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Resumen Introduccion Estandarizar los protocolos de adquisicion de 18F-Colina PET/TC, que permitan evitar la interferencia urinaria, evaluar el mejor tiempo del estudio de cuerpo completo y valorar si la «doble fase» permite la diferenciacion entre lesiones benignas frente a malignas. Metodo Estudio prospectivo que incluye 100 pacientes con cancer de prostata: 31 estadificacion y 69 recidiva bioquimica (32 posprostatectomia y 37 posradioterapia). Adquisicion pelvica inmediatamente tras inyeccion de 18F-Colina y estudio de cuerpo completo, 1 y 2 h p.i. Calculo de media SUVmax por territorios en todos los estudios secuenciales. Analisis de medias (χ2) y porcentaje de cambio del SUV (2/1 h; 1 h/0 min). Patron de dinamica metabolica: acumulativo frente a aclaramiento. Seguimiento tras tratamiento en todos los pacientes y de forma dirigida, cuando eticamente es posible. Resultados Cincuenta y tres focos prostaticos, en ninguna de las imagenes precoces actividad urinaria: Patron acumulativo en 42, porcentaje de aumento: 0 min/1 h: +16,7% (X2 0,94); 1/2 h: +10,0% (X2 0,83). Patron aclaramiento en 11, porcentaje de reduccion: 0 min/1 h: 21,4% (X2 0,91); 1/2 h: −7,7% (X2 0,85), correspondiendo en 7 a estadificacion y 4 a posradioterapia. Todos los focos infradiafragmaticos (n: 24) mostraron dinamica acumulativa, porcentaje de aumento: +9,1% (χ2 0,97), todas ellas visibles en el primer estudio. De los 12 focos supradiafragmaticos, 8 mostraron aclaramiento, porcentaje de reduccion: −13,0% (χ2 0,95). Los otros 4 dinamica acumulativa, porcentaje de aumento: +13,0% (χ2 0,96), siendo valorados invasivamente. Todos los focos oseos (n: 18) mostraron dinamica acumulativa, porcentaje de aumento: +17,1% (χ2 0,95), todas ellas visibles en el estudio 1 h. Conclusiones En la valoracion prostatica la mejor tecnica doble fase es 0 min/1 h. En la diferenciacion de adenopatias supradiafragmaticas es aconsejable la tecnica de doble fase: 1/2 h. Para la infiltracion infradiafragmatica y osea, ante hallazgos dudosos, las imagenes 2 h aumentan la confianza diagnostica.

Aim To standardize acquisition protocols for 18F-Choline PET/CT to prevent from urine interference, to determine the best time point for the whole-body study, and to assess whether “dual point” acquisition allows for differentiating malignant vs. benign lesions. Methods One hundred consecutive patients with prostate cancer were prospectively studied. Immediately after 18F-Choline injection, a pelvis study was acquired, and a whole-body was subsequently obtained 1 and 2 h p.i. Mean SUVmax was obtained in regions and for every sequential imaging. Mean analysis (χ2) and SUV percentage change (2/1 h; 1 h/0 min) were obtained. Metabolic pattern dynamics were assessed: accumulative vs. clearance. Patient follow-up after therapy and directed classification whenever ethically possible were performed. Results Fifty-three prostate foci, without disturbing urinary activity was ever found on early images. Accumulative pattern in 42, with percentage increase was: 0 min/1 h: +16.7% (χ2 0.94); 1/2 h: +10.0% (χ2 0.83). Clearance pattern in 11, with percentage decrease: 0 min/1 h: −21.4% (χ2 0.91): −7.7% (χ2 0.85), corresponding in 7 to initial staging and in 4 post-radiotherapy biochemical recurrence. Every infradiaphragmatic uptake (n: 24) showed accumulative pattern, with percentage increase of +9.1% (χ2 0.97), all of them depicted on early imaging. As for 12 supradiaphragmatic uptake, 8 of them showed clearance pattern with percentage decrease: −13.0% (χ2 0.95). Accumulative pattern showed in 4 of them with percentage increase +13.0% (χ2 0.96), thus being assessed as invasive/malignant. Every bone uptake (n: 18) showed accumulative pattern, with percentage increase: +17.1% (χ2 0.95), all of them depicted on 1 h imaging. Conclusions As for prostate assessment is concerned, dual point at 0 min/1 h proved to be the best procedure. As for supradiaphragmatic lymph-nodes detection, dual point with 1/2 h performed best. As for infradiaphragmatic and bone involvement, as well as for inconclusive findings, the 2 h imaging increased our diagnostic confidence.

