Pub Date : 2022-08-01Epub Date: 2022-07-28DOI: 10.1113/JP283448
Shaun A Hanycz, Vishaal Sumra, Anshu Kashyap, Anthony Pokhoy
Shaun A. Hanycz1 , Vishaal Sumra2,3, Anshu Kashyap1 and Anthony Pokhoy4 1Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada 2Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada 3Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada 4Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada
{"title":"Synaptic plasticity of medial olivocochlear efferent system: insights and application for neurotology.","authors":"Shaun A Hanycz, Vishaal Sumra, Anshu Kashyap, Anthony Pokhoy","doi":"10.1113/JP283448","DOIUrl":"https://doi.org/10.1113/JP283448","url":null,"abstract":"Shaun A. Hanycz1 , Vishaal Sumra2,3, Anshu Kashyap1 and Anthony Pokhoy4 1Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada 2Tanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, Ontario, Canada 3Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada 4Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"3653-3655"},"PeriodicalIF":5.5,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40511676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-08-01Epub Date: 2022-07-26DOI: 10.1113/JP283474
Jacqueline K Limberg
The carotid chemoreceptors are the body’s primary oxygen sensors. Located bilaterally at the bifurcation of the common carotid artery, they are well-situated to sense changes in arterial partial pressure of oxygen and elicit necessary reflex responses (e.g. hyperventilation). In addition to their known oxygen-sensing capabilities, the carotid chemoreceptors play an important role in the integrative cardiovascular response to exercise. Indeed, activity of the sympathetic nervous system increases with exercise and at least a portion of sympathetic vasoconstrictor tone can be attributed to the chemoreceptors. The role for the carotid chemoreceptors in the sympathetic response to exercise becomes particularly relevant in the context of clinical conditions such as hypertension, heart failure and perhaps even diabetes. In both pre-clinical models and human patients with heart failure, the contribution of the carotid chemoreceptors to sympathetic vasoconstrictor tone is evident even at rest. Inhibition of chemoreceptor activity can further improve cardiovascular regulation during exercise in heart failure (Collins et al., 2020). The mechanisms by which this may be occurring are many and include interactions between the exercise pressor reflex (i.e. mechanoand metaboreflex) and the carotid chemoreceptors (Edgell & Stickland, 2014). Thus, chemoreceptor activation in the context of exercise may potentiate cardiovascular consequences of such conditions. Notably, the metaboreflex was recently identified to contribute to enhanced peripheral vasoconstriction in patients with heart failure (Barrett-O’Keefe et al., 2018). When considered clinically, exaggerated sympathetically-mediated vasoconstriction in the context of exercise is not limited to the skeletal muscle circulation and has similarly been observed at the level of the kidney. Although this work has been shown to provide comparable results across species (e.g. dogs, humans), less is known regarding the translation of findings across sexes. A lack of understanding of sex-related differences in reflex interactions is primarily a result of the tendency of prior work to include only males or a very small proportion of females. As a result, sex-related differences have only recently been identified and remain poorly described in clinical cohorts. In the most recent issue of The Journal of Physiology, Wan et al. (2022) tested the hypothesis that reflex interactions between the muscle mechanoreflex (passive limb movement) and chemoreflex (hypoxia, hypercapnia) would restrict vascular conductance and blood flow in male but not female adults – attributed to effects of sympathetic activity on the peripheral vasculature. Although not a primary focus, a previous post hoc analysis of a mixed-sex cohort conducted by this group (Wan et al., 2020) found that the leg blood flow response to combined activation of the exercise pressor and chemoreflexes did not differ between male and female participants. However, as note
{"title":"Sex-related differences in the peripheral vascular response to reflex coactivation: Fun physiology or window of opportunity?","authors":"Jacqueline K Limberg","doi":"10.1113/JP283474","DOIUrl":"https://doi.org/10.1113/JP283474","url":null,"abstract":"The carotid chemoreceptors are the body’s primary oxygen sensors. Located bilaterally at the bifurcation of the common carotid artery, they are well-situated to sense changes in arterial partial pressure of oxygen and elicit necessary reflex responses (e.g. hyperventilation). In addition to their known oxygen-sensing capabilities, the carotid chemoreceptors play an important role in the integrative cardiovascular response to exercise. Indeed, activity of the sympathetic nervous system increases with exercise and at least a portion of sympathetic vasoconstrictor tone can be attributed