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Background Cancer cachexia, affecting up to 80% of patients with cancer, is characterized by muscle and fat loss with functional decline. Preclinical research seeks to uncover the molecular mechanisms underlying cachexia to identify potential targets. Housing laboratory mice at ambient temperature induces cold stress, triggering thermogenic activity and metabolic adaptations. Yet, the impact of housing temperature on preclinical cachexia remains unknown. Methods Colon 26 carcinoma (C26)‐bearing and PBS‐inoculated (Ctrl) mice were housed at standard (ST; 20°C–22°C) or thermoneutral temperature (TN; 28°C–32°C). They were monitored for body weight, composition, food intake and systemic factors. Upon necropsy, tissues were weighed and used for evaluation of ex vivo force and respiration, or snap frozen for biochemical assays. Results C26 mice lost 7.5% body weight (p = 0.0001 vs. Ctrls), accounted by decreased fat mass (−35%, p < 0.0001 vs. Ctrls), showing mild cachexia irrespective of housing temperature. All C26 mice exhibited reduced force (−40%, p < 0.0001 vs. Ctrls) and increased atrogene expression (3‐fold, p < 0.003 vs. Ctrls). Cancer altered white adipose tissue (WAT)'s functional gene signature (49%, p < 0.05 vs. Ctrls), whereas housing temperature reduced brown adipose tissue (BAT)'s (−78%, p < 0.05 vs. ST Ctrl). Thermogenic capacity measured by Ucp1 expression decreased upon cancer in both WAT and BAT (−93% and −63%, p < 0.0044 vs. Ctrls). Cancer‐driven glucose intolerance was noted at ST (26%, p = 0.0192 vs. ST Ctrl), but restored at TN (−23%, p = 0.005 vs. ST C26). Circulating FGF21, GDF‐15 and IL‐6 increased in all C26 mice (4‐fold, p < 0.009 vs. Ctrls), with a greater effect on IL‐6 at TN (76%, p = 0.0018 vs. ST C26). Tumour and WAT Il6 mRNA levels remained unchanged, while cancer induced skeletal muscle (SkM) Il6 (2‐fold, p = 0.0016 vs. Ctrls) at both temperatures. BAT Il6 was only induced in C26 mice at TN (116%, p = 0.0087 vs. ST C26). At the bioenergetics level, cancer increased SkM SERCA ATPase activity at ST (4‐fold, p = 0.0108 vs. ST Ctrl) but not at TN. In BAT, O2 consumption enhanced in C26 mice at ST (119%, p < 0.03 vs. ST Ctrl) but was blunted at TN (−44%, p < 0.0001 vs. ST C26). Cancer increased BAT ATP levels regardless of temperature (2‐fold, p = 0.0046 vs. Ctrls), while SERCA ATPase activity remained unchanged at ST and decreased at TN (−59%, p = 0.0213 vs. TN Ctrl). Conclusions In mild cachexia, BAT and SkM bioenergetics are susceptible to different housing temperatures, which influences cancer‐induced alterations in glucose metabolism and systemic responses.

Background Bifidobacteria represent an important gut commensal in humans, particularly during initial microbiome assembly in the first year of life. Enrichment of Bifidobacterium is mediated though the utilization of human milk oligosaccharides (HMOs), as several human-adapted species have dedicated genomic loci for transport and metabolism of these glycans. This results in the release of fermentation products into the gut lumen which may offer physiological benefits to the host. Synbiotic pairing of probiotic species with a cognate prebiotic delivers a competitive advantage, as the prebiotic provides a nutrient niche. Methods To determine the fitness advantage and metabolic characteristics of an HMO-catabolizing Bifidobacterium strain in the presence or absence of 2′-fucosyllactose (2′-FL), conventionally colonized mice were gavaged with either Bifidobacterium pseudocatenulatum MP80 ( B.p. MP80) (as the probiotic) or saline during the first 3 days of the experiment and received water or water containing 2′-FL (as the prebiotic) throughout the study. Results 16S rRNA gene sequencing revealed that mice provided only B.p. MP80 were observed to have a similar microbiota composition as control mice throughout the experiment with a consistently low proportion of Bifidobacteriaceae present. Using 1 H NMR spectroscopy, similar metabolic profiles of gut luminal contents and serum were observed between the control and B.p. MP80 group. Conversely, synbiotic supplemented mice exhibited dramatic shifts in their community structure across time with an overall increased, yet variable, proportion of Bifidobacteriaceae following oral inoculation. Parsing the synbiotic group into high and moderate bifidobacterial persistence based on the median proportion of Bifidobacteriaceae , significant differences in gut microbial diversity and metabolite profiles were observed. Notably, metabolites associated with the fermentation of 2′-FL by bifidobacteria were significantly greater in mice with a high proportion of Bifidobacteriaceae in the gut suggesting metabolite production scales with population density. Moreover, 1,2-propanediol, a fucose fermentation product, was only observed in the liver and brain of mice harboring high proportions of Bifidobacteriaceae . Conclusions This study reinforces that the colonization of the gut with a commensal microorganism does not guarantee a specific functional output. 3PG9EvfQrbeVULfWFqBZHn Video Abstract

