The human gut contains trillions of microorganisms that influence our health by metabolizing xenobiotics, including host-targeted drugs and antibiotics. Recent efforts have characterized the ...diversity of this host-associated community, but it remains unclear which microorganisms are active and what perturbations influence this activity. Here, we combine flow cytometry, 16S rRNA gene sequencing, and metatranscriptomics to demonstrate that the gut contains a distinctive set of active microorganisms, primarily Firmicutes. Short-term exposure to a panel of xenobiotics significantly affected the physiology, structure, and gene expression of this active gut microbiome. Xenobiotic-responsive genes were found across multiple bacterial phyla, encoding antibiotic resistance, drug metabolism, and stress response pathways. These results demonstrate the power of moving beyond surveys of microbial diversity to better understand metabolic activity, highlight the unintended consequences of xenobiotics, and suggest that attempts at personalized medicine should consider interindividual variations in the active human gut microbiome.
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► The gut microbiome is highly active, similar to nutrient-rich productive systems ► Firmicutes dominate the active and damaged subsets of the gut microbiome ► Both antibiotics and host-targeted drugs rapidly alter the active gut microbiome ► Xenobiotics induce genes for drug metabolism, drug resistance, and stress response
Moving beyond phylogenetic characterizations of the human gut microbiota, Maurice et al. characterize how the gene expression and metabolic activity of a distinctive set of active gut microbes are rapidly affected by host-targeted drugs and antibiotics. The findings highlight the unintended consequences of xenobiotics and indicate the microbiota as another factor to consider in developing personalized medicines.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
This book provides an accessible and self-contained introduction to the theory of algebraic curves over a finite field, a subject that has been of fundamental importance to mathematics for many years ...and that has essential applications in areas such as finite geometry, number theory, error-correcting codes, and cryptology. Unlike other books, this one emphasizes the algebraic geometry rather than the function field approach to algebraic curves.
The authors begin by developing the general theory of curves over any field, highlighting peculiarities occurring for positive characteristic and requiring of the reader only basic knowledge of algebra and geometry. The special properties that a curve over a finite field can have are then discussed. The geometrical theory of linear series is used to find estimates for the number of rational points on a curve, following the theory of Stöhr and Voloch. The approach of Hasse and Weil via zeta functions is explained, and then attention turns to more advanced results: a state-of-the-art introduction to maximal curves over finite fields is provided; a comprehensive account is given of the automorphism group of a curve; and some applications to coding theory and finite geometry are described. The book includes many examples and exercises. It is an indispensable resource for researchers and the ideal textbook for graduate students.
Impaired white adipose tissue (WAT) function has been recognized as a critical early event in obesity‐driven disorders, but high buoyancy, fragility, and heterogeneity of primary adipocytes have ...largely prevented their use in drug discovery efforts highlighting the need for human stem cell‐based approaches. Here, human stem cells are utilized to derive metabolically functional 3D adipose tissue (iADIPO) in a microphysiological system (MPS). Surprisingly, previously reported WAT differentiation approaches create insulin resistant WAT ill‐suited for type‐2 diabetes mellitus drug discovery. Using three independent insulin sensitivity assays, i.e., glucose and fatty acid uptake and suppression of lipolysis, as the functional readouts new differentiation conditions yielding hormonally responsive iADIPO are derived. Through concomitant optimization of an iADIPO‐MPS, it is abled to obtain WAT with more unilocular and significantly larger (≈40%) lipid droplets compared to iADIPO in 2D culture, increased insulin responsiveness of glucose uptake (≈2–3 fold), fatty acid uptake (≈3–6 fold), and ≈40% suppressing of stimulated lipolysis giving a dynamic range that is competent to current in vivo and ex vivo models, allowing to identify both insulin sensitizers and desensitizers.
This study uses human stem cells to derive metabolically functional 3D adipose tissue in a microphysiological system. Through concomitant optimization, the adipose system shows mostly unilocular and significantly larger lipid droplets, increased insulin responsiveness of glucose uptake, fatty acid uptake, and suppressing of stimulated lipolysis compared to 2D culture, providing a good dynamic range to identify insulin sensitizers and desensitizers.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Organ-on-a-chip systems possess a promising future as drug screening assays and as testbeds for disease modeling in the context of both single-organ systems and multi-organ-chips. Although it ...comprises approximately one fourth of the body weight of a healthy human, an organ frequently overlooked in this context is white adipose tissue (WAT). WAT-on-a-chip systems are required to create safety profiles of a large number of drugs due to their interactions with adipose tissue and other organs
via
paracrine signals, fatty acid release, and drug levels through sequestration. We report a WAT-on-a-chip system with a footprint of less than 1 mm
2
consisting of a separate media channel and WAT chamber connected
via
small micropores. Analogous to the
in vivo
blood circulation, convective transport is thereby confined to the vasculature-like structures and the tissues protected from shear stresses. Numerical and analytical modeling revealed that the flow rates in the WAT chambers are less than 1/100 of the input flow rate. Using optimized injection parameters, we were able to inject pre-adipocytes, which subsequently formed adipose tissue featuring fully functional lipid metabolism. The physiologically relevant microfluidic environment of the WAT-chip supported long term culture of the functional adipose tissue for more than two weeks. Due to its physiological, highly controlled, and computationally predictable character, the system has the potential to be a powerful tool for the study of adipose tissue associated diseases such as obesity and type 2 diabetes.