to the chemoreceptors. The role for the carotid chemoreceptors in the sympathetic response to exercise becomes particularly relevant in the context of clinical conditions such as hypertension, heart failure and perhaps even diabetes. In both pre-clinical models and human patients with heart failure, the contribution of the carotid chemoreceptors to sympathetic vasoconstrictor tone is evident even at rest. Inhibition of chemoreceptor activity can further improve cardiovascular regulation during exercise in heart failure (Collins et al., 2020). The mechanisms by which this may be occurring are many and include interactions between the exercise pressor reflex (i.e. mechanoand metaboreflex) and the carotid chemoreceptors (Edgell & Stickland, 2014). Thus, chemoreceptor activation in the context of exercise may potentiate cardiovascular consequences of such conditions. Notably, the metaboreflex was recently identified to contribute to enhanced peripheral vasoconstriction in patients with heart failure (Barrett-O’Keefe et al., 2018). When considered clinically, exaggerated sympathetically-mediated vasoconstriction in the context of exercise is not limited to the skeletal muscle circulation and has similarly been observed at the level of the kidney. Although this work has been shown to provide comparable results across species (e.g. dogs, humans), less is known regarding the translation of findings across sexes. A lack of understanding of sex-related differences in reflex interactions is primarily a result of the tendency of prior work to include only males or a very small proportion of females. As a result, sex-related differences have only recently been identified and remain poorly described in clinical cohorts. In the most recent issue of The Journal of Physiology, Wan et al. (2022) tested the hypothesis that reflex interactions between the muscle mechanoreflex (passive limb movement) and chemoreflex (hypoxia, hypercapnia) would restrict vascular conductance and blood flow in male but not female adults – attributed to effects of sympathetic activity on the peripheral vasculature. Although not a primary focus, a previous post hoc analysis of a mixed-sex cohort conducted by this group (Wan et al., 2020) found that the leg blood flow response to combined activation of the exercise pressor and chemoreflexes did not differ between male and female participants. However, as note","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"3639-3640"},"PeriodicalIF":5.5,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40516471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-08-01Epub Date: 2022-07-21DOI: 10.1113/JP283315
Joshua L Robinson, Jack R T Darby
The transition of the fetus to newborn life involves a number of physiological changes, specifically to the respiratory and cardiovascular systems. Prior to birth, the fetus receives well-oxygenated blood from the placenta via the umbilical vein, with no gas exchange occurring at the fluid-filled lungs. To ensure that not all the blood entering the right side of the fetal heart is sent towards the lungs as it would be after birth, the fetal circulation includes unique shunts: the foramen ovale (FO) and the ductus arteriosus (DA). The FO exists between the atria and allows well-oxygenated blood entering from the inferior vena cava to be preferentially shunted from the right to the left side of the heart, while the DA ensures the majority of right ventricular cardiac output bypasses the pulmonary circulation to instead join the blood flow within the descending aorta. Consequently, during fetal life only ∼7–8% of combined ventricular cardiac output perfuses the lungs (Rudolph, 1985). At birth, the lungs replace the function of the placenta in oxygenating the blood, and the neonatal circulation changes with closure of the DA and FO. When these circulatory changes do not occur, oxygenated and deoxygenated blood is mixed.ApatentDA leads to poor peripheral perfusion, tachycardia and pulmonary hypertension. As a result, there is much interest in the regulation of these circulatory changes at the time of birth and more specifically how to ensure that they occur in an appropriate timeframe to mitigate and prevent poor neonatal outcomes. Both the cessation of blood flow from the placenta and the start of respiration are stimuli to cause these cardiovascular changes in the newborn. Recently, studies have begun to explore the impact of the relative timing of these two stimuli on neonatal physiology. Historically, the cord is clamped immediately (ICC) after delivery, and the newborn subsequently begins breathing. However, current clinical practice is shifting to delay the clamping of the cord until after ventilation has begun (DCC) and potentially allow an easier switch from blood oxygenation at the placenta to oxygenation in the lungs. This could be more effective in preterm babies with a more immature cardiopulmonary circuitry. Practice guidelines developed by the International Liaison Committee on Resuscitation (ILCOR) recommend at least 30 s delay before cord clamping postpartum in preterm newborns (<34+0 weeks gestational age) not requiring immediate resuscitation (Costa-Nobre et al., 2021). This recommendation is due to improved clinical outcomes with DCC, including improved cardiovascular transition, reduced risks of intraventricular haemorrhage and necrotising enterocolitis, and higher haemoglobin and haematocrit. Additionally, DCC in preterm infants reduces mortality, with the number needed to benefit of 20 (Fogarty et al., 2018). Importantly, there is no recommendation for DCC when infants need immediate resuscitation. This Journal Club focuses on a
