronic RNA in the cell impacts the expression of other genes in trans. Here, we review possible new mechanisms of intron functions, with a focus on the role of yeast introns in regulating the cell growth response to starvation. Introns are ubiquitous in large genomes and most human genes have an average of eight introns In small genomes, few genes have introns, mostly in highly expressed genes. Introns regulate all levels of their host gene expression, including transcription, export, RNA stability, and even translation through the exon junction complex. Introns can also act beyond their host genes. In yeast, introns are dispensable when nutrients are abundant but required during starvation. [ABSTRACT FROM AUTHOR]

A complex relationship exists between environmental factors, signaling networks and phenotypic individuality in bacteria. In this review, we will focus on the organization, function and control points of multiple-input histidine kinase-based signaling cascades as a source of phenotypic heterogeneity. In particular, we will examine the quorum sensing cascade in Vibrio harveyi and the pyruvate sensor network in Escherichia coli. We will describe and compare these histidine kinase-based signaling networks in terms of robustness, the molecular mechanisms of signal transduction and the role of RNA switches. Finally, we will discuss the biological significance of phenotypic heterogeneity for the respective bacteria in relation to environmental factors. Unlabelled Image • Design principles of histidine kinase-based signaling networks • Three autoinducers control the expression level of multiple genes. • Pyruvate is taken up according to the needs of individual cells. [ABSTRACT FROM AUTHOR]

Methionine is an essential branch of diverse nutrient inputs that dictate mTORC1 activation. In the absence of methionine, SAMTOR binds to GATOR1 and inhibits mTORC1 signaling. However, how mTORC1 is activated upon methionine stimulation remains largely elusive. Here, we report that PRMT1 senses methionine/SAM by utilizing SAM as a cofactor for an enzymatic activity-based regulation of mTORC1 signaling. Under methionine-sufficient conditions, elevated cytosolic SAM releases SAMTOR from GATOR1, which confers the association of PRMT1 with GATOR1. Subsequently, SAM-loaded PRMT1 methylates NPRL2, the catalytic subunit of GATOR1, thereby suppressing its GAP activity and leading to mTORC1 activation. Notably, genetic or pharmacological inhibition of PRMT1 impedes hepatic methionine sensing by mTORC1 and improves insulin sensitivity in aged mice, establishing the role of PRMT1-mediated methionine sensing at physiological levels. Thus, PRMT1 coordinates with SAMTOR to form the methionine-sensing apparatus of mTORC1 signaling. [Display omitted] • PRMT1 senses methionine/SAM levels to mTORC1 • PRMT1 orchestrates methionine sensing in concert with SAMTOR • PRMT1 methylates NPRL2 and inhibits GATOR1 activity • PRMT1-NPRL2-mTORC1 axis confers organismal response to dietary methionine restriction Jiang et al. reveal that PRMT1 senses methionine levels to activate mTORC1 signaling via the inhibition of GATOR1 by taking SAM as a cofactor to facilitate the asymmetric dimethylation of NPRL2, which plays a key role in orchestrating the organismal response to dietary methionine restriction in aged mice. [ABSTRACT FROM AUTHOR]