Objective To assess the detection rate of 18F-Choline PET/MRI and subsequent changes in therapy approach for patients with prostate cancer treated by prostatectomy and with rising levels of PSA Methods Prospective study with our first 36 patients with prostatectomy for prostate cancer and rising levels of PSA, who were referred for an 18F-Choline PET/MRI study. A dual-phase study was acquired after intravenous administration of 185 ± 10% MBq of 18F-Choline: (1) early imaging (immediately after tracer administration) of prostate area (emission PET/Multiparametric MRI). (2) Whole-body imaging 1 h after tracer injection (emission PET/MRI: T1, T2, STIR, diffusion). The therapy approach for patients was decided upon the Oncology Committee consensus based on 18F-Choline PET/MRI findings. Results Twenty out of 36 patients (55.6%) were positive for the 18F-Choline PET/MRI study: 8 (22.2%) within the prostatectomy bed, 7 (19.4%) with infradiaphragmatic lymph nodes, 4 (11.1%) with local recurrence and infradiaphragmatic lymph nodes, and 1 (2.8%) with bone metastasis. Sixteen out of the 36 patients (44.4%) were negative for the 18F-Choline PET/MRI study. 18F-Choline PET/MRI findings had an impact on the therapy approach to follow: 15 patients (41.6%) showed oligometastatic disease which was treated by imaging-guided radiotherapy, 5 (13.9%) with multiple metastatic disease were treated by androgen deprivation therapy, 16 (44.4%) negative were under active surveillance. Conclusion Hybrid 18F-Choline PET/MRI procedure showed a high detection rate for recurrence in prostate cancer patients treated with prostatectomy and rising PSA levels

Resumen Objetivo Evaluar la tasa de deteccion de la PET/RM con 18F-colina y los cambios en el manejo terapeutico de los pacientes con cancer de prostata tratados con prostatectomia que presentan elevacion del PSA Metodo Estudio prospectivo de los 36 primeros pacientes con cancer de prostata tratados con prostatectomia, con elevacion de PSA Tras la administracion de 185±10% MBq de 18F-colina se ha adquirido un estudio en dos fases: 1) precoz prostatica (inmediatamente tras la administracion del trazador): emision PET/RM multiparametrica. 2) Estudio una hora postinyeccion de cuerpo completo: emision PET/RM: T1, T2, STIR, difusion. El comite oncologico ha decidido la estrategia terapeutica de los pacientes segun los hallazgos de la PET/RM con 18F-colina. Resultados De los 36 pacientes, 20 (55,6%) han mostrado positividad del estudio PET/RM con 18F-colina: en 8 (22,2%) lecho de prostatectomia, en 7 (19,4%) adenopatias infradiafragmaticas, en 4 (11,1%) recidiva local y adenopatias infradiafragmaticas, en 1 (2,8%) una metastasis osea. De los 36 pacientes, en 16 (44,4%) el estudio PET/RM con 18F-colina ha sido negativo. Los hallazgos de la PET/RM con 18F-colina han condicionado la estrategia terapeutica: en 15 pacientes (41,6%) enfermedad oligometastasica tratada con radioterapia guiada por la imagen, en 5 (13,9%) enfermedad multimetastasica tratada con privacion androgenica, en 16 (44,4%) negativo en vigilancia activa. Conclusion La tecnica hibrida PET/RM con 18F-colina ha demostrado una elevada tasa de deteccion de la recidiva en los pacientes tratados con prostatectomia que presentan PSA