{"title":"Something worth waiting for: is delayed cord clamping always beneficial?","authors":"Joshua L Robinson, Jack R T Darby","doi":"10.1113/JP283315","DOIUrl":"https://doi.org/10.1113/JP283315","url":null,"abstract":"The transition of the fetus to newborn life involves a number of physiological changes, specifically to the respiratory and cardiovascular systems. Prior to birth, the fetus receives well-oxygenated blood from the placenta via the umbilical vein, with no gas exchange occurring at the fluid-filled lungs. To ensure that not all the blood entering the right side of the fetal heart is sent towards the lungs as it would be after birth, the fetal circulation includes unique shunts: the foramen ovale (FO) and the ductus arteriosus (DA). The FO exists between the atria and allows well-oxygenated blood entering from the inferior vena cava to be preferentially shunted from the right to the left side of the heart, while the DA ensures the majority of right ventricular cardiac output bypasses the pulmonary circulation to instead join the blood flow within the descending aorta. Consequently, during fetal life only ∼7–8% of combined ventricular cardiac output perfuses the lungs (Rudolph, 1985). At birth, the lungs replace the function of the placenta in oxygenating the blood, and the neonatal circulation changes with closure of the DA and FO. When these circulatory changes do not occur, oxygenated and deoxygenated blood is mixed.ApatentDA leads to poor peripheral perfusion, tachycardia and pulmonary hypertension. As a result, there is much interest in the regulation of these circulatory changes at the time of birth and more specifically how to ensure that they occur in an appropriate timeframe to mitigate and prevent poor neonatal outcomes. Both the cessation of blood flow from the placenta and the start of respiration are stimuli to cause these cardiovascular changes in the newborn. Recently, studies have begun to explore the impact of the relative timing of these two stimuli on neonatal physiology. Historically, the cord is clamped immediately (ICC) after delivery, and the newborn subsequently begins breathing. However, current clinical practice is shifting to delay the clamping of the cord until after ventilation has begun (DCC) and potentially allow an easier switch from blood oxygenation at the placenta to oxygenation in the lungs. This could be more effective in preterm babies with a more immature cardiopulmonary circuitry. Practice guidelines developed by the International Liaison Committee on Resuscitation (ILCOR) recommend at least 30 s delay before cord clamping postpartum in preterm newborns (<34+0 weeks gestational age) not requiring immediate resuscitation (Costa-Nobre et al., 2021). This recommendation is due to improved clinical outcomes with DCC, including improved cardiovascular transition, reduced risks of intraventricular haemorrhage and necrotising enterocolitis, and higher haemoglobin and haematocrit. Additionally, DCC in preterm infants reduces mortality, with the number needed to benefit of 20 (Fogarty et al., 2018). Importantly, there is no recommendation for DCC when infants need immediate resuscitation. This Journal Club focuses on a ","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"3641-3642"},"PeriodicalIF":5.5,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40587879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-08-01Epub Date: 2022-07-27DOI: 10.1113/JP283306
Rachel E Szeghy, Nina L Stute
all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.
{"title":"Sticking your neck out for science.","authors":"Rachel E Szeghy, Nina L Stute","doi":"10.1113/JP283306","DOIUrl":"https://doi.org/10.1113/JP283306","url":null,"abstract":"all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"3651-3652"},"PeriodicalIF":5.5,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40604458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-01Epub Date: 2022-01-24DOI: 10.1113/JP282578
Erik R Swenson
