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High-fat diet-induced obesity affects alpha 7 nicotine acetylcholine receptor expressions in mouse lung myeloid cells.

ABSTRACT: Ample evidence indicates that obesity causes dysfunctions in the lung. Previous studies also show that cholinergic anti-inflammatory pathways play crucial roles in obesity-induced chronic inflammation via ?7 nicotinic acetylcholine receptor (?7nAChR) signaling. However, it remains unclear whether and how obesity affects the expressions of ?7nAChR in myeloid cells in the lung. To address this question, we treated regular chow diet-fed mice or high-fat diet induced obese mice with lipopolysaccharide (LPS) or vehicle via endotracheal injections. By using a multicolor flow cytometry approach to analyze and characterize differential cell subpopulations and ?7nAChR expressions, we find no detectable ?7nAChR in granulocytes, monocytes and alveolar macrophages, and low expression levels of ?7nAChR were detected in interstitial macrophages. Interestingly, we find that a challenge with LPS treatment significantly increased expression levels of ?7nAChR in monocytes, alveolar and interstitial macrophages. Meanwhile, we observed that the expression levels of ?7nAChR in alveolar and interstitial macrophages in high-fat diet induced obese mice were lower than regular chow diet-fed mice challenged by the LPS. Together, our findings indicate that obesity alters the expressions of ?7nAChR in differential lung myeloid cells.

SUBMITTER: Qi Y

PROVIDER: S-EPMC7592050 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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High-fat diet-induced obesity affects alpha 7 nicotine acetylcholine receptor expressions in mouse lung myeloid cells.

Qi Yong Y Si Dan D Zhu Li L Qi Yanan Y Wu Zhuhua Z Chen Dan D Yang Yunlei Y

Scientific reports 20201027 1

Ample evidence indicates that obesity causes dysfunctions in the lung. Previous studies also show that cholinergic anti-inflammatory pathways play crucial roles in obesity-induced chronic inflammation via α7 nicotinic acetylcholine receptor (α7nAChR) signaling. However, it remains unclear whether and how obesity affects the expressions of α7nAChR in myeloid cells in the lung. To address this question, we treated regular chow diet-fed mice or high-fat diet induced obese mice with lipopolysacchari ...[more]

PMID: 33110180

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Project description:UnlabelledThe intestines of obese humans and mice are enriched with Erysipelotrichi, a class within the Firmicutes. Clostridium ramosum, a member of the Erysipelotrichi, is associated with symptoms of the metabolic syndrome in humans. To clarify the possible obesogenic potential of this bacterial species and to unravel the underlying mechanism, we investigated the role of C. ramosum in obesity development in gnotobiotic mice. Mice were associated with a simplified human intestinal (SIHUMI) microbiota of eight bacterial species, including C. ramosum, with the SIHUMI microbiota except C. ramosum (SIHUMIw/oCra), or with C. ramosum only (Cra) and fed a high-fat diet (HFD) or a low-fat diet (LFD). Parameters related to the development of obesity and metabolic diseases were compared. After 4 weeks of HFD feeding, the mouse groups did not differ in energy intake, diet digestibility, gut permeability, and parameters of low-grade inflammation. However, SIHUMI and Cra mice fed the HFD gained significantly more body weight and body fat and displayed higher food efficiency than SIHUMIw/oCra mice fed the HFD. Gene expression of glucose transporter 2 (Glut2) in jejunal mucosa and of fatty acid translocase (CD36) in ileal mucosa was significantly increased in the obese SIHUMI and Cra mice compared with the less obese SIHUMIw/oCra mice. The data demonstrate that the presence of C. ramosum in SIHUMI and Cra mice enhanced diet-induced obesity. Upregulation of small intestinal glucose and fat transporters in these animals may contribute to their increased body fat deposition.ImportanceObesity is a growing health problem worldwide. Changes in the proportions of Bacteroidetes and Firmicutes, the two dominant phyla in the human and the murine intestinal tract, link the intestinal microbiota to obesity. Erysipelotrichi, a class within the Firmicutes, increase in response to high-fat feeding in mice. Clostridium ramosum, a member of the Erysipelotrichi, has been linked to symptoms of the metabolic syndrome. We hypothesized that C. ramosum promotes obesity development and related pathologies. Our experiments in gnotobiotic mice show that C. ramosum promoted diet-induced obesity, probably by enhancing nutrient absorption. Identification of obesogenic bacteria and understanding their mode of action enable the development of novel strategies for the treatment of this epidemic disease. Pharmaceuticals that target obesogenic bacteria or their metabolism could help to prevent and treat obesity and related disorders in the future.