The double-stranded RNA-dependent protein kinase activating protein (PACT), an RNA-binding protein that is part of the RNA-induced silencing complex, plays a key role in miR-mediated translational repression. Previous studies showed that PACT regulates the expression of various miRs, selects the miR strand to be loaded onto RNA-induced silencing complex, and determines proper miR length. Apart from PACT's role in mediating the antiviral response in immune cells, what PACT does in other cell types is unknown. Strikingly, it has also been shown that cold exposure leads to marked downregulation of PACT protein in mouse brown adipose tissue (BAT), where mitochondrial biogenesis and metabolism play a central role. Here, we show that PACT establishes a posttranscriptional brake on mitochondrial biogenesis (mitobiogenesis) by promoting the maturation of miR-181c, a key suppressor of mitobiogenesis that has been shown to target mitochondrial complex IV subunit I (Mtco1) and sirtuin 1 (Sirt1). Consistently, we found that a partial reduction in PACT expression is sufficient to enhance mitobiogenesis in brown adipocytes in culture as well as during BAT activation in mice. In conclusion, we demonstrate an unexpected role for PACT in the regulation of mitochondrial biogenesis and energetics in cells and BAT. © 2022 The Authors

Heat-sensory neurons arising from the dorsal root ganglia (DRG) play a pivotal role in the detection of cutaneous temperature and transmission of external signals to the brain, ensuring the maintenance of thermoregulation. However, whether these thermoreceptor neurons contribute to adaptive thermogenesis has remained elusive. We show that genetic ablation of heat sensing Calcitonin Gene-Related Peptide α (CGRPα) neurons promotes resistance to weight gain upon high fat diet (HFD) feeding and increases energy expenditure in mice. Mechanistically, we find that loss of CGRPα-expressing sensory neurons is associated with reduced lipid deposition in adipose tissue, enhanced expression of fatty-acid oxidation genes, higher ex-vivo lipolysis in primary white adipocytes and enhanced mitochondrial respiration from iBAT. Remarkably, mice lacking CGRPα sensory neurons manifest increased tail cutaneous vasoconstriction at room temperature. This exacerbated cold perception was not associated with reduced core temperature, suggesting that heat production and heat conservation mechanisms are engaged. Specific denervation of CGRPα neurons in intrascapular BAT did not contribute to the increased metabolic rate observed upon global sensory denervation. Taken together, these findings highlight an important role for cutaneous thermoreceptors in regulating energy metabolism, by triggering counter-regulatory responses involving energy dissipation processes including lipid fuel utilization and cutaneous vasodilation. Disclosure C. Riera: None. Funding American Diabetes Association/Pathway to Stop Diabetes (1-15-INI-12 to C.R.)

Objectives Heat-sensory neurons from the dorsal root ganglia (DRG) play a pivotal role in detecting the cutaneous temperature and transmission of external signals to the brain, ensuring the maintenance of thermoregulation. However, whether these thermoreceptor neurons contribute to adaptive thermogenesis remains elusive. It is also unknown whether these neurons play a role in obesity and energy metabolism. Methods We used genetic ablation of heat-sensing neurons expressing calcitonin gene-related peptide α (CGRPα) to assess whole-body energy expenditure, weight gain, glucose tolerance, and insulin sensitivity in normal chow and high-fat diet-fed mice. Exvivo lipolysis and transcriptional characterization were combined with adipose tissue-clearing methods to visualize and probe the role of sensory nerves in adipose tissue. Adaptive thermogenesis was explored using infrared imaging of intrascapular brown adipose tissue (iBAT), tail, and core temperature upon various stimuli including diet, external temperature, and the cooling agent icilin. Results In this report, we show that genetic ablation of heat-sensing CGRPα neurons promotes resistance to weight gain upon high-fat diet (HFD) feeding and increases energy expenditure in mice. Mechanistically, we found that loss of CGRPα-expressing sensory neurons was associated with reduced lipid deposition in adipose tissue, enhanced expression of fatty acid oxidation genes, higher exvivo lipolysis in primary white adipocytes, and increased mitochondrial respiration from iBAT. Remarkably, mice lacking CGRPα sensory neurons manifested increased tail cutaneous vasoconstriction at room temperature. This exacerbated cold perception was not associated with reduced core temperature, suggesting that heat production and heat conservation mechanisms were engaged. Specific denervation of CGRPα neurons in intrascapular BAT did not contribute to the increased metabolic rate observed upon global sensory denervation. Conclusions Taken together, these findings highlight an important role of cutaneous thermoreceptors in regulating energy metabolism by triggering counter-regulatory responses involving energy dissipation processes including lipid fuel utilization and cutaneous vasodilation., Highlights • Removal of sensory spinal neurons expressing CGRPα mitigates diet-induced obesity. • CGRPα afferents antagonize adaptive thermogenesis in brown adipose tissue. • Loss of CGRPα afferents leads to enhanced cold perception and vasoconstriction. • Specific adipose denervation of CGRPα afferents does not modulate energy metabolism.