Organs-on-a-chip possess a promising future as drug screening assays and testbeds for disease modeling in the context of both single-organ systems and multi-organ-chips.
The discovery and generation of effective therapeutics to combat disease lies at the heart of biomedical research. Preclinical studies form the foundation of potential disease treatments, guiding ...their journey from scientific discovery to impactful patient outcomes. However, over the past two decades, preclinical research has been frequently plagued by the failure to replicate consistent results, costing an estimated $28 billion USD per year. Potential therapeutics from preclinical studies entering phase I trials only had a 10.4% approval rate between 2003 and 2014 and an even lower 6% to 7% rate between 2011 and 2017. The disappointing reality of promising preclinical findings that fail to translate into effective therapies has raised serious concerns within the scientific community. The cause of this failure is potentially elucidated in a 2015 retrospective analysis of four large biotech companies that showed the most common causes of termination in phase I and II clinical trials since 2003 are the lack of efficacy (60% of all trials) and toxicity (30%). Given these insights and the emergence of advanced technologies that enable large-cohort, in vitro human testing, a pressing need to reassess our approaches to studying human diseases exists. Such changes are vital to facilitating the development of lifesaving therapeutics that can extend both health span and life span by more efficiently.
Chronic white adipose tissue (WAT) inflammation has been recognized as a critical early event in the pathogenesis of obesity‐related disorders. This process is characterized by the increased ...residency of proinflammatory M1 macrophages in WAT. However, the lack of an isogenic human macrophage‐adipocyte model has limited biological studies and drug discovery efforts, highlighting the need for human stem cell‐based approaches. Here, human induced pluripotent stem cell (iPSC) derived macrophages (iMACs) and adipocytes (iADIPOs) are cocultured in a microphysiological system (MPS). iMACs migrate toward and infiltrate into the 3D iADIPOs cluster to form crown‐like structures (CLSs)‐like morphology around damaged iADIPOs, recreating classic histological features of WAT inflammation seen in obesity. Significantly more CLS‐like morphologies formed in aged and palmitic acid‐treated iMAC‐iADIPO‐MPS, showing the ability to mimic inflammatory severity. Importantly, M1 (proinflammatory) but not M2 (tissue repair) iMACs induced insulin resistance and dysregulated lipolysis in iADIPOs. Both RNAseq and cytokines analyses revealed a reciprocal proinflammatory loop in the interactions of M1 iMACs and iADIPOs. This iMAC‐iADIPO‐MPS thus successfully recreates pathological conditions of chronically inflamed human WAT, opening a door to study the dynamic inflammatory progression and identify clinically relevant therapies.
Here, iPSC‐derived macrophages and adipocytes are cocultured in a microphysiological system. Macrophages migrate toward and infiltrate into the 3D adipocytes cluster to form crown‐like structures. M1 but not M2 macrophages induced insulin resistance and dysregulated lipolysis in adipocytes, causing a reciprocal proinflammatory loop. This isogenic system opens a door to study the dynamic inflammatory progression and identify clinically relevant therapies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Exercise confers protection against obesity, type 2 diabetes and other cardiometabolic diseases
. However, the molecular and cellular mechanisms that mediate the metabolic benefits of physical ...activity remain unclear
. Here we show that exercise stimulates the production of N-lactoyl-phenylalanine (Lac-Phe), a blood-borne signalling metabolite that suppresses feeding and obesity. The biosynthesis of Lac-Phe from lactate and phenylalanine occurs in CNDP2
cells, including macrophages, monocytes and other immune and epithelial cells localized to diverse organs. In diet-induced obese mice, pharmacological-mediated increases in Lac-Phe reduces food intake without affecting movement or energy expenditure. Chronic administration of Lac-Phe decreases adiposity and body weight and improves glucose homeostasis. Conversely, genetic ablation of Lac-Phe biosynthesis in mice increases food intake and obesity following exercise training. Last, large activity-inducible increases in circulating Lac-Phe are also observed in humans and racehorses, establishing this metabolite as a molecular effector associated with physical activity across multiple activity modalities and mammalian species. These data define a conserved exercise-inducible metabolite that controls food intake and influences systemic energy balance.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Green, natural environments may ameliorate adverse environmental exposures (e.g., air pollution, noise, and extreme heat), increase physical activity and social engagement, and lower stress.