Acute and chronic high altitude hypoxaemia evoke a variety of adaptive and maladaptive cardiovascular changes, including increased cardiac output, mild hypertension and vascular dysfunction, which may set the stage for stroke, myocardial injury and thrombosis. Sympathetic nervous system (SNS) activation acting directly on vascular smooth muscle and the vascular endothelium is thought to underlie the development of vascular dysfunction, but exactly how is not fully understood. The dysfunction is not at the smooth muscle level, but at the endothelium, and may involve increased oxidative stress as found in cardiovascular diseases at low altitude (Frei, 1999). Earlier work by Lewis et al. (2014) found an association of impaired vascular function and increased oxidative stress in both short term visitors and long term residents at high altitude (Lewis et al. 2014). In this issue of The Journal of Physiology, Stone et al. (2022) present convincing evidence supporting oxidative stress as a basis for the peripheral vascular dysfunction developing when healthy individuals ascend to high altitude. This vascular dysfunction resides at the endothelial cell, as studied by changes in flow-mediated dilatation (FMD). FMD is dependent on the vascular endothelium since the response to infused vasodilators acting directly on vascular smooth muscle, such as sodium nitroprusside (SNP), is not affected. In contrast, when drugs acting on the endothelium are administered, such as the vasodilator acetylcholine that generates nitric oxide (NO) formation, increases in stimulated blood flow are diminished when vascular dysfunction is present. A further finding supporting the role of the endothelium is that when α-adrenergic blockers are co-infused, even their effect to partially reverse vascular dysfunction is not altered when SNP is given. Stone and colleagues directly focused on oxidative stress, i.e. the formation of oxygen radicals with hypoxia. The various forms of oxygen radicals have myriad effects on cell signalling and vasoactive mediator balance. Importantly, NO is an endothelial cell-derived vasodilator that can be rapidly oxidized to non-vasodilating compounds by reactive oxygen species (ROS). To test the hypothesis that ROS generation underlies high altitude vascular dysfunction, as it does in many cardiovascular diseases (Frei, 1999), they took healthy people to 4300 m in the Peruvian Andean city of Cerro de Pasco and studied them over 3 weeks. They compared measurements of blood flow changes by the strain gauge venous occlusion plethysmography technique (which incorporates both macroand microvascular responses) at near sea level (344 m, Kelowna, British Columbia) and then, after flying to Lima and driving for 4–6 h, at Cerro de Pasco. Between 4 and 6 days after arrival, the subjects were restudied, at which time the average increase in blood pressure was 7%. The basic protocol involved placement of an antecubital arterial catheter for infusions of various amo
{"title":"High altitude vascular dysfunction: can we 'C' our way to a remedy?","authors":"Erik R Swenson","doi":"10.1113/JP282578","DOIUrl":"https://doi.org/10.1113/JP282578","url":null,"abstract":"Acute and chronic high altitude hypoxaemia evoke a variety of adaptive and maladaptive cardiovascular changes, including increased cardiac output, mild hypertension and vascular dysfunction, which may set the stage for stroke, myocardial injury and thrombosis. Sympathetic nervous system (SNS) activation acting directly on vascular smooth muscle and the vascular endothelium is thought to underlie the development of vascular dysfunction, but exactly how is not fully understood. The dysfunction is not at the smooth muscle level, but at the endothelium, and may involve increased oxidative stress as found in cardiovascular diseases at low altitude (Frei, 1999). Earlier work by Lewis et al. (2014) found an association of impaired vascular function and increased oxidative stress in both short term visitors and long term residents at high altitude (Lewis et al. 2014). In this issue of The Journal of Physiology, Stone et al. (2022) present convincing evidence supporting oxidative stress as a basis for the peripheral vascular dysfunction developing when healthy individuals ascend to high altitude. This vascular dysfunction resides at the endothelial cell, as studied by changes in flow-mediated dilatation (FMD). FMD is dependent on the vascular endothelium since the response to infused vasodilators acting directly on vascular smooth muscle, such as sodium nitroprusside (SNP), is not affected. In contrast, when drugs acting on the endothelium are administered, such as the vasodilator acetylcholine that generates nitric oxide (NO) formation, increases in stimulated blood flow are diminished when vascular dysfunction is present. A further finding supporting the role of the endothelium is that when α-adrenergic blockers are co-infused, even their effect to partially reverse vascular dysfunction is not altered when SNP is given. Stone and colleagues directly focused on oxidative stress, i.e. the formation of oxygen radicals with hypoxia. The various forms of oxygen radicals have myriad effects on cell signalling and vasoactive mediator balance. Importantly, NO is an endothelial cell-derived vasodilator that can be rapidly oxidized to non-vasodilating compounds by reactive oxygen species (ROS). To test the hypothesis that ROS generation underlies high altitude vascular dysfunction, as it does in many cardiovascular diseases (Frei, 1999), they took healthy