Bariatric surgery remains the only effective and durable treatment option for morbid obesity. Vertical Sleeve Gastrectomy (VSG) is currently the most widely performed of these surgeries primarily ...because of its proven efficacy in generating rapid onset weight loss, improved glucose regulation and reduced mortality compared with other invasive procedures. VSG is associated with reduced appetite, however, the relative importance of energy expenditure to VSG-induced weight loss and changes in glucose regulation, particularly that in brown adipose tissue (BAT), remains unclear. The aim of this study was to investigate the role of BAT thermogenesis in the efficacy of VSG in a rodent model.
Diet-induced obese male Sprague–Dawley rats were either sham-operated, underwent VSG surgery or were pair-fed to the food consumed by the VSG group. Rats were also implanted with biotelemetry devices between the interscapular lobes of BAT to assess local changes in BAT temperature as a surrogate measure of thermogenic activity. Metabolic parameters including food intake, body weight and changes in body composition were assessed. To further elucidate the contribution of energy expenditure via BAT thermogenesis to VSG-induced weight loss, a separate cohort of chow-fed rats underwent complete excision of the interscapular BAT (iBAT lipectomy) or chemical denervation using 6-hydroxydopamine (6-OHDA). To localize glucose uptake in specific tissues, an oral glucose tolerance test was combined with an intraperitoneal injection of 14C-2-deoxy-d-glucose (14C-2DG). Transneuronal viral tracing was used to identify 1) sensory neurons directed to the stomach or small intestine (H129-RFP) or 2) chains of polysynaptically linked neurons directed to BAT (PRV-GFP) in the same animals.
Following VSG, there was a rapid reduction in body weight that was associated with reduced food intake, elevated BAT temperature and improved glucose regulation. Rats that underwent VSG had elevated glucose uptake into BAT compared to sham operated animals as well as elevated gene markers related to increased BAT activity (Ucp1, Dio2, Cpt1b, Cox8b, Ppargc) and markers of increased browning of white fat (Ucp1, Dio2, Cited1, Tbx1, Tnfrs9). Both iBAT lipectomy and 6-OHDA treatment significantly attenuated the impact of VSG on changes in body weight and adiposity in chow-fed animals. In addition, surgical excision of iBAT following VSG significantly reversed VSG-mediated improvements in glucose tolerance, an effect that was independent of circulating insulin levels. Viral tracing studies highlighted a patent neural link between the gut and BAT that included groups of premotor BAT-directed neurons in the dorsal raphe and raphe pallidus.
Collectively, these data support a role for BAT in mediating the metabolic sequelae following VSG surgery, particularly the improvement in glucose regulation, and highlight the need to better understand the contribution from this tissue in human patients.
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•VSG results in increased BAT temperature and glucose uptake into BAT as well as elevated gene markers of BAT activity and browning of white fat.•Removal of BAT substantially limits the positive impact of VSG on both body weight and glycemic control.•Combination of two neurotropic viruses highlights a patent neural circuit between the gut and BAT that may underpin this response.
Ghrelin is a metabolic hormone that has neuroprotective actions in a number of neurological conditions, including Parkinson's disease (PD), stroke and traumatic brain injury. Acyl ghrelin treatment ...in vivo and in vitro also shows protective capacity in Alzheimer's disease (AD). In the present study, we used ghrelin knockout (KO) and their wild‐type littermates to test whether or not endogenous ghrelin is protective in a mouse model of AD, in which human amyloid β peptide 1‐40 (Aβ1‐40) was injected into the lateral ventricles i.c.v. Recognition memory, using the novel object recognition task, was significantly impaired in ghrelin KO mice and after i.c.v. Aβ1‐40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Spatial orientation, as assessed by the Y‐maze task, was also significantly impaired in ghrelin KO mice and after i.c.v. Aβ1‐40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Ghrelin KO mice had deficits in olfactory discrimination; however, neither i.c.v. Aβ1‐40 treatment, nor acyl ghrelin injections affected olfactory discrimination. We used stereology to show that ghrelin KO and Aβ1‐40 increased the total number of glial fibrillary acidic protein expressing astrocytes and ionised calcium‐binding adapter expressing microglial in the rostral hippocampus. Finally, Aβ1‐40 blocked long‐term potentiation induced by high‐frequency stimulation and this effect could be acutely blocked with co‐administration of acyl ghrelin. Collectively, our studies demonstrate that ghrelin deletion affects memory performance and also that acyl ghrelin treatment may delay the onset of early events of AD. This supports the idea that acyl ghrelin treatment may be therapeutically beneficial with respect to restricting disease progression in AD.