ObjectiveWe sought to determine the extent of SARS-CoV-2 seroprevalence and the factors associated with seroprevalence across a diverse cohort of healthcare workers.DesignObservational cohort study of healthcare workers, including SARS-CoV-2 serology testing and participant questionnaires.SettingsA multisite healthcare delivery system located in Los Angeles County.ParticipantsA diverse and unselected population of adults (n=6062) employed in a multisite healthcare delivery system located in Los Angeles County, including individuals with direct patient contact and others with non-patient-oriented work functions.Main outcomesUsing Bayesian and multivariate analyses, we estimated seroprevalence and factors associated with seropositivity and antibody levels, including pre-existing demographic and clinical characteristics; potential COVID-19 illness-related exposures; and symptoms consistent with COVID-19 infection.ResultsWe observed a seroprevalence rate of 4.1%, with anosmia as the most prominently associated self-reported symptom (OR 11.04, pConclusion and relevanceThe demographic factors associated with SARS-CoV-2 seroprevalence among our healthcare workers underscore the importance of exposure sources beyond the workplace. The size and diversity of our study population, combined with robust survey and modelling techniques, provide a vibrant picture of the demographic factors, exposures and symptoms that can identify individuals with susceptibility as well as potential to mount an immune response to COVID-19.

BackgroundSystemic Sclerosis (SSc) is a systemic autoimmune disease in which the gastrointestinal (GI) manifestation is one of the most frequent complications (90%), being esophagus and anorectal the most affected regions. The set of GI symptoms poses a diagnostic and therapeutic challenge, and the “Patient Reported Outcomes” (PRO) are good tools to address them. The UCLA GIT 2.0 validated questionnaire can be used as an instrument to measure the presence and severity of these symptoms, allowing screening, and improving subsequent management.ObjectivesTo describe gastrointestinal (GI) involvement in patients with SSc.MethodsDescriptive cross-sectional study conducted in a cohort of patients with SSc in a tertiary hospital. Sociodemographic, clinical, complementary tests and treatment variables were collected. Patients with established GI involvement needed to have urdergone some previous diagnostic test. The UCLA GIT 2.0 questionnaire was applied to all included patients, considering the presence of mild symptoms with a score of 0-0.49, moderate 0.49-1, and severe 1-3.Results88 patients (90% women) were recruited, with a mean age of 61.3 years. They presented the subtypes of limited and diffuse SSc in 63.3% and 13.6%, respectively. The most frequent antibodies were anticentromere (ACA) in 52.3% of the patients, anti-Ro52 in 20.5% and anti-topoisomerase I in 14.8%. The most frequent manifestations were Raynaud’s phenomenon in 98.8% of the patients followed by GI in 37.5% (gastro-esophageal reflux in 88.2%), diffuse interstitial lung disease in 18% and pulmonary hypertension in 10.22%. The most used treatment was proton pump inhibitors (PPI) in 47.7% of the patients.Patients with GI involvement presented the limited SSc subtype (72.7%) and ACA (60.6%) as main characteristics. Patients without digestive involvement had similar characteristics, but did not show a greater association with any specific antibody (p=0.321).67% of the total number of patients presented a score greater than 0 in the UCLA GIT 2.0 questionnaire, with the reflux section being the most frequent (52.27%). In relation to the total score, they presented mild, moderate, and severe symptoms in 77.3%, 21.6% and 1.1% of the patients respectively. The rest of the results by categories are summarized in Table 1.Table 1.Gastrointestinal involvement(n= 34)Without gastrointestinal involvement(n= 54)Subtype and antibodies Limited24 (70,58%)32 (59,25%) Diffuse5 (14,70%)7 (12,96%) ACA20 (58,82%)26 (48,14%) ATA5 (14,70%)8 (14,81%)Manifestations and treatment ILD5 (14,70%)11 (20,37%) PAH3 (8,82%)6 (11,11%) PPI31 (91,17%)11 (20,37%)UCLA GIT 2.0 (median) Total score0,300,05 Reflux0,350 Swelling0,620 Stain00 Diarrhea*00 Social functioning00 Emotional well-being0,220 Constipation Ɨ00ILD (intersticial lung disease), PAH (pulmonary arterial hypertension), ACA (anti-centromere), ATA (anti-topoisomerase), PPI (proton pump inhibitors).*In the “diarrhea” subcategory the maximum score is 2.Ɨ In the “constipation” subcategory the maximum score is 2,5.Patients with GI pathology presented higher scores (moderate-severe) compared to those without pathology (p=0.009). In this last group, 34.5% of the patients presented GI symptoms according to the test, observing high scores in the bloating, reflux, and constipation sections in 25.2%, 16.6% and 14.8% of the patients respectively.ConclusionGI involvement tends to be one of the most frequent manifestations in our cohort and occurs more frequently in patients with limited skin involvement and ACA +. Patients with established GI pathology had higher scores on the UCLA test. The questionnaire may be useful in detecting undiagnosed patients, but more studies are necessary to establish this possible correlation.References[1]Jose Luis Tandaipan, Ivan Castellví. Systemic sclerosis and gastrointestinal involvement. Rev Colomb Reumatol. 2020;27(S1):44-54.[2]Dinesh Khanna, et al. Measuring Response in the Gastrointestinal Tract in systemic sclerosis. Curr Opin Rheumatol. 2013;25(6).Disclosure of InterestsNone declared