Truncated BID (tBID), a proapoptotic BCL2 family protein, induces BAK/BAX‐dependent release of cytochrome c and other mitochondrial intermembrane proteins to the cytosol to induce apoptosis. The voltage‐dependent anion channels (VDACs) are the primary gates for solutes across the outer mitochondrial membrane (OMM); however, their role in apoptotic OMM permeabilization remains controversial. Here, we report that VDAC2 −/− (V2 −/− ) mouse embryonic fibroblasts (MEFs) are virtually insensitive to tBID‐induced OMM permeabilization and apoptosis, whereas VDAC1 −/− , VDAC3 −/− and VDAC1 −/− /VDAC3 −/− MEFs respond normally to tBID. V2 −/− MEFs regain tBID sensitivity after VDAC2 expression. Furthermore, V2 −/− MEFs are deficient in mitochondrial BAK despite normal tBID–mitochondrial binding and BAX/BAK expression. tBID sensitivity of BAK −/− MEFs is also reduced, although not to the same extent as V2 −/− MEFs, which might result from their strong overexpression of BAX. Indeed, addition of recombinant BAX also sensitized V2 −/− MEFs to tBID. Thus, VDAC2 acts as a crucial component in mitochondrial apoptosis by allowing the mitochondrial recruitment of BAK, thereby controlling tBID‐induced OMM permeabilization and cell death. Work by the Hajnoczky group reveals a novel function of the mitochondrial channel VDAC2 in enabling death receptor‐induced cell killing. The authors show that VDAC2 serves as a recruitment factor for the proapoptotic protein Bak, which is required for tBid‐induced mitochondrial apoptosis. There is a Literature Report in this issue, by Gordon Shore, that contextualises and explores this article.

Background Bifidobacterium longum subsp. infantis ( B. infantis ) is a commensal bacterium that colonizes the gastrointestinal tract of breast-fed infants. B. infantis can efficiently utilize the abundant supply of oligosaccharides found in human milk (HMO) to help establish residence. We hypothesized that metabolites from B. infantis grown on HMO produce a beneficial effect on the host. Results In a previous study, we demonstrated that B. infantis routinely dominated the fecal microbiota of a breast fed Bangladeshi infant cohort (1). Characterization of the fecal metabolome of binned samples representing high and low B. infantis populations from this cohort revealed higher amounts of the tryptophan metabolite indole-3-lactic acid (ILA) in feces with high levels of B. infantis . Further in vitro analysis confirmed that B. infantis produced significantly greater quantities of the ILA when grown on HMO versus lactose, suggesting a growth substrate relationship to ILA production. The direct effects of ILA were assessed in a macrophage cell line and intestinal epithelial cell lines. ILA (1-10 mM) significantly attenuated lipopolysaccharide (LPS)-induced activation of NF-kB in macrophages. ILA significantly attenuated TNF-α- and LPS-induced increase in the pro-inflammatory cytokine IL-8 in intestinal epithelial cells. ILA increased mRNA expression of the aryl hydrogen receptor (AhR)-target gene CYP1A1 and nuclear factor erythroid 2–related factor 2 (Nrf2)-targeted genes glutathione reductase 2 (GPX2), superoxide dismutase 2 (SOD2), and NAD(P) H dehydrogenase (NQO1). Pretreatment with either the AhR antagonist or Nrf-2 antagonist inhibited the response of ILA on downstream effectors. Conclusions These findings suggest that ILA, a predominant metabolite from B. infantis grown on HMO and elevated in infant stool high in B. infantis , and protects gut epithelial cells in culture via activation of the AhR and Nrf2 pathway.