HIF-1α (hypoxia-inducible factor-1 alpha) mediates the responses of mammalian cells to hypoxia/ischemia by inducing the expression of adaptive gene products (e.g., vascular endothelial growth factor ...(VEGF) and erythropoietin (EPO)). Persistent pulmonary hypertension of the newborn (PPHN) and cyanotic congenital heart disease (CCHD) are common neonatal diseases considered as paradigms of hypoxemia. Since the expression HIF-1α, VEGF and EPO in newborns diagnosed with these diseases has yet to be studied, we set out to define the expression of these genes in peripheral blood from newborn infants diagnosed with PPHN and CCHD.
The mRNA transcripts encoding HIF-1α, VEGF and EPO were measured by RT-PCR in healthy newborn infants and infants diagnosed with PPHN and CCHD.
An important increase in HIF-1α expression was observed in both pathological conditions, accompanied by significant increases in VEGF and EPO expression when compared to healthy infants.
HIF-1α mRNA expression increases in newborn infants with PPHN or CCHD, as does the expression of its target genes VEGF and EPO.
Obesity impairs arcuate (ARC) neuropeptide Y (NPY)/agouti‐releated peptide (AgRP) neuronal function and renders these homeostatic neurones unresponsive to the orexigenic hormone ghrelin. In the ...present study, we investigated the effect of diet‐induced obesity (DIO) on feeding behaviour, ARC neuronal activation and mRNA expression following another orexigenic stimulus, an overnight fast. We show that 9 weeks of high‐fat feeding attenuates fasting‐induced hyperphagia by suppressing ARC neuronal activation and hypothalamic NPY/AgRP mRNA expression. Thus, the lack of appropriate feeding responses in DIO mice to a fast is caused by failure ARC neurones to recognise and/or respond to orexigenic cues. We propose that fasting‐induced hyperphagia is regulated not by homeostatic control of appetite in DIO mice, but rather by changes in the reward circuitry.
Abstract Background Late gadolinium enhanced (LGE) cardiac magnetic resonance (CMR) imaging serves as a valuable non-invasive tool for visualizing and quantifying left atrial (LA) fibrosis in atrial ...fibrillation (AF) patients. The extent of pre-procedural LA-LGE, indicative of native atrial fibrosis, has proven to be a predictor of AF recurrence risk following AF ablation. Consequently, assessing the LA fibrotic burden has emerged as a potential guide for personalized patient management. Currently, most centers engaged in LA-LGE image acquisition apply a scan protocol based on a diaphragmatic navigator-gated 3D image strategy (dNAV). Recently introduced image navigated (iNAV) 3D LGE strategies are proposed to outperform the dNAV strategy. This advancement involves the dynamic tracking of the heart's respiratory position with an image reconstruction algorithm, yielding motion-compensated images in significantly reduced and more consistent scan durations. We performed an evaluation of the novel image navigated (iNAV) 3D LGE-CMR imaging strategy in comparison to the conventional diaphragm navigated (dNAV) 3D LGE-CMR strategy. Methods In twenty-six consecutive AF patients, both imaging techniques (i.e. iNAV and dNAV) were performed subsequently, with equivalent spatial resolution and timing in the cardiac cycle. Patients were randomized in the acquisition order of iNAV and dNAV. LA fibrosis was quantified (percentage of atrial fibrosis using image intensity ratio threshold 1.2) and overlap in atrial fibrosis areas was tested between the two methods. Results Acquisition time of iNAV was significantly lower compared to dNAV (5±1 minutes vs. 12±4 minutes, p<0.001, respectively). There was a significant correlation between the iNAV and dNAV LA fibrotic burden (r=0.69, p<0.001). LA fibrosis scores were lower for iNAV compared to dNAV (12±8% vs. 20±12%, p<0.001, respectively). Spatial correspondence between the atrial fibrosis maps was modest (Dice similarity coefficient 0.43±0.15). Notably, 13/23 (56%) patients underwent a shift in their UTAH fibrosis stage classification, depending on the chosen imaging strategy. Conclusion iNAV acquisition was more than twice as fast as dNAV, and iNAV resulted in a lower atrial fibrosis score as compared to dNAV. More than half of the patients were reclassified into a different UTAH fibrosis stage depending on the employed imaging strategy. This underscores the critical importance of recognizing that the choice of imaging strategy significantly impacts the categorization of patients into their respective fibrosis stages. This distinction carries potential clinical implications when evaluating the utility of UTAH fibrosis stages in the context of AF management and therapeutic decision-making, as patients in lower fibrosis stages are generally regarded as more suitable candidates for ablation, while those categorized in higher fibrosis stages face an increased risk of arrhythmia recurrence following PVI.Figure 1Figure 2