We aimed ...to examine the prospective association between residential greenness and mortality.
Using data from the U.S.-based Nurses' Health Study prospective cohort, we defined cumulative average time-varying seasonal greenness surrounding each participant's address using satellite imagery Normalized Difference Vegetation Index (NDVI). We followed 108,630 women and observed 8,604 deaths between 2000 and 2008.
In models adjusted for mortality risk factors (age, race/ethnicity, smoking, and individual- and area-level socioeconomic status), women living in the highest quintile of cumulative average greenness (accounting for changes in residence during follow-up) in the 250-m area around their home had a 12% lower rate of all-cause nonaccidental mortality 95% confidence interval (CI); 0.82, 0.94 than those in the lowest quintile. The results were consistent for the 1,250-m area, although the relationship was slightly attenuated. These associations were strongest for respiratory and cancer mortality. The findings from a mediation analysis suggested that the association between greenness and mortality may be at least partly mediated by physical activity, particulate matter < 2.5 μm, social engagement, and depression.
Higher levels of green vegetation were associated with decreased mortality. Policies to increase vegetation may provide opportunities for physical activity, reduce harmful exposures, increase social engagement, and improve mental health. Planting vegetation may mitigate the effects of climate change; in addition, evidence of an association between vegetation and lower mortality rates suggests it also might be used to improve health.
James P, Hart JE, Banay RF, Laden F. 2016. Exposure to greenness and mortality in a nationwide prospective cohort study of women. Environ Health Perspect 124:1344-1352; http://dx.doi.org/10.1289/ehp.1510363.
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CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
The activation of brown/beige adipose tissue (BAT) metabolism and the induction of uncoupling protein 1 (UCP1) expression are essential for BAT-based strategies to improve metabolic homeostasis. ...Here, we demonstrate that BAT utilizes actomyosin machinery to generate tensional responses following adrenergic stimulation, similar to muscle tissues. The activation of actomyosin mechanics is critical for the acute induction of oxidative metabolism and uncoupled respiration in UCP1+ adipocytes. Moreover, we show that actomyosin-mediated elasticity regulates the thermogenic capacity of adipocytes via the mechanosensitive transcriptional co-activators YAP and TAZ, which are indispensable for normal BAT function. These biomechanical signaling mechanisms may inform future strategies to promote the expansion and activation of brown/beige adipocytes.
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•BAT adrenergic stimulation induces an actomyosin-based mechanical response•Modulation of actomyosin responses alters oxidative metabolism in adipocytes•Thermogenic gene expression in adipocytes is in part regulated by YAP/TAZ
Tharp et al. show that brown adipocytes engage tensional actomyosin machinery, similar to muscle tissues, following adrenergic stimulation to mediate the thermogenic program and normal BAT function. These effects are mechanistically mediated through the YAP/TAZ pathway and, on a broad level, highlight the importance of cellular mechanics for cell metabolism.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Obesity-linked insulin resistance is a major precursor to the development of type 2 diabetes. Previous work has shown that phosphorylation of PPARγ (peroxisome proliferator-activated receptor γ) at ...serine 273 by cyclin-dependent kinase 5 (Cdk5) stimulates diabetogenic gene expression in adipose tissues. Inhibition of this modification is a key therapeutic mechanism for anti-diabetic drugs that bind PPARγ, such as the thiazolidinediones and PPARγ partial agonists or non-agonists. For a better understanding of the importance of this obesity-linked PPARγ phosphorylation, we created mice that ablated Cdk5 specifically in adipose tissues. These mice have both a paradoxical increase in PPARγ phosphorylation at serine 273 and worsened insulin resistance. Unbiased proteomic studies show that extracellular signal-regulated kinase (ERK) kinases are activated in these knockout animals. Here we show that ERK directly phosphorylates serine 273 of PPARγ in a robust manner and that Cdk5 suppresses ERKs through direct action on a novel site in MAP kinase/ERK kinase (MEK). Importantly, pharmacological inhibition of MEK and ERK markedly improves insulin resistance in both obese wild-type and ob/ob mice, and also completely reverses the deleterious effects of the Cdk5 ablation. These data show that an ERK/Cdk5 axis controls PPARγ function and suggest that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes.
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IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
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