Project description:Nicotine, the major psychoactive compound in tobacco, targets nicotinic acetylcholine receptors (nAChRs) and results in drug dependence. The nematode Caenorhabditis elegans' (C. elegans) genome encodes conserved and extensive nicotinic receptor subunits, representing a useful system to investigate nicotine-induced nAChR expressions in the context of drug dependence. However, the in vivo expression pattern of nAChR genes under chronic nicotine exposure has not been fully investigated. To define the role of nAChR genes involved in nicotine-induced locomotion changes and the development of tolerance to these effects, we characterized the locomotion behavior combining the use of two systems: the Worm Tracker hardware and the WormLab software. Our results indicate that the combined system is an advantageous alternative to define drug-dependent locomotion behavior in C. elegans. Chronic (24-h dosing) nicotine exposure at 6.17 and 61.7μM induced nicotine-dependent behaviors, including drug stimulation, tolerance/adaption, and withdrawal responses. Specifically, the movement speed of naïve worms on nicotine-containing environments was significantly higher than on nicotine-free environments, suggesting locomotion stimulation by nicotine. In contrast, the 24-h 6.17μM nicotine-treated worms exhibited significantly higher speeds on nicotine-free plates than on nicotine-containing plates. Furthermore significantly increased locomotion behavior during nicotine cessation was observed in worms treated with a higher nicotine concentration of 61.7μM. The relatively low locomotion speed of nicotine-treated worms on nicotine-containing environments also indicates adaption/tolerance of worms to nicotine following chronic nicotine exposure. In addition, this study provides useful information regarding the comprehensive in vivo expression profile of the 28 "core" nAChRs following different dosages of chronic nicotine treatments. Eleven genes (lev-1, acr-6, acr-7, acr-11, lev-8, acr-14, acr-16, acr-20, acr-21, ric-3, and unc-29) were significantly up-regulated following 61.7μM nicotine treatment, in which worms showed significantly increased locomotion behavior. This study provides insights into the linkage between nicotine-induced locomotion behavior and the regulation of nicotinic acetylcholine receptors.

Project description:Background/objectivesRecent findings have highlighted the detrimental influence of maternal overnutrition and obesity on fetal development and early life development. However, there are no evidence-based guidelines regarding the optimal strategy for dietary intervention before pregnancy.Subjects/methodsWe used a murine model to study whether switching from a high-fat (HF) diet to a normal-fat (NF) diet (H1N group) 1 week before pregnancy could lead to in utero reprogramming of female offspring obesity; comparator groups were offspring given a consistent maternal HF group or NF group until weaning. After weaning, all female offspring were given the HF diet for either 9 or 12 weeks before being killed humanely.ResultsH1N treatment did not result in maternal weight loss before pregnancy. NF offsprings were neither obese nor glucose intolerant during the entire experimental period. H1N offsprings were most obese after the 12-week postweaning HF diet and displayed glucose intolerance earlier than HF offsprings. Our mechanistic study showed reduced adipocyte insulin receptor substrate 1 (IRS1) and hepatic IRS2 expression and increased adipocyte p-Ser(636/639) and p-Ser(612) of H1N or HF offspring compared with that in the NF offspring. Among all groups, the H1N offspring had lowest level of IRS1 and the highest levels of p-Ser(636/639) and p-Ser(612) in gonadal adipocyte. In addition, the H1N offspring further reduced the expression of Glut4 and Glut2, vs those of the HF offspring, which was lower compared with the NF offspring. There were also enhanced expression of genes inhibiting glycogenesis and decreased hepatic glycogen in H1N vs HF or NF offspring. Furthermore, we showed extremely higher expression of lipogenesis and adipogenesis genes in gonadal adipocytes of H1N offspring compared with all other groups.ConclusionsOur results suggest that a transition from an HF diet to an NF diet shortly before pregnancy, without resulting in maternal weight loss, is not necessarily beneficial and may have deleterious effects on offspring.

