FGF21, a liver hormone that inhibits alcohol intake in mice, increases in human circulation after acute alcohol ingestion and sustained binge drinking at Oktoberfest

Objective: Excessive alcohol consumption is a leading cause of global morbidity and mortality. However, knowledge of the biological factors that influence ad libitum alcohol intake may be incomplete. Two large studies recently linked variants in the KLB locus with levels of alcohol intake in humans. KLB encodes β-klotho, co-receptor for the liver-derived hormone fibroblast growth factor 21 (FGF21). In mice, FGF21 reduces alcohol intake, and human Fgf21 variants are enriched among heavy drinkers. Thus, the liver may limit alcohol consumption by secreting FGF21. However, whether full-length, active plasma FGF21 (FGF21 (1–181)) levels in humans increase acutely or sub-chronically in response to alcohol ingestion is uncertain. Methods: We recruited 10 healthy, fasted male subjects to receive an oral water or alcohol bolus with concurrent blood sampling for FGF21 (1–181) measurement in plasma. In addition, we measured circulating FGF21 (1–181) levels, liver stiffness, triglyceride, and other metabolic parameters in three healthy Danish men before and after consuming an average of 22.6 beers/person/day (4.4 g/kg/day of ethanol) for three days during Oktoberfest 2017 in Munich, Germany. We further correlated fasting FGF21 (1–181) levels in 49 healthy, non-alcoholic subjects of mixed sex with self-reports of alcohol-related behaviors, emotional responses, and problems. Finally, we characterized the effect of recombinant human FGF21 injection on ad libitum alcohol intake in mice. Results: We show that alcohol ingestion (25.3 g or ∼2.5 standard drinks) acutely increases plasma levels of FGF21 (1–181) 3.4-fold in fasting humans. We also find that binge drinking for three days at Oktoberfest is associated with a 2.1-fold increase in baseline FGF21 (1–181) levels, in contrast to minor deteriorations in metabolic and hepatic biomarkers. However, basal FGF21 (1–181) levels were not correlated with differences in alcohol-related behaviors, emotional responses, or problems in our non-alcoholic subjects. Finally, we show that once-daily injection of recombinant human FGF21 reduces ad libitum alcohol intake by 21% in mice. Conclusions: FGF21 (1–181) is markedly increased in circulation by both acute and sub-chronic alcohol intake in humans, and reduces alcohol intake in mice. These observations are consistent with a role for FGF21 as an endocrine inhibitor of alcohol appetite in humans. Keywords: Fibroblast growth factor 21, FGF21, Alcohol, Alcohol appetit

Experimental Incubations Elicit Profound Changes in Community Transcription in OMZ Bacterioplankton

Sequencing of microbial community RNA (metatranscriptome) is a useful approach for assessing gene expression in microorganisms from the natural environment. This method has revealed transcriptional patterns in situ, but can also be used to detect transcriptional cascades in microcosms following experimental perturbation. Unambiguously identifying differential transcription between control and experimental treatments requires constraining effects that are simply due to sampling and bottle enclosure. These effects remain largely uncharacterized for “challenging” microbial samples, such as those from anoxic regions that require special handling to maintain in situ conditions. Here, we demonstrate substantial changes in microbial transcription induced by sample collection and incubation in experimental bioreactors. Microbial communities were sampled from the water column of a marine oxygen minimum zone by a pump system that introduced minimal oxygen contamination and subsequently incubated in bioreactors under near in situ oxygen and temperature conditions. Relative to the source water, experimental samples became dominated by transcripts suggestive of cell stress, including chaperone, protease, and RNA degradation genes from diverse taxa, with strong representation from SAR11-like alphaproteobacteria. In tandem, transcripts matching facultative anaerobic gammaproteobacteria of the Alteromonadales (e.g., Colwellia) increased 4–13 fold up to 43% of coding transcripts, and encoded a diverse gene set suggestive of protein synthesis and cell growth. We interpret these patterns as taxon-specific responses to combined environmental changes in the bioreactors, including shifts in substrate or oxygen availability, and minor temperature and pressure changes during sampling with the pump system. Whether such changes confound analysis of transcriptional patterns may vary based on the design of the experiment, the taxonomic composition of the source community, and on the metabolic linkages between community members. These data highlight the impressive capacity for transcriptional changes within complex microbial communities, underscoring the need for caution when inferring in situ metabolism based on transcript abundances in experimental incubations

Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight

Oxygen distribution and aerobic respiration in the north and south eastern tropical Pacific oxygen minimum zones

Highly sensitive STOX O2 sensors were used for determination of in situ O2 distribution in the eastern tropical north and south Pacific oxygen minimum zones (ETN/SP OMZs), as well as for laboratory determination of O2 uptake rates of water masses at various depths within these OMZs. Oxygen was generally below the detection limit (few nmol L−1) in the core of both OMZs, suggesting the presence of vast volumes of functionally anoxic waters in the eastern Pacific Ocean. Oxygen was often not detectable in the deep secondary chlorophyll maximum found at some locations, but other secondary maxima contained up to ~0.4 µmol L−1. Directly measured respiration rates were high in surface and subsurface oxic layers of the coastal waters, reaching values up to 85 nmol L−1 O2 h−1. Substantially lower values were found at the depths of the upper oxycline, where values varied from 2 to 33 nmol L−1 O2 h−1. Where secondary chlorophyll maxima were found the rates were higher than in the oxic water just above. Incubation times longer than 20 h, in the all-glass containers, resulted in highly increased respiration rates. Addition of amino acids to the water from the upper oxycline did not lead to a significant initial rise in respiration rate within the first 20 h, indicating that the measurement of respiration rates in oligotrophic Ocean water may not be severely affected by low levels of organic contamination during sampling. Our measurements indicate that aerobic metabolism proceeds efficiently at extremely low oxygen concentrations with apparent half-saturation concentrations (Km values) ranging from about 10 to about 200 nmol L−1

Non-selective β-adrenergic blockade prevents reduction of the cerebral metabolic ratio during exhaustive exercise in humans

Intense exercise decreases the cerebral metabolic ratio of oxygen to carbohydrates [O2/(glucose + ½lactate)], but whether this ratio is influenced by adrenergic stimulation is not known. In eight males, incremental cycle ergometry increased arterial lactate to 15.3 ± 4.2 mm (mean ± s.d.) and the arterial–jugular venous (a–v) difference from −0.02 ± 0.03 mm at rest to 1.0 ± 0.5 mm (P < 0.05). The a–v difference for glucose increased from 0.7 ± 0.3 to 0.9 ± 0.1 mm (P < 0.05) at exhaustion and the cerebral metabolic ratio decreased from 5.5 ± 1.4 to 3.0 ± 0.3 (P < 0.01). Administration of a non-selective β-adrenergic (β1 + β2) receptor antagonist (propranolol) reduced heart rate (69 ± 8 to 58 ± 6 beats min−1) and exercise capacity (239 ± 42 to 209 ± 31 W; P < 0.05) with arterial lactate reaching 9.4 ± 3.6 mm. During exercise with propranolol, the increase in a–v lactate difference (to 0.5 ± 0.5 mm; P < 0.05) was attenuated and the a–v glucose difference and the cerebral metabolic ratio remained at levels similar to those at rest. Together with the previous finding that the cerebral metabolic ratio is unaffected during exercise with administration of the β1-receptor antagonist metropolol, the present results suggest that the cerebral metabolic ratio decreases in response to a β2-receptor mechanism