The circadian clock is a cell-autonomous transcription–translation feedback mechanism that anticipates and adapts physiology and behavior to different phases of the day. A variety of factors including hormones, temperature, food-intake, and exercise can act on tissue-specific peripheral clocks to alter the expression of genes that influence metabolism, all in a time-of-day dependent manner. The aim of this study was to elucidate the effects of exercise timing on adipose tissue metabolism. We performed RNA sequencing on inguinal adipose tissue of mice immediately following maximal exercise or sham treatment at the early rest or early active phase. Only during the early active phase did exercise elicit an immediate increase in serum nonesterified fatty acids. Furthermore, early active phase exercise increased expression of markers of thermogenesis and mitochondrial proliferation in inguinal adipose tissue. In vitro, synchronized 3T3-L1 adipocytes showed a timing-dependent difference in Adrb2 expression, as well as a greater lipolytic activity. Thus, the response of adipose tissue to exercise is time-of-day sensitive and may be partly driven by the circadian clock. To determine the influence of feeding state on the time-of-day response to exercise, we replicated the experiment in 10-h-fasted early rest phase mice to mimic the early active phase metabolic status. A 10-h fast led to a similar lipolytic response as observed after active phase exercise but did not replicate the transcriptomic response, suggesting that the observed changes in gene expression are not driven by feeding status. In conclusion, acute exercise elicits timing-specific effects on adipose tissue to maintain metabolic homeostasis.

Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD + ) levels are hallmarks of skeletal muscle ageing and sarcopenia 1 – 3 , but it is unclear whether these defects result from local changes or can be mediated by systemic or dietary cues. Here we report a functional link between circulating levels of the natural alkaloid trigonelline, which is structurally related to nicotinic acid 4 , NAD + levels and muscle health in multiple species. In humans, serum trigonelline levels are reduced with sarcopenia and correlate positively with muscle strength and mitochondrial oxidative phosphorylation in skeletal muscle. Using naturally occurring and isotopically labelled trigonelline, we demonstrate that trigonelline incorporates into the NAD + pool and increases NAD + levels in Caenorhabditis elegans , mice and primary myotubes from healthy individuals and individuals with sarcopenia. Mechanistically, trigonelline does not activate GPR109A but is metabolized via the nicotinate phosphoribosyltransferase/Preiss–Handler pathway 5 , 6 across models. In C. elegans , trigonelline improves mitochondrial respiration and biogenesis, reduces age-related muscle wasting and increases lifespan and mobility through an NAD + -dependent mechanism requiring sirtuin. Dietary trigonelline supplementation in male mice enhances muscle strength and prevents fatigue during ageing. Collectively, we identify nutritional supplementation of trigonelline as an NAD + -boosting strategy with therapeutic potential for age-associated muscle decline. Trigonelline is identified as a human metabolite that can be used for NAD + synthesis and is shown to improve muscle function in aged worms and mice.

