Metabolic Homeostasis In Mice Research Articles

Colchicine disrupts bile acid metabolic homeostasis by affecting the enterohepatic circulation in mice.

Although the medicinal properties of colchicine (COL) have been widely known for centuries, its toxicity has been the subject of controversy. The narrow therapeutic window causes COL to induce gastrointestinal adverse effects even when taken at recommended doses, mainly manifested as nausea, vomiting, and diarrhea. However, the mechanism of COL-induced gastrointestinal toxic reactions remains obscure. In the present study, the mice were dosed with COL (2.5mg/kg b.w./day) for a week to explore the effect of COL on bile acid metabolism and the mechanism of COL-induced diarrhea. The results showed that COL treatment affected liver biochemistry in mice, resulting in a significant down-regulation of the mRNA expression levels of bile acid biosynthesis regulators Cyp7a1, Cyp8b1, Cyp7b1, and Cyp27a1 in liver tissues. The mRNA expression levels of bile acid transporters Ntcp, Oatp1, Mrp2, Ibabp, Mrp3, Osta, and Ostb in liver and ileum tissues were also significantly down-regulated. In addition, COL treatment significantly inhibited the mRNA expression levels of Fxr and its downstream target genes Shp, Lrh1, and Fgf15 in liver and ileum tissues, affecting the feedback regulation of bile acid biosynthesis. More importantly, the inhibition of COL on bile acid transporters in ileal and hepatic tissues affected bile acid recycling in the ileum as well as their reuptake in the liver, leading to a significantly increased accumulation of bile acids in the colon, which may be an important cause of diarrhea. In conclusion, our study revealed that COL treatment affected bile acid biosynthesis and enterohepatic circulation, thereby disrupting bile acid metabolic homeostasis in mice.

Combined exposure to polyvinyl chloride and polystyrene microplastics induces liver injury and perturbs gut microbial and serum metabolic homeostasis in mice

A variety of microplastics (MPs) have become ubiquitous environmental pollutants, leading to inevitable human contact and health impacts. Most previous research has explored the toxic effects of a single type of MPs exposure. However, the effects of co-exposure to both common types of MPs, polyvinyl chloride (PVC) and polystyrene (PS) MPs on mammals have not been explored. Here, adult mice were exposed to PS-PVC (1.0 µm PS and 2.0 µm PVC both at the concentration of 0.5 mg/day) for 60 days. The results showed that PS-PVC co-exposure-induced hepatotoxicity was evidenced by liver histopathological changes, the release of inflammatory cytokines, and the activation of oxidative stress. Moreover, the intestinal mucosal barrier was damaged after PS-PVC treatment. The results of 16S rRNA gene sequencing reported there was a marked shift in the gut microbial structure accompanied by decreased relative abundances of probiotics, such as Clostridium, Lachnospiraceae_UCG-006, Desulfovibrio, Clostridiales_unclassified and Ruminococcaceae_unclassified and increased the conditional pathogen abundances, such as Erysipelatoclostridium. Furthermore, the triglyceride (TG) and total cholesterol (TCH) expression levels in the serum and liver were increased after PS-PVC co-exposure. Serum metabolomics analysis showed that there were 717 differential expression metabolites found in the positive- and negative-ion modes, including 476 up-regulated and 241 down-regulated, mainly enriched in butyrate metabolism, thiamine metabolism, and phenylacetate metabolism. In addition, remarked changes in the gut microbiota and serum metabolic profiles were closely related to hepatic and intestinal injuries after PS-PVC co-exposure. These results have provided new insights into the toxic effects of PS and PVC MPs co-exposure through the gut-liver axis and the health risks of PS and PVC MPs should be paid more attention to humans.

High-Carbohydrate Diet Consumption Poses a More Severe Liver Cholesterol Deposition than a High-Fat and High-Calorie Diet in Mice.

