Insulin/insulin-like growth factor signalling (IIS) is a critical regulator of an organism's most important biological decisions from growth, development, and metabolism to reproduction and ...longevity. It primarily does so through the activity of the DAF-16 transcription factor (forkhead box O (FOXO) homologue), whose global targets were identified in Caenorhabditis elegans using whole-worm transcriptional analyses more than a decade ago. IIS and FOXO also regulate important neuronal and adult behavioural phenotypes, such as the maintenance of memory and axon regeneration with age, in both mammals and C. elegans, but the neuron-specific IIS/FOXO targets that regulate these functions are still unknown. By isolating adult C. elegans neurons for transcriptional profiling, we identified both the wild-type and IIS/FOXO mutant adult neuronal transcriptomes for the first time. IIS/FOXO neuron-specific targets are distinct from canonical IIS/FOXO-regulated longevity and metabolism targets, and are required for extended memory in IIS daf-2 mutants. The activity of the forkhead transcription factor FKH-9 in neurons is required for the ability of daf-2 mutants to regenerate axons with age, and its activity in non-neuronal tissues is required for the long lifespan of daf-2 mutants. Together, neuron-specific and canonical IIS/FOXO-regulated targets enable the coordinated extension of neuronal activities, metabolism, and longevity under low-insulin signalling conditions.
Time-restricted feeding (TRF) is an emerging behavioral nutrition intervention that involves a daily cycle of feeding and fasting. In both animals and humans, TRF has pleiotropic health benefits that ...arise from multiple organ systems, yet the molecular basis of TRF-mediated benefits is not well understood. Here, we subjected mice to isocaloric ad libitum feeding (ALF) or TRF of a western diet and examined gene expression changes in samples taken from 22 organs and brain regions collected every 2 h over a 24-h period. We discovered that TRF profoundly impacts gene expression. Nearly 80% of all genes show differential expression or rhythmicity under TRF in at least one tissue. Functional annotation of these changes revealed tissue- and pathway-specific impacts of TRF. These findings and resources provide a critical foundation for future mechanistic studies and will help to guide human time-restricted eating (TRE) interventions to treat various disease conditions with or without pharmacotherapies.
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•80% of genes are differentially expressed or rhythmic under TRF in at least one tissue•TRF decreases genes involved in inflammatory signaling and glycerolipid metabolism•TRF increases genes involved in RNA processing, protein folding, and autophagy•TRF causes multi-tissue rewiring of BCAA, glucose, and lipid metabolism
Deota et al. present a diurnal transcriptome atlas to map changes in response to time-restricted feeding (TRF) in 22 organs and brain regions. Under TRF, rhythmic gene expression increases across most tissues, and 80% of all genes show differential expression or rhythmicity in at least one tissue. TRF-induced feeding-fasting cycles lead to phase consolidation of anabolic and catabolic genes, improve metabolic flexibility, and cause multi-tissue rewiring of nutrient metabolism.
A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8+ tumor infiltrating lymphocytes (TILs) ...respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8+ TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8+ TILs, which also correlated with progressive T cell dysfunction. Cd36−/− T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8+ TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8+ T cell dysfunction and serves as a therapeutic avenue for immunotherapies.
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•The tumor microenvironment is enriched with lipids and oxidized lipids•Dysfunctional CD8+ TILs increase CD36 expression and OxLDL uptake•OxLDL uptake via CD36 inhibits T cell effector functions through lipid peroxidation•GPX4 overexpression promotes CD8+ TIL functionality
Lipid accumulation is a common metabolic alteration in the tumor microenvironment. Xu et al. show that intratumoral CD8+ T cells adapt to increased lipid concentrations by increasing expression of the scavenger receptor CD36. This, in turn, leads to intracellular accumulation of oxidized lipid and T cell dysfunction downstream of lipid peroxidation.
Cancers arise through the accumulation of genetic and epigenetic alterations that enable cells to evade telomere-based proliferative barriers and achieve immortality. One such barrier is replicative ...crisis-an autophagy-dependent program that eliminates checkpoint-deficient cells with unstable telomeres and other cancer-relevant chromosomal aberrations
. However, little is known about the molecular events that regulate the onset of this important tumour-suppressive barrier. Here we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as a regulator of the crisis program. A crisis-associated isoform of ZBP1 is induced by the cGAS-STING DNA-sensing pathway, but reaches full activation only when associated with telomeric-repeat-containing RNA (TERRA) transcripts that are synthesized from dysfunctional telomeres. TERRA-bound ZBP1 oligomerizes into filaments on the outer mitochondrial membrane of a subset of mitochondria, where it activates the innate immune adapter protein mitochondrial antiviral-signalling protein (MAVS). We propose that these oligomerization properties of ZBP1 serve as a signal amplification mechanism, where few TERRA-ZBP1 interactions are sufficient to launch a detrimental MAVS-dependent interferon response. Our study reveals a mechanism for telomere-mediated tumour suppression, whereby dysfunctional telomeres activate innate immune responses through mitochondrial TERRA-ZBP1 complexes to eliminate cells destined for neoplastic transformation.
More than 33% of adults in the US have prediabetes yet only 11% report having been diagnosed with the condition (CDC). Lifestyle counseling has been shown to reduce risk for progression to diabetes.
...To evaluate the prevalence of lifestyle counseling for diabetes prevention and demographic associations of adults who have self-reported prediabetes.
Data include adults who self-reported they were informed by a provider to have prediabetes, be at risk for diabetes and/or be borderline for diabetes (n = 1110) from the National Health and Nutrition Examination Survey 2015-2016.
Lifestyle counseling outcomes are weight loss, physical activity and nutrition recommendations. Frequencies of demographics (gender, poverty level, race/ethnicity, age and BMI) are summarized for these outcomes. Chi-square testing determined association for outcomes and multiple logistic regression showed predictive association between outcomes and demographics.
Rates of lifestyle counseling for the self-reported prediabetes population range between 31% - 60%. BMI is associated with all counseling outcomes, with obesity being the largest predictor of provider counseling about weight loss (OR 20.0; CL 7.0, 57.5), physical activity (OR 4.0; CL 2.0, 7.8), reduction of fat/calories (OR 4.4; CL 2.7, 7.4), and reduction of sodium (OR 5.6; CL 2.9, 11.0). Sodium reduction is the only outcome associated with multiple demographics: poverty (P = .0007), race/ethnicity (P < .0001), age (P < .0001), and BMI (P < .0001).
Provider conversations about lifestyle change for diabetes prevention are variable. To better understand how providers give lifestyle counseling to prevent prediabetes progression to diabetes, future research can examine salience of topics, barriers and causes of possible disparities.
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