Objective Calcitonin Gene-Related Peptide α (CGRPα) is a multifunctional neuropeptide found in the central and peripheral nervous system with cardiovascular, nociceptive, and gastrointestinal activities. CGRPα has been linked to obesity and insulin secretion but the role of this circulating peptide in energy metabolism remains unclear. Here, we thought to utilize a monoclonal antibody against circulating CGRPα to assess its ability to improve glucose homeostasis in mouse models of hyperglycemia and diabetes. Methods We examined the outcome of anti-CGRPα treatment in mouse models of diabetes and diet-induced obesity, using db/db mice, Streptozotocin (STZ) treatment to eliminate pancreatic islets, and high fat diet-fed mice. We also correlated these data with application of recombinant CGRPα peptide on cultured mature adipocytes to measure its impact on mitochondrial bioenergetics and fatty acid oxidation. Furthermore, we applied recombinant CGRPα to primary islets to measure glucose-stimulated insulin secretion (GSIS) and gene expression. Results BL6-db diabetic mice receiving anti-CGRPα treatment manifested weight loss, reduced adiposity, improved glucose tolerance, insulin sensitivity, GSIS and reduced pathology in adipose tissue and liver. Anti-CGRPα failed to modulate weight or glucose homeostasis in STZ-treated animals. High fat diet-fed mice showed reduced adiposity but no benefit on glucose homeostasis. Considering these findings, we postulated that CGRPα may have dual effects on adipocytes to promote lipid utilization while acting on pancreatic β-cells to modulate insulin secretion. Analysis of CGRPα in the pancreas showed that the peptide localized to insulin-positive cells and perivascular nerves surrounding islets. Ex-vivo analysis of pancreatic islets determined that CGRPα blocked GSIS and reduced insulin-2 gene expression. Mechanistical analysis revealed that recombinant CGRPα was able to reduce glycolytic capacity as well as fatty acid oxidation in primary white adipocytes. Conclusions These results establish a multifaceted role in energy metabolism for circulating CGRPα, with the ability to modulate thermogenic pathways in adipose tissue, as well as pancreatic β-cell dependent insulin secretion. Reducing circulating CGRPα levels with monoclonal therapy presents therapeutic potential for type 2 diabetes as shown in BL6-db/db mice but has reduced potential for models of hyperglycemia resulting from loss of β-cells (STZ treatment).