In the past few decades, many researchers believed that a high-fat and high-calorie diet is the most critical factor leading to metabolic diseases. However, increasing evidence shows a high-carbohydrate and low-fat diet may also be a significant risk factor. It needs a comprehensive evaluation to prove which viewpoint is more persuasive. We systematically compared the effects of high-fat and high-calorie diets and high-carbohydrate and low-fat ones on glycolipid metabolism in mice to evaluate and compare the effects of different dietary patterns on metabolic changes in mice. Sixty 8-week-old male C57BL/6 mice were divided into four groups after acclimatization and 15% (F-15), 25% (F-25), 35% (F-35), and 45% (F-45) of their dietary energy was derived from fat for 24 weeks. The body weight, body-fat percentage, fasting blood glucose, lipid content in the serum, and triglyceride content in the livers of mice showed a significantly positive correlation with dietary oil supplementation. Interestingly, the total cholesterol content in the livers of mice in the F-15 group was significantly higher than that in other groups (p < 0.05). Compared with the F-45 group, the mRNA expression of sterol synthesis and absorption-related genes (e.g., Asgr1, mTorc1, Ucp20, Srebp2, Hmgcr, and Ldlr), liver fibrosis-related genes (e.g., Col4a1 and Adamts1) and inflammation-related genes (e.g., Il-1β and Il-6) were significantly higher in the F-15 group. Compared with the F-45 group, the relative abundance of unclassified_f_Lachnospiraceae and Akkermansia was decreased in the F-15 group. While unclassified_f_Lachnospiraceae and Akkermansia are potentially beneficial bacteria, they have the ability to produce short-chain fatty acids and modulate cholesterol metabolism. In addition, the relative abundance of unclassified_f_Lachnospiraceae and Akkermansia was significantly positively correlated with fatty acid transporters expression and negatively correlated with that of cholesteryl acyltransferase 1 and cholesterol synthesis-related genes. In conclusion, our study delineated how a high-fat and high-calorie diet (fat supplied higher than or equal to 35%) induced obesity and hepatic lipid deposition in mice. Although the high-carbohydrate and low-fat diet did not cause weight gain in mice, it induced cholesterol deposition in the liver. The mechanism is mainly through the induction of endogenous synthesis of cholesterol in mice liver through the ASGR1-mTORC1-USP20-HMGCR signaling pathway. The appropriate oil and carbon water ratio (dietary energy supply from fat of 25%) showed the best gluco-lipid metabolic homeostasis in mice.

1654-P: Hepatic FGF21 Is Required for Curcumin and Resveratrol to Exert Their Metabolic Beneficial Effect in Male Mice

Intensive investigations have shown the profound metabolic beneficial effect of dietary intervention with plant polyphenols including curcumin and resveratrol. Recent studies have also shown that hepatic FGF21 is among the targets of dietary polyphenol intervention as well as intermittent fasting or nutritional restriction. Here we assessed whether hepatic FGF21 is required for dietary polyphenol intervention on metabolic homeostasis in mice on high fat high fructose diet (HFHF) challenge. Liver specific FGF21 null mice (Lfgf21-/-) were generated by mating Alb-Cre mice with Fgf21fl/fl mice. No appreciable defect on glucose disposal was observed in male or female Lfgf21-/- mice when they were fed with regular chow diet. In chow diet fed male but not female Lfgf21-/- mice, fat tolerance was impaired, associated with elevated fasting plasma TG level and reduced hepatic expression of Ehhadh and Ppargc1 (two downstream targets of FGF21). Following HFHF challenge, the control Fgf21fl/fl male mice exhibited response to 12-week curcumin intervention on reducing body weight, serum and hepatic TG elevation, and on improving fat tolerance. Those beneficial effects were absent in male Lfgf21-/- mice. In high fat diet challenged wild type mice, concomitant resveratrol intervention exhibited anticipated metabolic beneficial effect, associated with increased hepatic FGF21 mRNA and protein expression. Importantly, the metabolic beneficial effects of resveratrol intervention were observed in HFHF challenged Fgf21fl/fl mice but not in Lfgf21-/- mice. In wild type or transgenic female mice, we did not see appreciable beneficial effect with resveratrol intervention. Together we introduced a transgenic mouse model into the investigation of metabolic function of dietary intervention. We conclude that hepatic FGF21 is required for curcumin or resveratrol to exert its beneficial effect in male mice. Disclosure W.Shao: None. J.Feng: None. T.Jin: None. Funding Canadian Institutes of Health Research

Adipose tissue macrophages exert systemic metabolic control by manipulating local iron concentrations.