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Intestinal nutrient sensing and enteroendocrine functions are critical in controlling feed intake and nutrient transport, yet have been overlooked in agricultural animals. Enteroendocrine cells (EECs) residing on intestinal epithelium monitor luminal chemical environment and orchestrate body neuronal and hormonal responses. After nutrient stimulation, the EECs release hormones, such as glucagon-like peptide 2 (GLP2), which dynamically regulates intestinal nutrient transport and epithelial barrier homeostasis. In pigs, early weaning stress has negatively impacted intestinal development and functions. The objective of the present study is to evaluate effects of early weaning on intestinal nutrient sensing functions, EEC-derived GLP2 production, and epithelial nutrient transport in pigs. Commercial pig littermates (females, n = 9) were split-weaned at the age of d15 (early weaning, EW) and d 26 (late weaning, LW). Piglets were all raised under the same conditions and euthanized at 35 days of age. Intestinal tissues were collected and preserved for later immunohistochemistry staining and gene expression analyses. Immediately post euthanasia, the mucosal layers from jejunum and ileum were mounted on the Ussing chambers to investigate physiological functions. Nutrients transport activities were measured by short circuit current changes (ΔIsc) in response to luminal nutrients (glucose, alanine, lysine, and di-peptide) applications. Nutrient sensing function was measured by GLP2 release rate following glucose stimulation in Ussing chambers. Serum and intestinal tissue concentrations of GLP2 were also measured by ELISA. Data were analyzed by the student's t-test. Our results showed altered electrogenic nutrients and ion transport activities between EW and LW pigs. The ileal basal Isc was significantly less in EW pigs, indicating a reduction in ions transport. The EW pigs significantly downregulated electrogenic lysine transport, while upregulated active transport of dipeptide. The EECs number in ileum was reduced in EW pigs, indicated by less ChgA (EEC cell marker) mRNA and significantly less ChgA positive-stained cells. In addition, EW pigs exhibited a pattern of EECs relocation, in which the ChgA-positive cells enriched towards the lower half of villi. Nutrient sensing activities of the EECs were suppressed in both jejunum and ileum in EW pigs, indicated by a significant reduction in the glucose-stimulated GLP2 release on Ussing chambers. Moreover, in contrast with the significantly greater GLP2 concentration in ileum, the serum GLP2 concentration was significantly less in the EW pigs, which reflected a decreased GLP2 release rate. In summary, our results suggested that early weaning stress altered EECs number and locations on epithelium, reduced EECs nutrient sensing activities and endogenous GLP2 release, and changed nutrient transport activities. Understanding the mechanism by which early weaning stress regulates intestinal nutrient sensing and transport functions will lead to novel feeding strategies that improve intestinal health and animal production. [ABSTRACT FROM AUTHOR]

The mammalian/mechanistic target of rapamycin (mTOR) is a key component of cellular metabolism that integrates nutrient sensing with cellular processes that fuel cell growth and proliferation. Although the involvement of the mTOR pathway in regulating life span and aging has been studied extensively in the last decade, the underpinning mechanisms remain elusive. In this review, we highlight the emerging insights that link mTOR to various processes related to aging, such as nutrient sensing, maintenance of proteostasis, autophagy, mitochondrial dysfunction, cellular senescence, and decline in stem cell function.

All organisms confront the challenges of maintaining metabolic homeostasis in light of both variabilities in nutrient supplies and energetic costs of different physiologies and behaviors. While all cells are nutrient sensitive, only relative few cells within Metazoans are nutrient sensing cells. Nutrient sensing cells organize systemic behavioral and physiological responses to changing metabolic states. One group of cells present in the arthropods, is the adipokinetic hormone producing cells (APCs). APCs possess intrinsic nutrient sensors and receive contextual information regarding metabolic state through other endocrine connections. APCs express receptors for different hormones which modulate APC physiology and the secretion of the adipokinetic hormone (AKH). APCs are functionally similar to alpha cells in the mammalian pancreas and display a similar physiological organization. AKH release results in both hypertrehalosemia and hyperlipidemia through high affinity binding to the AKH receptor (AKHR). Another hallmark of AKH signaling is heightened locomotor activity, which accompanies starvation and is thought to enhance foraging. In this review, we discuss mechanisms of nutrient sensing and modulation of AKH release. Additionally, we compare the organization of AKH/AKHR signaling in different taxa. Lastly, we consider the signals that APCs integrate as well as recent experimental results that have expanded the functional repertoire of AKH signaling, further establishing this as both a metabolic and stress hormone.

Dietary protein restriction and dietary methionine restriction (MR) produce a comparable series of behavioral, physiological, biochemical, and transcriptional responses. Both dietary regimens produce a similar reduction in intake of sulfur amino acids (e.g., methionine and cystine), and both diets increase expression and release of hepatic FGF21. Given that FGF21 is an essential mediator of the metabolic phenotype produced by both diets, an important unresolved question is whether dietary protein restriction represents de facto methionine restriction. Using diets formulated from either casein or soy protein with matched reductions in sulfur amino acids, we compared the ability of the respective diets to recapitulate the metabolic phenotype produced by methionine restriction using elemental diets. Although the soy-based control diets supported faster growth compared to casein-based control diets, casein-based protein restriction and soy-based protein restriction produced comparable reductions in body weight and fat deposition, and similar increases in energy intake, energy expenditure, and water intake. In addition, the prototypical effects of dietary MR on hepatic and adipose tissue target genes were similarly regulated by casein- and soy-based protein restriction. The present findings support the feasibility of using restricted intake of diets from various protein sources to produce therapeutically effective implementation of dietary methionine restriction.

