Delayed Pulmonary Apoptosis of Diet-Induced Obesity Mice following Escherichia coli Infection through the Mitochondrial Apoptotic Pathway.
ABSTRACT: Escherichia coli (E. coli) is one of pathogens causing nosocomial pneumonia and could induce pulmonary excessive apoptosis. Although much has been learned about metabolic diseases induced by obesity, the information linking bacterial pneumonia to obesity is limited. Accordingly, we investigated the apoptosis of normal (lean) and diet-induced obesity (DIO, fed a high-fat diet) mice after nasal instillation with E. coli. Lung tissues were obtained at 0 (preinfection), 12, 24, and 72?h after infection, and acute pulmonary inflammation was observed at 12?h. Elevated cell apoptosis and percentage of pulmonary cells depolarized with collapse of the mitochondrial transmembrane potential (??m) occurred in response to bacterial infection. The relative mRNA and protein expressions of Bax, caspase-3, and caspase-9 increased, but Bcl-2 decreased in the lung. Interestingly, the apoptotic percentage and most of apoptosis-associated factors mentioned above peaked at 12 or 24?h in the lean-E. coli group, while at 24 or 72?h in the DIO-E. coli group. Taken together, these findings indicated that the E. coli pneumonia caused excessive pulmonary apoptosis through the mitochondria-mediated pathway, and the apoptosis was delayed in the DIO mice with E. coli pneumonia.
Project description:Splenic immune function was enhanced in diet-induced-obese (DIO) mice caused by Escherichia coli. The changes in spleen function on apoptosis were still unknown. Two hundred mice in groups Lean-E. coli and DIO-E. coli were intranasal instillation of E. coli. And another two hundred mice in groups Lean-PBS and DIO-PBS were given phosphate-buffered saline (PBS). Subsequently, spleen histology was analyzed. Then the rates of spleen cell (SC) apoptosis, and expression of the genes and proteins of Bcl-2, Bax, caspase-3 and caspase-9 were quantified in each group at 0 h (uninfected), 12 h, 24 h, and 72 h postinfection. The SC apoptosis rates of the DIO-E. coli groups were lower than those of the DIO-PBS groups at 12, 24 and 72 h (p < 0.05). Anti-apoptotic Bcl-2 expression gene and protein of the DIO-E. coli groups were higher than those of the DIO-PBS groups (p < 0.05). Gene expressions of pro-apoptotic Bax, caspase-3 and caspase-9 of the DIO-E. coli groups were lower than those of DIO-PBS groups at 12, 24 and 72 h (p < 0.05). The SC apoptosis rates of the Lean-E. coli groups were higher than those of the Lean- PBS groups at 12 h and 24 h (p < 0.05). Interestingly, the SC apoptosis rates in the DIO-E. coli groups were lower than those of the Lean-E. coli groups at 12 h (p < 0.05). In conclusion, our results suggested that the DIO mice presented stronger anti-apoptotic abilities than Lean mice in non-fatal acute pneumonia induced by E. coli infection, which is more conducive to protecting the spleen and improving the immune defense ability of the body.
Project description:Obesity has developed into a considerable health problem in the whole world. Escherichia coli (E. coli) can cause nosocomial pneumonia and induce cell apoptosis during injury and infection. Normal (lean) and diet-induced obesity mice (DIO, fed with high-fat diet) were chosen to perform nasal instillation with E. coli to establish a nonfatal acute pneumonia model. At 0?h, 12?h, 24?h, and 72?h postinfection, lung tissues were obtained to measure cell apoptosis. As shown in this study, both lean and DIO mice exhibited histopathological lesions of acute pneumonia and increased cell apoptosis in the lung infected with E. coli. Interestingly, the relative mRNA and protein expressions associated with either endoplasmic reticulum stress or death receptor apoptotic pathway were all dramatically increased in the DIO mice after infection, while only significant upregulation of death receptor apoptotic pathway in the lean mice at 72?h. These results indicated that the DIO mice executed excess cell apoptosis in the nonfatal acute pneumonia induced by E. coli infection through endoplasmic reticulum stress and death receptor apoptotic pathway.