people to 4300 m in the Peruvian Andean city of Cerro de Pasco and studied them over 3 weeks. They compared measurements of blood flow changes by the strain gauge venous occlusion plethysmography technique (which incorporates both macroand microvascular responses) at near sea level (344 m, Kelowna, British Columbia) and then, after flying to Lima and driving for 4–6 h, at Cerro de Pasco. Between 4 and 6 days after arrival, the subjects were restudied, at which time the average increase in blood pressure was 7%. The basic protocol involved placement of an antecubital arterial catheter for infusions of various amo","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1271-1272"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39637577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-01Epub Date: 2022-02-19DOI: 10.1113/JP282699
Evani Patel, Ishita Patel
Glucocorticoids play a crucial role in the maturation of foetal organs during pregnancy, as well as the preparation of extrauterine life and increased energy demands upon removal of the nutrient-rich placenta following birth. The administration of synthetic glucocorticoids, as either Celestone, a formulation of betamethasone acetate with betamethasone phosphate, or solely betamethasone acetate, is routine in many countries (Agnew et al. 2018). The benefits of antenatal corticosteroid treatment are vast, one of which is its ability to help with the maturation of fetal lung tissue and prevent neonatal respiratory distress syndrome in preterm babies (McGoldrick et al. 2020). Endogenously, glucocorticoids are associated with the development of the heart (Hillman et al. 2012). Cardiomyocytes undergo terminal differentiation during pregnancy, including changes to mitochondria, energy metabolism, calcium-handling, and more. Abundant literature exists on the effects of glucocorticoids on cardiomyocytes perinatally, but the direct effects of glucocorticoids, through the glucocorticoid receptor (GR), are not as well established. Furthermore, the role of synthetic glucocorticoids on thematuration of cardiomyocytes during different stages of gestation is also unknown. Elucidating the differences between endogenous and exogenous glucocorticoid administration can help clarify relationships between cardiac pathology and steroidogenesis and also provide a basis for future interventions to minimize the risk of developing cardiovascular disease, which may be influenced by synthetic glucocorticoid administration perinatally. Current research by Ivy et al. (2021), recently published in The Journal of Physiology, shows the impact of glucocorticoids on cardiomyocytes, specifically by looking at its effects on energy metabolism. This study follows a trifold experimental method to observe the effects of glucocorticoids on various levels of tissue: fetal cardiomyocytes with dexamethasone treatment depicting endogenous effects, neonatal mice with dexamethasone treatment to observe postnatal changes after birth, and pregnant dams with dexamethasone treatment to depict late-gestation effects of exogenous corticosteroids. A translational lamb model was also established to mimic the effects of synthetic corticosteroid injections.
{"title":"The switch: the role of glucocorticoids during fetal cardiomyocyte energy metabolism.","authors":"Evani Patel, Ishita Patel","doi":"10.1113/JP282699","DOIUrl":"https://doi.org/10.1113/JP282699","url":null,"abstract":"Glucocorticoids play a crucial role in the maturation of foetal organs during pregnancy, as well as the preparation of extrauterine life and increased energy demands upon removal of the nutrient-rich placenta following birth. The administration of synthetic glucocorticoids, as either Celestone, a formulation of betamethasone acetate with betamethasone phosphate, or solely betamethasone acetate, is routine in many countries (Agnew et al. 2018). The benefits of antenatal corticosteroid treatment are vast, one of which is its ability to help with the maturation of fetal lung tissue and prevent neonatal respiratory distress syndrome in preterm babies (McGoldrick et al. 2020). Endogenously, glucocorticoids are associated with the development of the heart (Hillman et al. 2012). Cardiomyocytes undergo terminal differentiation during pregnancy, including changes to mitochondria, energy metabolism, calcium-handling, and more. Abundant literature exists on the effects of glucocorticoids on cardiomyocytes perinatally, but the direct effects of glucocorticoids, through the glucocorticoid receptor (GR), are not as well established. Furthermore, the role of synthetic glucocorticoids on thematuration of cardiomyocytes during different stages of gestation is also unknown. Elucidating the differences between endogenous and exogenous glucocorticoid administration can help clarify relationships between cardiac pathology and steroidogenesis and also provide a basis for future interventions to minimize the risk of developing cardiovascular disease, which may be influenced by synthetic glucocorticoid administration perinatally. Current research by