Iron is essential to many fundamental biological processes, but its cellular compartmentalization and concentration must be tightly controlled. Although iron overload can contribute to obesity-associated metabolic deterioration, the subcellular localization and accumulation of iron in adipose tissue macrophages is largely unknown. Here, we show that macrophage mitochondrial iron levels control systemic metabolism in male mice by altering adipocyte iron concentrations. Using various transgenic mouse models to manipulate the macrophage mitochondrial matrix iron content in an inducible fashion, we demonstrate that lowering macrophage mitochondrial matrix iron increases numbers of M2-like macrophages in adipose tissue, lowers iron levels in adipocytes, attenuates inflammation and protects from high-fat-diet-induced metabolic deterioration. Conversely, elevating macrophage mitochondrial matrix iron increases M1-like macrophages and iron levels in adipocytes, exacerbates inflammation and worsens high-fat-diet-induced metabolic dysfunction. These phenotypes are robustly reproduced by transplantation of a small amount of fat from transgenic to wild-type mice. Taken together, we identify macrophage mitochondrial iron levels as a crucial determinant of systemic metabolic homeostasis in mice.

Elucidating the role of Rgs2 expression in the PVN for metabolic homeostasis in mice

ObjectiveRGS2 is a GTPase activating protein that modulates GPCR-Gα signaling and mice lacking RGS2 globally exhibit metabolic alterations. While RGS2 is known to be broadly expressed throughout the body including the brain, the relative contribution of brain RGS2 to metabolic homeostasis remains unknown. The purpose of this study was to characterize RGS2 expression in the paraventricular nucleus of hypothalamus (PVN) and test its role in metabolic homeostasis. MethodsWe used a combination of RNAscope in situ hybridization (ISH), immunohistochemistry, and bioinformatic analyses to characterize the pattern of Rgs2 expression in the PVN. We then created mice lacking Rgs2 either prenatally or postnatally in the PVN and evaluated their metabolic consequences. ResultsRNAscope ISH analysis revealed a broad but regionally enriched Rgs2 mRNA expression throughout the mouse brain, with the highest expression being observed in the PVN along with several other brain regions, such as the arcuate nucleus of hypothalamus and the dorsal raphe nucleus. Within the PVN, we found that Rgs2 is specifically enriched in CRH+ endocrine neurons and is further increased by calorie restriction. Functionally, although Sim1-Cre-mediated prenatal deletion of Rgs2 in PVN neurons had no major effects on metabolic homeostasis, AAV-mediated adult deletion of Rgs2 in the PVN led to significantly increased food intake, body weight (both fat and fat-free masses), body length, and blood glucose levels in both male and female mice. Strikingly, we found that prolonged postnatal loss of Rgs2 leads to neuronal cell death in the PVN, while rapid body weight gain in the early phase of viral-mediated PVN Rgs2 deletion is independent of PVN neuronal loss. ConclusionsOur results provide the first evidence to show that PVN Rgs2 expression is not only sensitive to metabolic challenge but also critically required for PVN endocrine neurons to function and maintain metabolic homeostasis.

Early Life Polychlorinated Biphenyl 126 Exposure Disrupts Gut Microbiota and Metabolic Homeostasis in Mice Fed with High-Fat Diet in Adulthood.

Evidence supports the potential influence of persistent organic pollutants (POPs) on the pathogenesis and progression of obesity and diabetes. Diet-toxicant interactions appear to be important in diet-induced obesity/diabetes; however, the factors influencing this interaction, especially the early life environmental exposure, are unclear. Herein, we investigated the metabolic effects following early life five-day exposure (24 μg/kg body weight per day) to 3,3′,4,4′,5-pentacholorobiphenyl (PCB 126) at four months after exposure in mice fed with control (CTRL) or high-fat diet (HFD). Activation of aryl hydrocarbon receptor (AHR) signaling as well as higher levels of liver nucleotides were observed at 4 months after PCB 126 exposure in mice, independent of diet status. Inflammatory responses including higher levels of serum cytokines and adipose inflammatory gene expression caused by early life PCB 126 were observed only in HFD-fed mice in adulthood. Notably, early life PCB 126 exposure worsened HFD-induced impaired glucose homeostasis characterized by glucose intolerance and elevated gluconeogenesis and tricarboxylic acid (TCA) cycle flux without worsening the effects of HFD related to adiposity in adulthood. Furthermore, early life PCB 126 exposure resulted in diet-dependent changes in bacterial community structure and function later in life, as indicated by metagenomic and metabolomic analyses. These data contribute to a more comprehensive understanding of the interactions between diet and early life environmental chemical exposure.