Project description:This research was to investigate the difference of hepatic histopathology and apoptosis between the diet-induced obesity (DIO) and normal (lean) mice after Escherichia coli (E. coli) pneumonia. A total of 128 ICR mice were selected to be challenged intranasally with phosphate-buffered saline (PBS) or 4×109CFUs/mL of E. coli, and the liver histopathology and apoptosis were examined pre- and post-infection. Results showed that the liver index, levels of lipid droplets, cytokines, adipocytokines, oxidative stress, apoptotic percentage, and apoptotic related factors in the E. coli-infected mice were generally higher than those in the uninfected mice, whereas the hepatic glycogen and Bcl-2 were the opposite. Interestingly, after E. coli infection, the DIO-E. coli mice exhibited decreased liver index and apoptotic percentages, and reduced levels of TNF-?, IL-6, resistin, MDA, GSH, CAT, Caspase-3, Caspase-9, Bax as well as Bax/Bcl-2 ratio in comparison to the lean-E. coli mice. Our results indicated that E. coli-induced pneumonia caused hepatic histopathological damage, increased hepatic apoptosis, oxidative damages, and higher levels of cytokines and adipocytokines. However, such changes showed less severely in the DIO mice than in the lean mice following E. coli pneumonia.
Project description:Obesity is a known risk factor for allergic asthma. It has been recognized as a key player in the pathogenesis of several inflammatory disorders via activation of macrophages, which is also vital to the development of allergic asthma. We investigated the mechanism of obesity-related asthma and whether treating obesity through exercise or diet ameliorates the severity of asthma in the obesity-related asthma model. We generated diet-induced obesity (DIO) in C57BL/6 mice by high-fat-feeding and ovalbumin-induced asthma (lean-OVA or DIO-OVA). The DIO-OVA mice were then treated with tumor necrosis factor (TNF)-? neutralizing antibody as a TNF-? blockade or a Cl2MDP-containing liposome to induce an alveolar macrophage deficiency. To treat obesity, the DIO-OVA mice were under dietary restrictions or exercised. The pathophysiological and immunological responses were analyzed. Airway hyperresponsiveness (AHR), serum IgE and TNF-? levels in the lung tissue increased in the DIO-OVA mice compared to the lean-OVA mice. Both the TNF-? blockade and depletion of alveolar macrophages in the DIO-OVA mice decreased AHR compared to the DIO-OVA mice. Treating obesity by exercise or through dietary means also reduced pulmonary TNF-? levels and AHR in the DIO-OVA mice. These results suggest that restoring normal body weight is an appropriate strategy for reducing TNF-? levels, and controlling inflammation may help improve asthma severity and control in obesity-related asthma.
Project description:Obesity is causally linked to a number of comorbidities, including cardiovascular disease, diabetes, renal dysfunction, and cancer. Obesity has also been linked to pulmonary disorders, including pulmonary arterial hypertension (PAH). It was long believed that obesity-related PAH was the result of hypoventilation and hypoxia due to the increased mechanical load of excess body fat. However, in recent years it has been proposed that the metabolic and inflammatory disturbances of obesity may also play a role in the development of PAH. To determine whether PAH develops in obese rats in the absence of hypoxia, we assessed pulmonary hemodynamics and pulmonary artery (PA) structure in the diet-resistant/diet-induced obesity (DR/DIO) and Zucker lean/fatty rat models. We found that high-fat feeding (DR/DIO) or overfeeding (Zucker) elicited PA remodeling, neomuscularization of distal arterioles, and elevated PA pressure, accompanied by right ventricular (RV) hypertrophy. PA thickening and distal neomuscularization were also observed in DIO rats on a low-fat diet. No evidence of hypoventilation or chronic hypoxia was detected in either model, nor was there a correlation between blood glucose or insulin levels and PAH. However, circulating inflammatory cytokine levels were increased with high-fat feeding or calorie overload, and hyperlipidemia and oxidant damage in the PA wall correlated with PAH in the DR/DIO model. We conclude that hyperlipidemia and peripheral inflammation correlate with the development of PAH in obese subjects. Obesity-related inflammation may predispose to PAH even in the absence of hypoxia.
Project description:Investigating alterations the intestinal microbiome in a diet induced obesity (DIO) rat model after fecal transplant from rats, which underwent Roux-Y-Gastric-Bypass surgery (RYGB). The microbiomes of the RYGB-donor rats, the DIO rats, and DIO rats after receiving the fecal transplant from the RYGB rats. As controls lean rats as well as lean, RYGB and DIO rats after antibiotics treatment were used.