Ivy et al. (2021), recently published in The Journal of Physiology, shows the impact of glucocorticoids on cardiomyocytes, specifically by looking at its effects on energy metabolism. This study follows a trifold experimental method to observe the effects of glucocorticoids on various levels of tissue: fetal cardiomyocytes with dexamethasone treatment depicting endogenous effects, neonatal mice with dexamethasone treatment to observe postnatal changes after birth, and pregnant dams with dexamethasone treatment to depict late-gestation effects of exogenous corticosteroids. A translational lamb model was also established to mimic the effects of synthetic corticosteroid injections.","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1291-1293"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39895773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-01Epub Date: 2022-01-24DOI: 10.1113/JP282777
Yoshihiro Kubo
The inward rectifier K+ channel subfamily (Kir) consists of seven channels (Kir1–7). Genetic mutations of Kir channels are known to induce hereditary diseases, such as Bartter syndrome (Kir1.1), Anderson syndrome (Kir2.1) and familial hypoglycaemia (Kir6.2). Kir3 is a G-protein coupled inward rectifier K+ channel which is activated by the Gβγ subunit released in response to the stimulation of Gi/o-coupled receptors. It is known to play physiological roles in various cells such as neuronal cells, cardiac muscle cells and adrenal cortex endocrine cells. Some hereditary diseases are also kinked to Kir3 channels. Mutations of Kir3.2 in the ion selectivity filter or in the pore helix are known to cause Keppen-Lubinsky syndrome (Masotti et al. 2015), and those of Kir3.4 (GIRK4) are reported to induce adrenal aldosterone producing adenoma and hyperaldosteronism (Choi et al. 2011). K+ channelsmaintain the resting potential and contribute to the repolarizing phase of the action potential. Hyperaldosteronism can be caused by the hyper-excitability of aldosterone secreting cells in adrenal cortex endocrine cells. How can this hyper-excitability be caused by an abnormality of Kir3.4? One possibility is loss of ion selectivity. If Kir3.4 also allows permeation of Na+, the resting potential cannot be maintained, and Ca2+ influx could evoke hormonal secretion. Another possibility is loss-of-function. If Kir3.4 currents are decreased, the resting potential cannot be maintained. The pathophysiological mechanisms arising from these mutations have not been solved conclusively. They may be, at least partly, due to variation of the induced abnormality depending on the position of the mutation. In this issue of The Journal of Physiology, Shalomov et al. (2022) revisited the pathophysiological mechanisms by intensively characterizing the Kir3.4 mutants. Choi et al. (2011) analyzed the ion selectivity of Kir3.1/Kir3.4 (wt or G151R or L168R or T158A) expressed in HEK293T cells, and beautifully showed that all these mutants allow Na+ to permeate as well. They discussed the loss of K+ selectivity induced depolarization and Ca2+ influx, which caused constitutive aldosterone production and cell proliferation. G151 is located in the selectivity filter, while L168 is in the pore helix behind the selectivity filter and T158 is in the extracellular loop just above the selectivity filter. Considering the location of these amino acid residues, an abnormality due to loss of ion selectivity is both understandable and acceptable. Murthy et al. (2014) characterized new disease associated Kir3.4 mutants R52H and E246K in the cytosolic region of Xenopus oocytes. They showed that the K+ selectivity, rectification and sensitivity to the block by TPN-Q were remarkably reduced. Judging from the position of the mutations, the observed phenotypes were rather unexpected and the mechanism underlying the abnormality remained to be elucidated. Shalomov and co-authors aimed to clarify the pathophy
{"title":"How do Kir3.4 mutations cause hereditary hyperaldosteronism?","authors":"Yoshihiro Kubo","doi":"10.1113/JP282777","DOIUrl":"https://doi.org/10.1113/JP282777","url":null,"abstract":"The inward rectifier K+ channel subfamily (Kir) consists of seven channels (Kir1–7). Genetic mutations of Kir channels are known to induce hereditary diseases, such as Bartter syndrome (Kir1.1), Anderson syndrome (Kir2.1) and familial hypoglycaemia (Kir6.2). Kir3 is a G-protein coupled inward rectifier K+ channel which is activated by the Gβγ subunit released in response to the stimulation of Gi/o-coupled receptors. It is known to play physiological roles in various cells such as neuronal cells, cardiac muscle cells and adrenal cortex endocrine cells. Some hereditary diseases are also kinked to Kir3 channels. Mutations of Kir3.2 in the ion selectivity filter or in the pore helix are known to cause Keppen-Lubinsky syndrome (Masotti et al. 2015), and those of Kir3.4 (GIRK4) are reported to induce adrenal aldosterone producing adenoma and hyperaldosteronism (Choi et al. 2011). K+ channelsmaintain the resting potential and contribute to the repolarizing phase of