ImportanceAntibody testing is important for understanding patterns of exposure and potential immunity to SARS-CoV-2. Prior data on seroprevalence have been subject to variations in selection of individuals and nature as well as timing of testing in relation to exposures.ObjectiveWe sought to determine the extent of SARS-CoV-2 seroprevalance and the factors associated with seroprevelance across a diverse cohort of healthcare workers.DesignObservational cohort study of healthcare workers, including SARS-CoV-2 serology testing and participant questionaires.ParticipantsA diverse and unselected population of adults (n=6,062) employed in a multi-site healthcare delivery system located in Los Angeles County, including individuals with direct patient contact and others with non-patient-oriented work functions.ExposureExposure and infection with the SARS-CoV-2 virus, as determined by seropositivity.Main OutcomesUsing Bayesian and multi-variate analyses, we estimated seroprevalence and factors associated with seropositivity and antibody titers, including pre-existing demographic and clinical characteristics; potential Covid-19 illness related exposures; and, symptoms consistent with Covid-19 infection.ResultsWe observed a seroprevalence rate of 4.1%, with anosmia as the most prominently associated self-reported symptom in addition to fever, dry cough, anorexia, and myalgias. After adjusting for potential confounders, pre-existing medical conditions were not associated with antibody positivity. However, seroprevalence was associated with younger age, Hispanic ethnicity, and African-American race, as well as presence of either a personal or household member having a prior diagnosis of Covid-19. Importantly, African American race and Hispanic ethnicity were associated with antibody positivity even after adjusting for personal Covid-19 diagnosis status, suggesting the contribution of unmeasured structural or societally factors. Notably, number of people, or children, in the home was not associated with antibody positivity.Conclusion and RelevanceThe demographic factors associated with SARS-CoV-2 seroprevalence among our healthcare workers underscore the importance of exposure sources beyond the workplace. The size and diversity of our study population, combined with robust survey and modeling techniques, provide a vibrant picture of the demographic factors, exposures, and symptoms that can identify individuals with susceptibility as well as potential to mount an immune response to Covid-19.Key PointsQuestionWhat is the SARS-CoV-2 IgG seroprevalence rate across a large and diverse healthcare worker population, and which clinical, envionrmental, and symptom-based measures are associated with seropositivity?FindingsWe observed a seroprevalence rate of 4.1%. Adjusting for potential confounders, seropositivity was associated with younger age, Hispanic ethnicity, African-American race, and the symptom of anosmia, while not significantly associated with any pre-existing medical conditions.MeaningFactors associated with SARS-CoV-2 seroprevalence among our healthcare workers underscore the importance of exposure sources beyond the workplace.

Of individuals with SARS-CoV-2 IgG antibody testing performed, those who contemporaneously experienced a cluster of Covid-19 relevant symptoms in the 1-2 months preceding the antibody assay were more likely to test positive whereas those who experienced the symptom clustering in the prior 3-6 months were more likely to test negative. These findings suggest that antibodies likely wane over a period of months, particularly in relation to the timing of symptoms.

Olfactory inputs are important for hedonic evaluation of food, resulting in food choice and possible consumption. The hypothalamus is a master regulator of whole-body energy homeostasis, integrating internal and external stimuli to modulate energy intake and expenditure accordingly. However, how the hypothalamus adjusts circuits regulating energy homeostasis depending on external stimuli, such as smell, remains an intriguing mystery. Here, we determined the role of olfactory inputs on energy homeostasis by using chemogenetic approach and chemical ablation of OSN to inhibit or stimulate olfaction. Acute inhibition of olfaction changed gene expression of some key neuropeptides in hypothalamus in fasted and refed mice. Chronic silencing of mitral cells in OB promotes resistance to diet-induced obesity, mainly by decreasing food intake. Additionally, chemical ablation of mature OSNs decreases neuronal activity in olfactory cortex and in ARC suggesting that loss of smell, in addition to impacting olfactory pathways, also affects neuronal activity in the ARC, and therefore is likely to alter energy homeostasis. Acute stimulation of mitral cells layer in OB increases neuronal activity in ARC as well as dorsomedial hypothalamus (DMH). Observed increase in ARC neuronal activity is mainly due to activation of glutaminergic neurons. Acute stimulation of olfaction led to increased oxygen consumption and heat production, with no changes observed upon chronic stimulation. Further studies are required to determine specific neuronal cell types within the ARC and DMH that respond to inhibition/stimulation of olfaction and therefore modulating energy homeostasis. Disclosure C. Riera: None. Funding American Diabetes Association Pathway to Stop Diabetes (1-15-INI-12)