Fasciola hepatica Fatty Acid Binding Protein 1 Modulates T cell Polarization by Promoting Dendritic Cell Thrombospondin-1 Secretion Without Affecting Metabolic Homeostasis in Obese Mice.

BackgroundThe parasitic trematode Fasciola hepatica evades host immune defenses through secretion of various immunomodulatory molecules. Fatty Acid Binding Proteins (fhFABPs) are among the main excreted/secreted proteins and have been shown to display anti-inflammatory properties. However, little is currently known regarding their impact on dendritic cells (DCs) and their subsequent capacity to prime specific CD4+ T cell subsets.Methodology/Principal FindingsThe immunomodulatory effects of both native F. hepatica extracts and recombinant fhFABPs were assessed on monocyte-derived human DCs (moDCs) and the underlying mechanism was next investigated using various approaches, including DC-allogenic T cell co-culture and DC phenotyping through transcriptomic, proteomic and FACS analyses. We mainly showed that fhFABP1 induced a tolerogenic-like phenotype in LPS-stimulated moDCs characterized by a dose-dependent increase in the cell-surface tolerogenic marker CD103 and IL-10 secretion, while DC co-stimulatory markers were not affected. A significant decrease in secretion of the pro-inflammatory cytokines IL-12p70 and IL-6 was also observed. In addition, these effects were associated with an increase in both Th2-on-Th1 ratio and IL-10 secretion by CD4+ T cells following DC-T cell co-culture. RNA sequencing and targeted proteomic analyses identified thrombospondin-1 (TSP-1) as a non-canonical factor highly expressed and secreted by fhFABP1-primed moDCs. The effect of fhFABP1 on T cell skewing was abolished when using a TSP-1 blocking antibody during DC-T cell co-culture. Immunomodulation by helminth molecules has been linked to improved metabolic homeostasis during obesity. Although fhFABP1 injection in high-fat diet-fed obese mice induced a potent Th2 immune response in adipose tissue, it did not improved insulin sensitivity or glucose homeostasis.Conclusions/SignificanceWe show that fhFABP1 modulates T cell polarization, notably by promoting DC TSP-1 secretion in vitro, without affecting metabolic homeostasis in a mouse model of type 2 diabetes.

Acox2 is a regulator of lysine crotonylation that mediates hepatic metabolic homeostasis in mice

Acyl-CoA oxidase 2 (Acox2) is an enzyme involved in peroxisomal bile acid synthesis and branched-chain fatty acid degradation. Acox2 knockout (−/−) mice spontaneously developed liver cancer with marked lymphocytic infiltrate. Tandem-affinity purification coupled with mass spectrometry analysis revealed that Acox2 interacted with methylcrotonoyl-CoA carboxylase followed by co-immunoprecipitation confirmation. Here we reported that non-histone lysine crotonylation (Kcr) levels were downregulated in Acox2−/− mice livers. Interestingly, Kcr signals were concentrated in the nucleus of tumor cells but mostly located in the cytoplasm of adjacent normal liver cells of Acox2−/− mice. Quantitative analysis of the global crotonylome further revealed that 54% (27/50) of downregulated non-histone Kcr sites were located in mitochondrial (11/50) and peroxisomal (17/50) enzymes including Ehhadh, Scp2, Hsd17b4, Crot, Etfa, Cpt1a, Eci1/2, Hadha, Etfdh, and Idh2. Subsequent site-directed mutagenesis and transcriptome analysis revealed that Ehhadh K572cr might have site-specific regulatory roles by downregulating TOP3B expression that lead to increased DNA damage in vitro. Our findings suggested Acox2 is a regulator of Kcr that might play critical role on hepatic metabolic homeostasis.