the action potential. Hyperaldosteronism can be caused by the hyper-excitability of aldosterone secreting cells in adrenal cortex endocrine cells. How can this hyper-excitability be caused by an abnormality of Kir3.4? One possibility is loss of ion selectivity. If Kir3.4 also allows permeation of Na+, the resting potential cannot be maintained, and Ca2+ influx could evoke hormonal secretion. Another possibility is loss-of-function. If Kir3.4 currents are decreased, the resting potential cannot be maintained. The pathophysiological mechanisms arising from these mutations have not been solved conclusively. They may be, at least partly, due to variation of the induced abnormality depending on the position of the mutation. In this issue of The Journal of Physiology, Shalomov et al. (2022) revisited the pathophysiological mechanisms by intensively characterizing the Kir3.4 mutants. Choi et al. (2011) analyzed the ion selectivity of Kir3.1/Kir3.4 (wt or G151R or L168R or T158A) expressed in HEK293T cells, and beautifully showed that all these mutants allow Na+ to permeate as well. They discussed the loss of K+ selectivity induced depolarization and Ca2+ influx, which caused constitutive aldosterone production and cell proliferation. G151 is located in the selectivity filter, while L168 is in the pore helix behind the selectivity filter and T158 is in the extracellular loop just above the selectivity filter. Considering the location of these amino acid residues, an abnormality due to loss of ion selectivity is both understandable and acceptable. Murthy et al. (2014) characterized new disease associated Kir3.4 mutants R52H and E246K in the cytosolic region of Xenopus oocytes. They showed that the K+ selectivity, rectification and sensitivity to the block by TPN-Q were remarkably reduced. Judging from the position of the mutations, the observed phenotypes were rather unexpected and the mechanism underlying the abnormality remained to be elucidated. Shalomov and co-authors aimed to clarify the pathophy","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1277-1278"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39659947","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-01Epub Date: 2022-01-17DOI: 10.1113/JP282690
Boris Shalomov, Reem Handklo-Jamal, Haritha P Reddy, Neta Theodor, Amal K Bera, Nathan Dascal
<p><p>G protein-gated, inwardly rectifying potassium channels (GIRK) mediate inhibitory transmission in brain and heart, and are present in the adrenal cortex. GIRK4 (KCNJ5) subunits are abundant in the heart and adrenal cortex. Multiple mutations of KCNJ5 cause primary aldosteronism (PA). Mutations in the pore region of GIRK4 cause loss of K<sup>+</sup> selectivity, Na<sup>+</sup> influx and depolarization of zona glomerulosa cells followed by hypersecretion of aldosterone. The concept of selectivity loss has been extended to mutations in cytosolic domains of GIRK4 channels, remote from the pore. We expressed aldosteronism-linked GIRK4<sub>R52H</sub> , GIRK4<sub>E246K</sub> and GIRK4<sub>G247R</sub> mutants in Xenopus oocytes. Whole-cell currents of heterotetrameric GIRK1/4<sub>R52H</sub> and GIRK1/4<sub>E246K</sub> channels were greatly reduced compared with GIRK1/4<sub>WT</sub> . Nevertheless, all heterotetrameric mutants retained full K<sup>+</sup> selectivity and inward rectification. When expressed as homotetramers, only GIRK4<sub>WT</sub> , but none of the mutants, produced whole-cell currents. Confocal imaging, single-channel and Förster Resonance Energy Transfer (FRET) analyses showed: (1) reduction of membrane abundance of all mutated channels, especially as homotetramers, (2) impaired interaction with Gβγ subunits, and (3) reduced open probability of GIRK1/4<sub>R52H</sub> . VU0529331, a GIRK4 opener, activated homotetrameric GIRK4<sub>G247R</sub> channels, but not GIRK4<sub>R52H</sub> or GIRK4<sub>E246K</sub> . In the human adrenocortical carcinoma cell line (HAC15), VU0529331 and overexpression of heterotetrameric GIRK1/4<sub>WT</sub> , but not overexpression of GIRK1/4 mutants, reduced aldosterone secretion. Our results suggest that, contrary to pore mutants of GIRK4, non-pore mutants R52H and E246K mutants are loss-of-function rather than gain-of-function/selectivity-loss mutants. Hence, GIRK4 openers may be a potential course of treatment for patients with cytosolic N- and C-terminal mutations. KEY POINTS: Mutations in GIRK4 (KCNJ5) G protein-gated channels cause primary aldosteronism, a major cause of secondary hypertension. The primary mechanism is believed to be loss of K<sup>+</sup> selectivity. R52H and E246K, aldosteronism-causing mutations in cytosolic N- and C- termini of GIRK4, were reported to cause loss of K<sup>+</sup> selectivity. We show that R52H, E246K and G247R mutations render homotetrameric GIRK channels non-functional. In heterotetrameric context with GIRK1, these mutations impair membrane expression, interaction with Gβγ and open probability, but do not alter K<sup>+</sup> selectivity or inward rectification. In the human aldosterone-secreting cell line, a GIRK4 opener and overexpression of heterotetrameric GIRK1/4<sub>WT</sub> , but not overexpression of GIRK1/4 mutants, reduced aldosterone secretion. Aldosteronism-causing mutations in the cytosolic domain of GIRK4 are loss-of-function mutations rather than g