The principal sensing of dietary methionine restriction (MR) occurs in the liver, where it activates multiple transcriptional programs that mediate various biological components of the response. Hepatic Fgf21 is a key target and essential endocrine mediator of the metabolic phenotype produced by dietary MR. The transcription factor, Nfe2l2, is also activated by MR and functions in tandem with hepatic Atf4 to transactivate multiple, antioxidative components of the integrated stress response. However, it is unclear whether the transcriptional responses linked to Nfe2l2 activation by dietary MR are essential to the biological efficacy of the diet. Using mice with liver-specific deletion of Nfe2l2 (Nfe2l2fl/(Alb)) and their floxed littermates (Nfe2l2fl/fl) fed either Control or MR diets, the absence of hepatic Nfe2l2 had no effect on the ability of the MR diet to increase FGF21, reduce body weight and adiposity, and increase energy expenditure. Moreover, the primary elements of the hepatic transcriptome were similarly affected by MR in both genotypes, with the only major differences occurring in induction of the P450-associated drug metabolism pathway and the pentose glucuronate interconversion pathway. The biological significance of these pathways is uncertain but we conclude that hepatic Nfe2l2 is not essential in mediating the metabolic effects of dietary MR.

The global burden of obesity and the challenges of prevention prompted researchers to investigate the mechanisms that control food intake. Food ingestion triggers several physiological responses in the digestive system, including the release of gastrointestinal hormones from enteroendocrine cells that are involved in appetite signalling. Disturbed regulation of gut hormone release may affect energy homeostasis and contribute to obesity. In this review, we summarize the changes that occur in the gut hormone balance during the pre- and postprandial state in obesity and the alterations in the diurnal dynamics of their plasma levels. We further discuss how obesity may affect nutrient sensors on enteroendocrine cells that sense the luminal content and provoke alterations in their secretory profile. Gastric bypass surgery elicits one of the most favorable metabolic outcomes in obese patients. We summarize the effect of different strategies to induce weight loss on gut enteroendocrine function. Although the mechanisms underlying obesity are not fully understood, restoring the gut hormone balance in obesity by targeting nutrient sensors or by combination therapy with gut peptide mimetics represents a novel strategy to ameliorate obesity.

Obesity currently represents a major societal and health challenge worldwide. Its prevalence has reached epidemic proportions and trends continue to rise, reflecting the need for more effective preventive measures. Hypothalamic circuits that control energy homeostasis in response to food intake are interesting targets for body-weight management, for example, through interventions that reinforce the gut-to-brain nutrient signalling, whose malfunction contributes to obesity. Gut microbiota–diet interactions might interfere in nutrient sensing and signalling from the gut to the brain, where the information is processed to control energy homeostasis. This gut microbiota–brain crosstalk is mediated by metabolites, mainly short chain fatty acids, secondary bile acids or amino acids-derived metabolites and subcellular bacterial components. These activate gut–endocrine and/or neural-mediated pathways or pass to systemic circulation and then reach the brain. Feeding time and dietary composition are the main drivers of the gut microbiota structure and function. Therefore, aberrant feeding patterns or unhealthy diets might alter gut microbiota–diet interactions and modify nutrient availability and/or microbial ligands transmitting information from the gut to the brain in response to food intake, thus impairing energy homeostasis. Herein, we update the scientific evidence supporting that gut microbiota is a source of novel dietary and non-dietary biological products that may beneficially regulate gut-to-brain communication and, thus, improve metabolic health. Additionally, we evaluate how the feeding time and dietary composition modulate the gut microbiota and, thereby, the intraluminal availability of these biological products with potential effects on energy homeostasis. The review also identifies knowledge gaps and the advances required to clinically apply microbiome-based strategies to improve the gut–brain axis function and, thus, combat obesity.