Survivin is essential for thermogenic program and metabolic homeostasis in mice

ObjectiveSurvivin is a member of the inhibitor of apoptosis family. Our previous study showed that survivin expression could be strongly induced by long-term, high-fat diet (HFD) exposure in vivo. It could also be induced by insulin through the PI3K/mTOR signaling pathway in vitro. Therefore, we hypothesized that under certain conditions, survivin expression might be required for adipocyte function. In the current study, we aim to further investigate the regulation of survivin expression in mature adipocytes upon various nutritional stimuli and the role of survivin using adipocyte-specific survivin knockout (SKO) mice. MethodsSKO mice were obtained by crossing survivinflox/flox mice with Adiponectin-Cre+/- mice. The overall metabolic phenotype was observed under chow diet (CD) and HFD feeding conditions. The thermogenic program of mice was detected upon cold exposure. The inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT) stromal vascular fraction cells were isolated and differentiated into mature adipocytes, and the effects of survivin deletion on mature adipocyte function were detected in vitro. ResultsSurvivin expression in adipose tissue and adipocytes was regulated by short-term nutritional stress both in vivo and in vitro. The postnatal development of BAT was impaired in SKO mice, which resulted in drastically reduced BAT mass and decreased expression of the thermogenic protein Ucp1 in 24-week-old mice fed with CD. After HFD feeding, the iWAT and BAT mass of SKO mice were significantly decreased, causing ectopic lipid accumulation in the liver, which was associated with insulin resistance and glucose intolerance. Upon cold exposure, the expression of thermogenic genes and proteins was markedly reduced in BAT and iWAT of SKO mice, accompanied by abnormal mitochondrial structure and induced autophagy. Consistently, thermogenic program and mitochondrial oxidative phosphorylation were reduced in survivin-depleted brown and beige adipocytes in vitro. ConclusionsOur findings showed that survivin could be regulated by nutritional stress in adipocytes and revealed a new role of survivin in maintaining normal BAT mass and positively regulating the thermogenic program and mitochondrial oxidative phosphorylation.

IL-25-induced shifts in macrophage polarization promote development of beige fat and improve metabolic homeostasis in mice.

Beige fat dissipates energy and functions as a defense against cold and obesity, but the mechanism for its development is unclear. We found that interleukin (IL)-25 signaling through its cognate receptor, IL-17 receptor B (IL-17RB), increased in adipose tissue after cold exposure and β3-adrenoceptor agonist stimulation. IL-25 induced beige fat formation in white adipose tissue (WAT) by releasing IL-4 and IL-13 and promoting alternative activation of macrophages that regulate innervation and up-regulate tyrosine hydroxylase (TH) up-regulation to produce more catecholamine including norepinephrine (NE). Blockade of IL-4Rα or depletion of macrophages with clodronate-loaded liposomes in vivo significantly impaired the beige fat formation in WAT. Mice fed with a high-fat diet (HFD) were protected from obesity and related metabolic disorders when given IL-25 through a process that involved the uncoupling protein 1 (UCP1)-mediated thermogenesis. In conclusion, the activation of IL-25 signaling in WAT may have therapeutic potential for controlling obesity and its associated metabolic disorders.

Short-Term Intake of Hesperetin-7-O-Glucoside Affects Fecal Microbiota and Host Metabolic Homeostasis in Mice.

Hesperetin-7-O-glucoside (Hes-7-G) is a typical flavonoid monoglucoside isolated from Citri Reticulatae Pericarpium (CRP), which is commonly used as a food adjuvant and exhibits potential biological activities. To explore the interaction between Hes-7-G ingestion and microbiome and host metabolism, here, 16S rRNA gene sequencing was first used to analyze the alteration of fecal microbiome in mice after Hes-7-G intake. Metabolic homeostasis in mice was subsequently investigated using untargeted 1H NMR-based metabolomics and targeted metabolite profiling. We found that dietary Hes-7-G significantly regulated fecal microbiota and its derived metabolites, including short-chain fatty acids (SCFAs) and tryptophan metabolites (indole and its derivatives), in feces of mice. Regulation of microbiota was further confirmed by the significantly changed urinary hippurate and trimethylamine N-oxide (TMAO), co-metabolites of the microbe and host. We also found that dietary Hes-7-G modulated the host tricarboxylic acid cycle (TCA) involved in energy metabolism. These findings suggested that Hes-7-G exhibits potential beneficial effects for human health.