Project description:Sepsis is one of the leading causes of death in hospitalized patients and the chronic and low-grade inflammation observed in obesity seems to worsen susceptibility and morbidity of infections. However, little is known with respect to a short-term high-fat diet (HFD) and its role in the development of sepsis. Here, we show for the first time, that short-term HFD consumption impairs early nicotinic acetylcholine receptor α7 subunit (α7nAChR)- mediated signaling, one of the major components of the cholinergic anti-inflammatory pathway, with a focus on hypothalamic inflammation and innate immune response. Mice were randomized to a HFD or standard chow (SC) for 3 days, and sepsis was subsequently induced by a lethal intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) or by cecal ligation and puncture (CLP) surgery. In a separate experiment, both groups received LPS (i.p.) or LPS (i.p.) in conjunction with the selective α7nAChR agonist, PNU-282987 (i.p. or intracerebroventricular; i.c.v.), and were sacrificed 2 h after the challenge. Short-term HFD consumption significantly reduced the α7nAChR mRNA and protein levels in the hypothalamus and liver (p < 0.05). Immunofluorescence microscopy demonstrated lower cholinergic receptor nicotinic α7 subunit (α7nAChR)+ cells in the arcuate nucleus (ARC) (α7nAChR+ cells in SC = 216 and HFD = 84) and increased F4/80+ cells in the ARC (2.6-fold) and median eminence (ME) (1.6-fold), which can contribute to neuronal damage. Glial fibrillary acidic protein (GFAP)+ cells and neuronal nuclear antigen (NeuN)+ cells were also increased following consumption of HFD. The HFD-fed mice died quickly after a lethal dose of LPS or following CLP surgery (2-fold compared with SC). The LPS challenge raised most cytokine levels in both groups; however, higher levels of TNF-α (Spleen and liver), IL-1β and IL-6 (in all tissues evaluated) were observed in HFD-fed mice. Moreover, PNU-282987 administration (i.p. or i.c.v.) reduced the levels of inflammatory markers in the hypothalamus following LPS injection. Nevertheless, when the i.c.v. injection of PNU-282987 was performed the anti-inflammatory effect was much smaller in HFD-fed mice than SC-fed mice. Here, we provide evidence that a short-term HFD impairs early α7nAChR expression in central and peripheral tissues, contributing to a higher probability of death in sepsis.

Project description:Aims/hypothesisMicroRNAs (miRNAs) are short endogenous RNAs that regulate multiple biological processes including adipogenesis and fat metabolism. We sought to identify miRNAs that correlate with BMI and to elucidate their upstream regulation and downstream targets.MethodsMicroarray-based expression profiling of 233 miRNAs was performed on subcutaneous abdominal adipose tissue biopsies from 29 non-diabetic Pima Indian participants. Correlation of the expression levels of eight miRNAs with BMI was assessed by quantitative reverse transcription (QRT) PCR in adipose samples from 80 non-diabetic Pima Indians with a BMI of 21.6-54.0 kg/m(2). The upstream regulation of one of these miRNAs, miR-221, was tested by treating cultured human pre-adipocytes with leptin, TNF-α and insulin. Predicted targets of miR-221 were validated using QRT-PCR, immunoblots and luciferase assays. The downstream effects of miR-221 overexpression were assayed by proteomic analysis.ResultsExpression levels of miR-221 were positively correlated with BMI (particularly in women) and fasting insulin concentrations, while the levels of miR-193a-3p and miR-193b-5p were negatively correlated with BMI; other miRNAs did not show significant associations in the 80 samples. miR-221 was downregulated by leptin and TNF-α treatment in cultured human pre-adipocytes. Conversely, miR-221 overexpression upregulated several proteins involved in fat metabolism, mimicking peroxisome proliferator-activated receptor (PPAR) activation. Furthermore, miR-221 directly downregulated the adiponectin receptor 1 (ADIPOR1) and the transcription factor v-ets erythroblastosis virus E26 oncogene homolog 1 (ETS1). Adiponectin signalling is known to promote insulin sensitivity, and ETS1 is crucial for angiogenesis.Conclusions/interpretationOur data suggest that miR-221 may contribute to the development of the insulin resistance that typically accompanies obesity, by affecting PPAR signalling pathways and by directly downregulating ADIPOR1 and ETS1.

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High-fat diet-induced obesity affects alpha 7 nicotine acetylcholine receptor expressions in mouse lung myeloid cells.

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High-fat diet-induced obesity affects alpha 7 nicotine acetylcholine receptor expressions in mouse lung myeloid cells.

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