Abstract This review examines the biology of the Fat mass- and obesity-associated gene (FTO), and the implications of genetic association of FTO SNPs with obesity and genetic aging. Notably, we focus on the role of FTO in the regulation of methylation status as possible regulators of weight gain and genetic aging. We present a theoretical review of the FTO gene with a particular emphasis on associations with UCP2, AMPK, RBL2, IRX3, CUX1, mTORC1 and hormones involved in hunger regulation. These associations are important for dietary behavior regulation and cellular nutrient sensing via amino acids. We suggest that these pathways may also influence telomere regulation. Telomere length (TL) attrition may be influenced by obesity-related inflammation and oxidative stress, and FTO gene-involved pathways. There is additional emerging evidence to suggest that telomere length and obesity are bi-directionally associated. However, the role of obesity risk-related genotypes and associations with TL are not well understood. The FTO gene may influence pathways implicated in regulation of TL, which could help to explain some of the non-consistent relationship between weight phenotype and telomere length that is observed in population studies investigating obesity.

In both Drosophila melanogaster and mammalian systems, epithelial structure and underlying cell polarity are essential for proper tissue morphogenesis and organ growth. Cell polarity interfaces with multiple cellular processes that are regulated by the phosphorylation status of large protein networks. To gain insight into the molecular mechanisms that coordinate cell polarity with tissue growth, we screened a boutique collection of RNAi stocks targeting the kinome for their capacity to modify Drosophila “cell polarity” eye and wing phenotypes. Initially, we identified kinase or phosphatase genes whose depletion modified adult eye phenotypes associated with the manipulation of cell polarity complexes (via overexpression of Crb or aPKC). We next conducted a secondary screen to test whether these cell polarity modifiers altered tissue overgrowth associated with depletion of Lgl in the wing. These screens identified Hippo, Jun kinase (JNK), and Notch signaling pathways, previously linked to cell polarity regulation of tissue growth. Furthermore, novel pathways not previously connected to cell polarity regulation of tissue growth were identified, including Wingless (Wg/Wnt), Ras, and lipid/Phospho-inositol-3-kinase (PI3K) signaling pathways. Additionally, we demonstrated that the “nutrient sensing” kinases Salt Inducible Kinase 2 and 3 (SIK2 and 3) are potent modifiers of cell polarity phenotypes and regulators of tissue growth. Overall, our screen has revealed novel cell polarity-interacting kinases and phosphatases that affect tissue growth, providing a platform for investigating molecular mechanisms coordinating cell polarity and tissue growth during development.

Class 1 Phosphoinositide-3-Kinases (PI3Ks) have been widely studied and mediate essential roles in cellular proliferation, chemotaxis, insulin sensitivity, and immunity. Here, we provide a comprehensive overview of how macrophage expressed PI3Ks and their downstream pathways orchestrate responses to metabolic stimuli and nutrients, polarizing macrophages, shaping their cellular identity and function. Particular emphasis will be given to adipose tissue macrophages, crucial players of insulin resistance and chronic metabolically triggered inflammation during obesity. An understanding of PI3K dependent wiring of macrophage responses is important as this is involved in various diseases ranging from obesity, type 2 diabetes to chronic inflammatory disease.

Nutrient sensing is critical for adaptation of fungi to environmental and host conditions. The conserved cAMP/PKA signaling pathway contributes to adaptation by sensing the availability of key nutrients such as glucose and directing changes in gene expression and metabolism. Interestingly, the cAMP/PKA pathway in fungal pathogens also influences the expression of virulence determinants in response to nutritional and host signals. For instance, protein kinase A (PKA) in the human pathogen Cryptococcus neoformans plays a central role in orchestrating phenotypic changes, such as capsule elaboration and melanin production, that directly impact disease development. In this review, we focus first on insights into the role of the cAMP/PKA pathway in nutrient sensing for the model yeast Saccharomyces cerevisiae to provide a foundation for understanding the pathway in C. neoformans. We then discuss key features of cAMP/PKA signaling in C. neoformans including new insights emerging from the analysis of transcriptional and proteomic changes in strains with altered PKA activity and expression. Finally, we highlight recent studies that connect the cAMP/PKA pathway to cell surface remodeling and the formation of titan cells.