ABSTRACT Objective: The metabolic master-switch AMP-activated protein kinase (AMPK) mediates insulin-independent glucose uptake in muscle and regulates the metabolic activity of brown and beige adipose tissue (BAT). The regulatory AMPKγ3 isoform is uniquely expressed in skeletal muscle and also potentially in BAT. Here, we investigated the role that AMPKγ3 plays in mediating skeletal muscle glucose uptake and whole-body glucose clearance in response to small-molecule activators that act on AMPK via distinct mechanisms. We also assessed if γ3 plays a role in adipose thermogenesis and browning. Methods: Global AMPKγ3 knockout (KO) mice were generated. A systematic whole-body, tissue and molecular phenotyping linked to glucose homeostasis was performed in γ3 KO and wild type (WT) mice. Glucose uptake in glycolytic and oxidative skeletal muscle ex vivo, as well as blood glucose clearance in response to small molecule AMPK activators that target nucleotide-binding domain of γ subunit (AICAR) and allosteric drug and metabolite (ADaM) site located at the interface of the α and β subunit (991, MK-8722) were assessed. Oxygen consumption, thermography, and molecular phenotyping with a β3-adrenergic receptor agonist (CL-316,243) treatment were performed to assess BAT thermogenesis, characteristics and function. Results: Genetic ablation of γ3 did not affect body weight, body composition, physical activity, and parameters associated with glucose homeostasis under chow or high fat diet. γ3 deficiency had no effect on fiber-type composition, mitochondrial content and components, or insulin-stimulated glucose uptake in skeletal muscle. Glycolytic muscles in γ3 KO mice showed a partial loss of AMPKα2 activity, which was associated with reduced levels of AMPKα2 and β2 subunit isoforms. Notably, γ3 deficiency resulted in a selective loss of AICAR-, but not MK-8722-induced blood glucose-lowering in vivo and glucose uptake specifically in glycolytic muscle ex vivo. We detected γ3 in BAT and found that it preferentially interacts with α2 and β2. We observed no differences in oxygen consumption, thermogenesis, morphology of BAT and inguinal white adipose tissue (iWAT), or markers of BAT activity between WT and γ3 KO mice. Conclusions: These results demonstrate that γ3 plays a key role in mediating AICAR- but not ADaM site binding drug-stimulated blood glucose clearance and glucose uptake specifically in glycolytic skeletal muscle. We also showed that γ3 is dispensable for thermogenesis and browning of iWAT. Competing Interest Statement The authors have declared no competing interest.

Bifidobacterium infantis EVC001 silenced intestinal Th2 and Th17 immune responses, while inducing IFNβ, and its metabolites skew T-cell polarization in vitro, from Th2 towards Th1, suggesting a healthier immune imprinting during the first critical months of life. HIGHLIGHTS An ordered sequence of immune changes after birth, driven by microbial interactions Low gut Bifidobacterium abundance is associated with markers of intestinal inflammation Feeding B. infantis EVC001 silenced intestinal Th2 and Th17 but upregulates IFNβ B. infantis EVC001 metabolites and/or enteric cytokines skew naïve T-cell polarization towards Th1 and away from Th2 Competing Interest Statement PB, JM and TL are founders and shareholders of Cytodelics AB (Stockholm, Sweden). PB is an advisor to Scailyte AG (Zurich, Switzerland). RDM, SC, JP, HKB, SAF, and BMH are employees of Evolve BioSystems, a company focused on restoring the infant microbiome. JTS received funding to conduct the IMPRINT trial and AME received funding to assist in writing the manuscript. JBG is a co-founder of Evolve BioSystems. SAF and BMH serve as Adjunct Assistant Professors in Food Science & Technology Department, University of Nebraska Lincoln. Footnotes * ↵12 Lead contact * Labels in Figure 4a-b were swapped in the original submission. These have been reversed and are now correct. Credit to Stephanie N Langel, Duke University for spotting this error (ref: @stephanielangel at Twitter). * https://brodinlab.com/data-repository/

Objective: To determine whether dementia status and medical burden were independent predictors of emergency department (ED) visits and hospitalizations in older patients from an urban geriatric practice participating in a primary care based cognitive screening program. Participants and Methods: A comprehensive chart review was conducted for 300 African American and Caucasian patients, including 46 with prevalent dementia and 28 with incident dementia using the Cumulative Illness Burden Scale. Hospital-based claims data was used to retrieve ED visits and hospital admissions for 5 years following baseline assessment. Results: Patients with dementia had a 49% higher rate of ED visits (IRR = 1.49; 95% CI = 1.06, 2.09) and an 83% higher risk of death than patients without dementia (HR = 1.83; 95% CI = 3.07, 0.03). Dementia status predicted hospital admissions after adjustment for medical burden (IRR = 1.37; 95% CI = 0.99, 1.89). For each one point increase in medical burden, there was an 11% increase in ED visits (IRR = 1.11; 95% CI = 1.06, 1.16), a 13% increase in hospital admissions (IRR = 1.13; 95% CI = 1.09, 1.17), and an 11% higher risk of death (HR = 1.11; 95% CI = 1.04, 1.17). Age did not predict utilization. Conclusion: Dementia status and medical burden were independent predictors of ED visits and death in patients with clinically diagnosed dementia followed from the early stage of disease.