Astaxanthin-Shifted Gut Microbiota Is Associated with Inflammation and Metabolic Homeostasis in Mice

Astaxanthin is a red lipophilic carotenoid that is often undetectable in human plasma due to the limited supply in typical Western diets. Despite its presence at lower than detectable concentrations, previous clinical feeding studies have reported that astaxanthin exhibits potent antioxidant properties. We examined astaxanthin accumulation and its effects on gut microbiota, inflammation, and whole-body metabolic homeostasis in wild-type C57BL/6J (WT) and β-carotene oxygenase 2 (BCO2) knockout (KO) mice. Six-wk-old male and female BCO2 KO and WT mice were provided with either nonpurified AIN93M (e.g., control diet) or the control diet supplemented with 0.04% astaxanthin (wt/wt) ad libitum for 8 wk. Whole-body energy expenditure was measured by indirect calorimetry. Feces were collected from individual mice for short-chain fatty acid assessment. Hepatic astaxanthin concentrations and liver metabolic markers, cecal gut microbiota profiling, inflammation markers in colonic lamina propria, and plasma samples were assessed. Data were analyzed by 3-way ANOVA followed by Tukey's post hoc analysis. BCO2 KO but not WT mice fed astaxanthin had ∼10-fold more of this compound in liver than controls (P <0.05). In terms of the microbiota composition, deletion of BCO2 was associated with a significantly increased abundance of Mucispirillum schaedleri in mice regardless of gender. In addition to more liver astaxanthin in male KO compared with WT mice fed astaxanthin, the abundance of gut Akkermansia muciniphila was 385% greater, plasma glucagon-like peptide 1 was 27% greater, plasma glucagon and IL-1β were 53% and 30% lower, respectively, and colon NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation was 23% lower (all P <0.05) in male KO mice than the WT mice. Astaxanthin affects the gut microbiota composition in both genders, but the association with reductions in local and systemic inflammation, oxidative stress, and improvement of metabolic homeostasis only occurs in male mice.

Abstract 3457: Plasma metabolomic changes in mice with time restricted feeding-attenuated pulmonary metastasis of Lewis lung carcinoma

Abstract Erratic eating behavior disrupts diurnal rhythms of metabolism and may contribute to obesity. Time-restricted feeding (TRF), in which food is available in the active period of the day (the dark phase for nocturnal animals), restores metabolic homeostasis in mice. In a mouse model of Lewis lung carcinoma (LLC), we found that TRF (12 hours, dark phase) attenuates obesity-enhanced spontaneous metastasis to the lungs in a study that compared differences in the extent of metastasis among four dietary groups: non-LLC-bearing mice fed the standard AIN93G diet and LLC-bearing mice fed the AIN93G, an obesogenic high-fat diet (HFD) or TRF with the HFD. With the goal of determining potential plasma fingerprints underlying TRF efficacy, we performed untargeted metabolomic analysis upon the plasma samples from this study. Using gas chromatography time-of-flight mass spectrometry, we identified 152 compounds of which 24 differed among the four groups. Ten analytes that were the most influential in treatment separation were alpha-tocopherol, phenylalanine, isoleucine, leucine, pyruvic acid, dihydrocholestrol, arachidonic acid (ARA), docosahexaenoic acid (DHA), lactic acid, and cholesterol. In mice fed the AIN93G diet, compared to non-LLC-bearing mice LLC elevated alpha-tocopherol, ARA, isoleucine, phenylalanine, cholesterol, lauric acid, and 4-hydroxybenzoate and decreased lactic acid, lactamide, and pyruvic acid. In LLC-bearing mice, compared to the AIN93G diet the HFD elevated asparagine, leucine, phenylalanine, dehydrocholesterol, p-cresol sulfate, and hexuronic acid and decreased 1,5-anhydroglucitol, palmitoleic acid, myristic acid, lauric acid, and 4-hydrobenzoate. Compared to the HFD, TRF elevated linoleic acid and 2-hydroxyhexanoic acid and decreased alpha-tocopherol, asparagine, isoleucine, leucine, phenylalanine, dihydrocholesterol, p-cresol sulfate, hexuronic acid, and DHA. This study showed that LLC metastatic growth and an increase in dietary fat consumption disrupted metabolic homeostasis, as reflected in plasma analyte changes compared to their respective controls. TRF, through its temporal regulation of food intake, restored HFD-mediated metabolic disruption and may have contributed to its inhibition of obesity-enhanced LLC metastasis. Citation Format: Lin Yan, Bret M. Rust, Matthew J. Picklo. Plasma metabolomic changes in mice with time restricted feeding-attenuated pulmonary metastasis of Lewis lung carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3457.