More than 1.5 million fungal species are estimated to live in vastly different environmental niches. Despite each unique host environment, fungal cells sense certain fundamentally conserved elements, such as nutrients, pheromones and stress, for adaptation to their niches. Sensing these extracellular signals is critical for pathogens to adapt to the hostile host environment and cause disease. Hence, dissecting the complex extracellular signal-sensing mechanisms that aid in this is pivotal and may facilitate the development of new therapeutic approaches to control fungal infections. In this review, we summarize the current knowledge on how two important pathogenic yeasts, Candida albicans and Cryptococcus neoformans, sense nutrient availability, such as carbon sources, amino acids, and ammonium, and different stress signals to regulate their morphogenesis and pathogenicity in comparison with the non-pathogenic model yeast Saccharomyces cerevisiae. The molecular interactions between extracellular signals and their respective sensory systems are described in detail. The potential implication of analyzing nutrient and stress-sensing systems in antifungal drug development is also discussed.

Root exudation is an important process determining plant interactions with the soil environment. Many studies have linked this process to soil nutrient mobilization. Yet, it remains unresolved how exudation is controlled and how exactly and under what circumstances plants benefit from exudation. The majority of root exudates including primary metabolites (sugars, amino acids, and organic acids) are believed to be passively lost from the root and used by rhizosphere-dwelling microbes. In this review, we synthetize recent advances in ecology and plant biology to explain and propose mechanisms by which root exudation of primary metabolites is controlled, and what role their exudation plays in plant nutrient acquisition strategies. Specifically, we propose a novel conceptual framework for root exudates. This framework is built upon two main concepts: (1) root exudation of primary metabolites is driven by diffusion, with plants and microbes both modulating concentration gradients and therefore diffusion rates to soil depending on their nutritional status; (2) exuded metabolite concentrations can be sensed at the root tip and signals are translated to modify root architecture. The flux of primary metabolites through root exudation is mostly located at the root tip, where the lack of cell differentiation favors diffusion of metabolites to the soil. We show examples of how the root tip senses concentration changes of exuded metabolites and translates that into signals to modify root growth. Plants can modify the concentration of metabolites either by controlling source/sink processes or by expressing and regulating efflux carriers, therefore challenging the idea of root exudation as a purely unregulated passive process. Through root exudate flux, plants can locally enhance concentrations of many common metabolites, which can serve as sensors and integrators of the plant nutritional status and of the nutrient availability in the surrounding environment. Plant-associated micro-organisms also constitute a strong sink for plant carbon, thereby increasing concentration gradients of metabolites and affecting root exudation. Understanding the mechanisms of and the effects that environmental stimuli have on the magnitude and type of root exudation will ultimately improve our knowledge of processes determining soil CO2 emissions, ecosystem functioning, and how to improve the sustainability of agricultural production.

Lysosomes are more than just cellular recycling bins; they play a crucial role in regulating key cellular functions. Proper lysosomal function is essential for growth pathway regulation, cell proliferation, and metabolic homeostasis. Impaired lysosomal function is associated with lipid storage disorders and neurodegenerative diseases. Lysosomes form extensive and dynamic close contacts with the membranes of other organelles, including the endoplasmic reticulum, mitochondria, peroxisomes, and lipid droplets. These membrane contacts sites (MCSs) are vital for many lysosomal functions. In this chapter, we will explore lysosomal MCSs focusing on the machinery that mediates these contacts, how they are regulated, and their functional implications on physiology and pathology., (Copyright © 2024. Published by Elsevier Inc.)