Project description:We have previously reported that obesity attenuates pulmonary inflammation in both patients with acute respiratory distress syndrome (ARDS) and in mouse models of the disease. We hypothesized that obesity-associated hyperleptinemia, and not body mass per se, drives attenuation of the pulmonary inflammatory response and that this e_ect could also impair the host response to pneumonia. We examined the correlation between circulating leptin levels and risk, severity, and outcome of pneumonia in 2 patient cohorts (NHANES III and ARDSNet-ALVEOLI) and in mouse models of diet-induced obesity and lean hyperleptinemia. Plasma leptin levels in ambulatory subjects (NHANES) correlated positively with annual risk of respiratory infection independent of BMI. In patients with severe pneumonia resulting in ARDS (ARDSNet-ALVEOLI), plasma leptin levels were found to correlate positively with subsequent mortality. In obese mice with pneumonia, plasma leptin levels were associated with pneumonia severity, and in obese mice with sterile lung injury, leptin levels were inversely related to bronchoalveolar lavage neutrophilia, as well as to plasma IL-6 and G-CSF levels. These results were recapitulated in lean mice with experimentally induced hyperleptinemia. Our findings suggest that the association between obesity and elevated risk of pulmonary infection may be driven by hyperleptinemia.
Project description:Obesity is characterized by hyperleptinemia and decreased response to exogenous leptin. This has been widely attributed to the development of leptin resistance, a state of impaired leptin signaling proposed to contribute to the development and persistence of obesity. To directly determine endogenous leptin activity in obesity, we treated lean and obese mice with a leptin receptor antagonist. The antagonist increased feeding and body weight (BW) in lean mice, but not in obese models of leptin, leptin receptor, or melanocortin-4 receptor deficiency. In contrast, the antagonist increased feeding and BW comparably in lean and diet-induced obese (DIO) mice, an increase associated with decreased hypothalamic expression of Socs3, a primary target of leptin. These findings demonstrate that hyperleptinemic DIO mice retain leptin suppression of feeding comparable to lean mice and counter the view that resistance to endogenous leptin contributes to the persistence of DIO in mice.
Project description:Many reports detail taste dysfunction in humans and animals with obesity. For example, mice consuming an obesogenic diet for a short period have fewer taste buds than their lean littermates. Further, rats with diet-induced obesity (DIO) show blunted electrophysiological responses to taste in the brainstem. Here, we studied the effects of high energy diet (HED)-induced peripheral taste damage in rats, and whether this deficiency could be reversed by returning to a regular chow diet. Separate groups of rats consumed a standard chow diet (Chow), a HED for 10 weeks followed by a return to chow (HED/chow), or a HED for 10 weeks followed by a restricted HED that was isocaloric with consumption by the HED/chow group (HED/isocal). Fungiform taste papilla (FP) and circumvallate taste bud abundance were quantified several months after HED groups switched diets. Results showed that both HED/chow and HED/isocal rats had significantly fewer FP and lower CV taste bud abundance than control rats fed only chow. Neutrophil infiltration into taste tissues was also quantified, but did not vary with treatment on this timeline. Finally, the number of cells undergoing programmed cell death, measured with caspase-3 staining, inversely correlated with taste bud counts, suggesting taste buds may be lost to apoptosis as a potential mechanism for the taste dysfunction observed in obesity. Collectively, these data show that DIO has lasting deleterious effects on the peripheral taste system, despite a change from a HED to a healthy diet, underscoring the idea that obesity rather than diet predicts damage to the taste system.
Project description:Taste perception changes with obesity but the underlying neural changes remain poorly understood. To address this issue, we recorded taste responses from single cells in the nucleus tractus solitarius (NTS, the first synapse in the central gustatory circuit) in awake, diet-induced obese [(DIO; ? 8 weeks on a high-energy diet (45%fat, 17% sugar; HED)], and lean rats. Rats were implanted with a bundle of microelectrodes in the NTS and allowed to recover. Water-deprived rats were allowed to freely lick various tastants in an experimental chamber. Taste stimuli included an array of sapid stimuli dissolved in artificial saliva (AS). Each taste trial consisted of five consecutive licks followed by five AS licks presented on a VR5 schedule. Results showed that taste responses (n = 49 for DIO; n = 74 for lean rats) in NTS cells in DIO rats were smaller in magnitude, shorter in duration, and longer in latency that those in lean rats. However, there were proportionately more taste-responsive cells in DIO than in lean rats. Lick coherence in DIO rats was significantly lower than in lean rats, both in taste-responsive, and lick-related cells (n = 172 in lean; n = 65 in DIO). Analyses of temporal coding showed that taste cells in DIO rats conveyed less information about taste quality than cells in lean rats. Collectively, results suggest that a HED produces blunted, but more prevalent, responses to taste in the NTS, and a weakened association of taste responses with ingestive behavior. These neural adaptations may represent both negative effects and compensatory mechanisms of a HED that may underlie deficits in taste-related behavior associated with obesity.