Sensory neurons arising from the dorsal root ganglia play a pivotal role in thermoregulation through the detection of cutaneous temperature and transmission of sensory signals to the brain. However, the functional significance of sensory perception in thermogenesis and weight loss has remained elusive. Here, we show that genetic ablation of heat sensing neurons containing Calcitonin Gene-Related Peptide (CGRPα) promotes resistance to weight gain upon high fat diet (HFD) feeding and drives a thermogenic program in brown and white adipose tissues. Remarkably, mice lacking CGRPα-expressing sensory neurons feel colder when challenged with cooling stimuli and their brown fat displays increased energy utilization during cold and HFD challenges. As these neurons are peptidergic, we also investigated the role of the CGRPα secreted peptide in this process. Depletion of CGRPα with a monoclonal antibody leads to a lesser weight loss than full neural depletion on HFD and partially recapitulates the increased energy expenditure and brown fat thermogenic profile observed with sensory ablation. Mechanistically, recombinant CGRPα impaired glycolysis and reduced fatty acid oxidation in cultured cells. Collectively, our results suggest that CGRPα-expressing sensory neurons are the first step to regulate adaptive thermogenesis in brown adipose tissue by detecting alterations in environmental temperatures. These neural processes have the dual ability to both influence central regulation of adrenergic stimulation of thermogenesis and to release peptidergic signals inhibiting fuel consumption in adipocytes.

Preservation of mitochondrial function, which is dependent on mitochondrial homeostasis (biogenesis, dynamics, disposal/recycling), is critical for maintenance of skeletal muscle function. Skeletal muscle performance declines upon aging (sarcopenia) and is accompanied by decreased mitochondrial function in fast-glycolytic muscles. Oxidative metabolism promotes mitochondrial homeostasis, so we investigated whether mitochondrial function is preserved in oxidative muscles. We compared tibialis anterior (predominantly glycolytic) and soleus (oxidative) muscles from young (3 mo) and old (28-29 mo) C57BL/6J mice. Throughout life, the soleus remained more oxidative than the tibialis anterior and expressed higher levels of markers of mitochondrial biogenesis, fission/fusion and autophagy. The respiratory capacity of mitochondria isolated from the tibialis anterior, but not the soleus, declined upon aging. The soleus and tibialis anterior exhibited similar aging-associated changes in mitochondrial biogenesis, fission/fusion, disposal and autophagy marker expression, but opposite changes in fiber composition: the most oxidative fibers declined in the tibialis anterior, while the more glycolytic fibers declined in the soleus. In conclusion, oxidative muscles are protected from mitochondrial aging, probably due to better mitochondrial homeostasis ab initio and aging-associated changes in fiber composition. Exercise training aimed at enriching oxidative fibers may be valuable in preventing mitochondria-related aging and its contribution to sarcopenia.

International audience; The PASSAM (Passive and Active Systems on Severe Accident source term Mitigation) project was launched in the frame of the 7th framework programme of the European Commission. Coordinated by IRSN, this four year project (2013–2016) involved nine partners from six countries IRSN, EDF and university of Lorraine (France); CIEMAT and CSIC (Spain); PSI (Switzerland); RSE (Italy); VTT (Finland) and AREVA GmbH (Germany). It was mainly an RandD project of experimental nature aimed at investigating phenomena that might enhance source term mitigation in case of a severe accident in a Nuclear Power Plant (NPP). Both existing systems (i.e., water scrubbing and sand bed filters plus metallic pre-filters) and innovative ones (i.e., high pressure sprays, electrostatic precipitators, acoustic agglomerators and, advanced zeolites and combined wet-dry filtration systems), were experimentally studied in conditions as close as possible from those anticipated for severe accidents. This paper presents the main experimental results of the project which represent a significant extension of the current database on these existing or innovative mitigation systems. Application of some of these data for improving existing models or developing new ones should eventually enhance the capability of modelling Severe Accident Management measures and developing improved guidelines. © 2018