Increased anthropogenic emissions of carbon dioxide (CO 2 ) have resulted in ocean acidification (OA) that is intertwined with enhanced ocean stratification. Diatoms are assumed to suffer from a more nutrient-limited condition in the future ocean. This study aimed to explore how OA affects the diatom dynamics under nutrient-poor conditions and the ability of diatoms to perceive nutrients (nitrogen, phosphorus, silicon, and trace metals) and cadmium (Cd) stimuli and assimilate nitrogen when receiving nutrients or Cd supplementation. Our study observed that diatom population grown under OA condition declined faster than those grown under ambient condition. Ocean acidification greatly lower intracellular Ca 2+ concentration in diatom cells. Intracellular Ca 2+ burst was involved in phosphorus accumulation but not in nitrogen, silicon, essential metals, and cadmium uptake. Our data demonstrate slower NO 3 - assimilation rates of diatoms grown in acidified seawater. Our study also indicates that diatoms have a poor perception of phosphorus availability under OA condition., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Potassium (K) is an essential macronutrient for plant growth, and its availability in the soil varies widely, requiring plants to respond and adapt to the changing K nutrient status. We show here that plant growth rate is closely correlated with K status in the medium, and this K-dependent growth is mediated by the highly conserved nutrient sensor, target of rapamycin (TOR). Further study connected the TOR complex (TORC) pathway with a low-K response signaling network consisting of calcineurin B-like proteins (CBL) and CBL-interacting kinases (CIPK). Under high K conditions, TORC is rapidly activated and shut down the CBL-CIPK low-K response pathway through regulatory-associated protein of TOR (RAPTOR)-CIPK interaction. In contrast, low-K status activates CBL-CIPK modules that in turn inhibit TORC by phosphorylating RAPTOR, leading to dissociation and thus inactivation of the TORC. The reciprocal regulation of the TORC and CBL-CIPK modules orchestrates plant response and adaptation to K nutrient status in the environment.

Cell cycle errors can lead to mutations, chromosomal instability, or death; thus, the precise control of cell cycle progression is essential for viability. The nutrient-sensing posttranslational modification, O-GlcNAc, regulates the cell cycle allowing one central control point directing progression of the cell cycle. O-GlcNAc is a single N-acetylglucosamine sugar modification to intracellular proteins that is dynamically added and removed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. These enzymes act as a rheostat to fine-tune protein function in response to a plethora of stimuli from nutrients to hormones. O-GlcNAc modulates mitogenic growth signaling, senses nutrient flux through the hexosamine biosynthetic pathway, and coordinates with other nutrient-sensing enzymes to progress cells through Gap phase 1 (G 1 ). At the G 1 /S transition, O-GlcNAc modulates checkpoint control, while in S Phase, O-GlcNAcylation coordinates the replication fork. DNA replication errors activate O-GlcNAcylation to control the function of the tumor-suppressor p53 at Gap Phase 2 (G 2 ). Finally, in mitosis (M phase), O-GlcNAc controls M phase progression and the organization of the mitotic spindle and midbody. Critical for M phase control is the interplay between OGT and OGA with mitotic kinases. Importantly, disruptions in OGT and OGA activity induce M phase defects and aneuploidy. These data point to an essential role for the O-GlcNAc rheostat in regulating cell division. In this review, we highlight O-GlcNAc nutrient sensing regulating G 1 , O-GlcNAc control of DNA replication and repair, and finally, O-GlcNAc organization of mitotic progression and spindle dynamics., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Receptors located on enteroendocrine cells (EECs) of the colon can detect nutrients in the lumen. These receptors regulate appetite through a variety of mechanisms, including hormonal and neuronal signals. We assessed the effect of obesity on the expression of these G-protein coupled receptors (GPCRs) and hormones at both mRNA and protein level. Methods: qPCR and immunohistochemistry were used to examine colonic tissue from cohorts of patients from the Netherlands (proximal and sigmoid tissue) and the United Kingdom (tissue from across the colon) and patients were grouped by body mass index (BMI) value (BMI < 25 and BMI ≥ 25). Results: The mRNA expression of the hormones/signaling molecules serotonin, glucagon, peptide YY (PYY), CCK and somatostatin were not significantly different between BMI groups. GPR40 mRNA expression was significantly increased in sigmoid colon samples in the BMI ≥ 25 group, but not proximal colon. GPR41, GPR109a, GPR43, GPR120, GPRC6A, and CaSR mRNA expression were unaltered between low and high BMI. At the protein level, serotonin and PYY containing cell numbers were similar in high and low BMI groups. Enterochromaffin cells (EC) showed high degree of co-expression with amino acid sensing receptor, CaSR while co-expression with PYY containing L-cells was limited, regardless of BMI. Conclusions: While expression of medium/long chain fatty acid receptor GPR40 was increased in the sigmoid colon of the high BMI group, expression of other nutrient sensing GPCRs, and expression profiles of EECs involved in peripheral mechanisms of appetite regulation were unchanged. Collectively, these data suggest that in human colonic tissue, EEC and nutrient-sensing receptor expression profiles are not affected despite changes to BMI.