Ghrelin is a metabolic hormone that has neuroprotective actions in a number of neurological conditions, including Parkinson's disease (PD), stroke and traumatic brain injury. Acyl ghrelin treatment ...in vivo and in vitro also shows protective capacity in Alzheimer's disease (AD). In the present study, we used ghrelin knockout (KO) and their wild-type littermates to test whether or not endogenous ghrelin is protective in a mouse model of AD, in which human amyloid beta peptide 1-40 (Abeta1-40) was injected into the lateral ventricles i.c.v. Recognition memory, using the novel object recognition task, was significantly impaired in ghrelin KO mice and after i.c.v. Abeta1-40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Spatial orientation, as assessed by the Y-maze task, was also significantly impaired in ghrelin KO mice and after i.c.v. Abeta1-40 treatment. These deficits could be prevented by acyl ghrelin injections for 7 days. Ghrelin KO mice had deficits in olfactory discrimination; however, neither i.c.v. Abeta1-40 treatment, nor acyl ghrelin injections affected olfactory discrimination. We used stereology to show that ghrelin KO and Abeta1-40 increased the total number of glial fibrillary acidic protein expressing astrocytes and ionised calcium-binding adapter expressing microglial in the rostral hippocampus. Finally, Abeta1-40 blocked long-term potentiation induced by high-frequency stimulation and this effect could be acutely blocked with co-administration of acyl ghrelin. Collectively, our studies demonstrate that ghrelin deletion affects memory performance and also that acyl ghrelin treatment may delay the onset of early events of AD. This supports the idea that acyl ghrelin treatment may be therapeutically beneficial with respect to restricting disease progression in AD.
AgRP neurons control peripheral substrate utilization and nutrient partitioning during conditions of energy deficit and nutrient replenishment, although the molecular mechanism is unknown. We ...examined whether carnitine acetyltransferase (Crat) in AgRP neurons affects peripheral nutrient partitioning. Crat deletion in AgRP neurons reduced food intake and feeding behavior and increased glycerol supply to the liver during fasting, as a gluconeogenic substrate, which was mediated by changes to sympathetic output and peripheral fatty acid metabolism in the liver. Crat deletion in AgRP neurons increased peripheral fatty acid substrate utilization and attenuated the switch to glucose utilization after refeeding, indicating altered nutrient partitioning. Proteomic analysis in AgRP neurons shows that Crat regulates protein acetylation and metabolic processing. Collectively, our studies highlight that AgRP neurons require Crat to provide the metabolic flexibility to optimize nutrient partitioning and regulate peripheral substrate utilization, particularly during fasting and refeeding.
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•Crat in AgRP neurons helps nutrient replenishment as food is available after fasting•Crat in AgRP neurons helps maintain appropriate hepatic glucose production during fasting•Crat in AgRP neurons facilitates peripheral substrate switching upon acute refeeding•Crat regulates protein expression and acetylation in AgRP cells in fasting and refeeding
Reichenbach et al. demonstrate that AgRP neurons require carnitine acetyltransferase to regulate peripheral substrate switching from fatty acid to glucose utilization during fasting and the transition to refeeding. This mechanism preserves fatty acids when glucose from food becomes available and maximizes energy conservation for future periods of energy deficit.
Tobacco use is of particular concern to the U.S. Department of Defense because the military historically has had higher and heavier rates of tobacco use than civilians. Few prospective studies have ...examined the association of cigarette smoking with medical outcomes, particularly among initially healthy female military personnel.
This prospective cohort study followed over 5,000 young U.S. Navy female recruits varying in their smoking status at entry into the Navy and collected their subsequent hospitalization data (i.e., International Classification of Diseases, Ninth Revision codes) for up to 7-8 years of service.
Results indicated that after adjusting for differences in time at risk and sociodemographic variables, daily smokers (compared with never-and other smokers) had higher rates of hospitalization for any reason and for musculoskeletal conditions. Daily smokers also had higher rates than never- and other smokers for non-pregnancy-related hospitalizations and for mental disorders, although only the daily/other differences reached statistical significance. Daily smokers' average number of days hospitalized was significantly longer than that of never- and other smokers.
Results suggest that young women do not have to wait decades to experience the harmful effects of smoking. A recent history of cigarette smoking is an important determinant of hospitalization risk for even young healthy women in the U.S. Navy.
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