Lactobacillus pentosus S-PT84 Prevents Low-Grade Chronic Inflammation-Associated Metabolic Disorders in a Lipopolysaccharide and High-Fat Diet C57/BL6J Mouse Model.

A long-term exposure to lipopolysaccharides results in the gut inflammation and its impaired barrier function, leading to the development of metabolic disorders. In this study, the role of dietary heat killed Lactobacillus pentosus S-PT84 on preventing endotoxemia to maintain metabolic homeostasis was studied. We demonstrated that the treatment of L. pentosus S-PT84 improved the gut integrity by maintaining tight-junction protein expression, in order to suppress the infiltration of endotoxin into plasma. The systemic inflammatory responses were inhibited via reducing the secretion of TNF-α and MCP-1. Furthermore, the blood lipid profile and glucose level as well as adiponectin in both plasma and white adipose tissues (WAT) were preserved by L. pentosus S-PT84 through upregulation of PPAR-γ and IRS-1 expression in WAT. The above findings suggest that the metabolic homeostasis in mice treated with HFD and LPS was sustained by L. pentosus S-PT84, leading to reducing the early risk for progression into metabolic disorders.

Differentiating external zeitgeber impact on peripheral circadian clock resetting

Circadian clocks regulate physiological functions, including energy metabolism, along the 24-hour day cycle. The mammalian clock system is organized in a hierarchical manner with a coordinating pacemaker residing in the hypothalamic suprachiasmatic nucleus (SCN). The SCN clock is reset primarily by the external light-dark cycle while other zeitgebers such as the timing of food intake are potent synchronizers of many peripheral tissue clocks. Under conflicting zeitgeber conditions, e.g. during shift work, phase synchrony across the clock network is disrupted promoting the development of metabolic disorders. We established a zeitgeber desynchrony (ZD) paradigm to quantify the differential contributions of the two main zeitgebers, light and food, to the resetting of specific tissue clocks and the effect on metabolic homeostasis in mice. Under 28-hour light-dark and 24-hour feeding-fasting conditions SCN and peripheral clock, as well as activity and hormonal rhythms showed specific periodicities aligning in-between those of the two zeitgebers. During ZD, metabolic homeostasis was cyclic with mice gaining weight under synchronous and losing weight under conflicting zeitgeber conditions. In summary, our study establishes an experimental paradigm to compare zeitgeber input in vivo and study the physiological consequences of chronodisruption.

The Janus Face of Cereals: Wheat-Derived Prebiotics Counteract the Detrimental Effect of Gluten on Metabolic Homeostasis in Mice Fed a High-Fat/High-Sucrose Diet.

ScopeCereals are important sources of carbohydrates, but also contain nutrients that could impact adiposity. The contribution of gluten to obesity and the effects of prebiotics—arabinoxylo‐oligosaccharides (AXOS) and fructo‐oligosaccharides (FOS)—that can be extracted from gluten‐containing cereals are analyzed.Methods and resultsMice are fed a control diet, Western diet (WD, consisting of high fat/high sucrose), or WD with 5% gluten. Prebiotics are tested in the WD with gluten. Gluten does not increase body weight and has a minor effect on ileal inflammation. Gluten decreases the expression of browning markers in the fat and increases the triglycerides synthesis in the muscle. AXOS decreases body weight and adiposity in fat pads muscle and liver. AXOS promotes gluten cleavage by the induction of prolyl endopeptidase that is translated into a reduction of gluten immunogenic peptides. Gluten has minor effects on cecal microbiota composition, whereas prebiotics increased Bifidobacterium, Butyricicoccus, Prevotella, and Parasutterella, which are all negatively correlated to the cecal content of gluten peptides.ConclusionWhile gluten may affect metabolic homeostasis, these effects are lessened when gluten is consumed along with cereal‐derived fibers. If confirmed in humans, the authors bring new arguments to eat fiber‐rich cereals to promote a healthy diet.

Exposure to Nanoscale Particulate Matter from Gestation to Adulthood Impairs Metabolic Homeostasis in Mice

Emerging evidence from epidemiological and animal studies suggests that exposure to traffic-related air pollutants and particulate matter less than 2.5 µm in diameter (PM2.5) contributes to development of obesity and related metabolic abnormalities. However, it is not known whether nanoscale particulate matter (nPM) with aerodynamic diameter ≤200 nm have similar adverse metabolic effects. The goal of the present study was to determine the effects of prenatal and early life exposure to nPM on metabolic homeostasis in mice. C57BL/6 J mice were exposed to nPM or filtered air from gestation until 17 weeks of age and characterized for metabolic and behavioral parameters. In male mice, nPM exposure increased food intake, body weight, fat mass, adiposity, and whole-body glucose intolerance (p < 0.05). Consistent with these effects, male mice exposed to nPM displayed alterations in the expression of metabolically-relevant neuropeptides in the hypothalamus and decreased expression of insulin receptor signaling genes in adipose (p < 0.05). There were no differences in exploratory behavior or motor function, fasting lipid levels, or the inflammatory profile of adipose tissue. Our results provide evidence that chronic nPM exposure from gestation to early adulthood in male mice promotes metabolic dysregulation in part through modulation of feeding behavior and in the absence of an obesogenic diet.

Adipocyte-specific deficiency of Nfe2l1 disrupts plasticity of white adipose tissues and metabolic homeostasis in mice

The maintenance of healthy adipose tissues is essential for efficient regulation of energy homeostasis. Nuclear factor-erythroid 2-related factor 1 (NFE2L1, also known as Nrf1), a CNC-bZIP protein, is a master regulator of the cellular adaptive response to stresses. To investigate the role of NFE2L1 in adipocytes, we bred a line of mice with adipocyte-specific Nfe2l1 knockout (Nfe2l1(f)-KO), and found that Nfe2l1(f)-KO mice exhibited a dramatically reduced subcutaneous adipose tissue (SAT) mass, insulin resistance, adipocyte hypertrophy, and severe adipose inflammation. Mechanistic studies revealed that Nfe2l1 deficiency may disturb the expression of lipolytic genes in adipocytes, leading to adipocyte hypertrophy followed by inflammation, pyroptosis, and insulin resistance. Our findings reveal a novel role for NFE2L1 in regulating adipose tissue plasticity and energy homeostasis.

Targeted Metabolomics Reveals Abnormal Hepatic Energy Metabolism by Depletion of \u03b2-Carotene Oxygenase 2 in Mice

β-carotene oxygenase 2 (BCO2) is a carotenoid cleavage enzyme located in the inner mitochondrial membrane. Ablation of BCO2 impairs mitochondrial function leading to oxidative stress. Herein, we performed a targeted metabolomics study using ultrahigh performance liquid chromatography-tandem mass spectroscopy and gas chromatography-mass spectroscopy to discriminate global metabolites profiles in liver samples from six-week-old male BCO2 systemic knockout (KO), heterozygous (Het), and wild type (WT) mice fed a chow diet. Principal components analysis revealed distinct differences in metabolites in the livers of KO mice, compared to WT and Het mice. However, no marked difference was found in the metabolites of the Het mouse liver compared to the WT. We then conducted random forest analysis to classify the potential biomarkers to further elucidate the different metabolomics profiles. We found that systemic ablation of BCO2 led to perturbations in mitochondrial function and metabolism in the TCA cycle, amino acids, carnitine, lipids, and bile acids. In conclusion, BCO2 is essential to macronutrient and mitochondrial metabolism in the livers of mice. The ablation of BCO2 causes dysfunctional mitochondria and altered energy metabolism, which further leads to systemic oxidative stress and inflammation. A single functional copy of BCO2 largely rescues the hepatic metabolic homeostasis in mice.