{"title":"A revised mechanism of action of hyperaldosteronism-linked mutations in cytosolic domains of GIRK4 (KCNJ5).","authors":"Boris Shalomov, Reem Handklo-Jamal, Haritha P Reddy, Neta Theodor, Amal K Bera, Nathan Dascal","doi":"10.1113/JP282690","DOIUrl":"https://doi.org/10.1113/JP282690","url":null,"abstract":"<p><p>G protein-gated, inwardly rectifying potassium channels (GIRK) mediate inhibitory transmission in brain and heart, and are present in the adrenal cortex. GIRK4 (KCNJ5) subunits are abundant in the heart and adrenal cortex. Multiple mutations of KCNJ5 cause primary aldosteronism (PA). Mutations in the pore region of GIRK4 cause loss of K<sup>+</sup> selectivity, Na<sup>+</sup> influx and depolarization of zona glomerulosa cells followed by hypersecretion of aldosterone. The concept of selectivity loss has been extended to mutations in cytosolic domains of GIRK4 channels, remote from the pore. We expressed aldosteronism-linked GIRK4<sub>R52H</sub> , GIRK4<sub>E246K</sub> and GIRK4<sub>G247R</sub> mutants in Xenopus oocytes. Whole-cell currents of heterotetrameric GIRK1/4<sub>R52H</sub> and GIRK1/4<sub>E246K</sub> channels were greatly reduced compared with GIRK1/4<sub>WT</sub> . Nevertheless, all heterotetrameric mutants retained full K<sup>+</sup> selectivity and inward rectification. When expressed as homotetramers, only GIRK4<sub>WT</sub> , but none of the mutants, produced whole-cell currents. Confocal imaging, single-channel and Förster Resonance Energy Transfer (FRET) analyses showed: (1) reduction of membrane abundance of all mutated channels, especially as homotetramers, (2) impaired interaction with Gβγ subunits, and (3) reduced open probability of GIRK1/4<sub>R52H</sub> . VU0529331, a GIRK4 opener, activated homotetrameric GIRK4<sub>G247R</sub> channels, but not GIRK4<sub>R52H</sub> or GIRK4<sub>E246K</sub> . In the human adrenocortical carcinoma cell line (HAC15), VU0529331 and overexpression of heterotetrameric GIRK1/4<sub>WT</sub> , but not overexpression of GIRK1/4 mutants, reduced aldosterone secretion. Our results suggest that, contrary to pore mutants of GIRK4, non-pore mutants R52H and E246K mutants are loss-of-function rather than gain-of-function/selectivity-loss mutants. Hence, GIRK4 openers may be a potential course of treatment for patients with cytosolic N- and C-terminal mutations. KEY POINTS: Mutations in GIRK4 (KCNJ5) G protein-gated channels cause primary aldosteronism, a major cause of secondary hypertension. The primary mechanism is believed to be loss of K<sup>+</sup> selectivity. R52H and E246K, aldosteronism-causing mutations in cytosolic N- and C- termini of GIRK4, were reported to cause loss of K<sup>+</sup> selectivity. We show that R52H, E246K and G247R mutations render homotetrameric GIRK channels non-functional. In heterotetrameric context with GIRK1, these mutations impair membrane expression, interaction with Gβγ and open probability, but do not alter K<sup>+</sup> selectivity or inward rectification. In the human aldosterone-secreting cell line, a GIRK4 opener and overexpression of heterotetrameric GIRK1/4<sub>WT</sub> , but not overexpression of GIRK1/4 mutants, reduced aldosterone secretion. Aldosteronism-causing mutations in the cytosolic domain of GIRK4 are loss-of-function mutations rather than g","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1419-1437"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39764573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-01Epub Date: 2021-12-08DOI: 10.1113/JP282143
Sabrina Noel, Nathalie Servel, Aurélie Hatton, Anita Golec, Mayuree Rodrat, Demi R S Ng, Hongyu Li, Iwona Pranke, Alexandre Hinzpeter, Aleksander Edelman, David N Sheppard, Isabelle Sermet-Gaudelus
Dysfunction of the epithelial anion channel cystic fibrosis transmembrane conductance regulator (CFTR) causes a wide spectrum of disease, including cystic fibrosis (CF) and CFTR-related diseases (CFTR-RDs). Here, we investigate genotype-phenotype-CFTR function relationships using human nasal epithelial (hNE) cells from a small cohort of non-CF subjects and individuals with CF and CFTR-RDs and genotypes associated with either residual or minimal CFTR function using electrophysiological techniques. Collected hNE cells were either studied directly with the whole-cell patch-clamp technique or grown as primary cultures at an air-liquid interface after conditional reprogramming. The properties of cAMP-activated whole-cell Cl- currents in freshly isolated hNE cells identified them as CFTR-mediated. Their magnitude varied between hNE cells from individuals within the same genotype and decreased in the rank order: non-CF > CFTR residual function > CFTR minimal function. CFTR-mediated whole-cell Cl- currents in hNE cells isolated from fully differentiated primary cultures were identical to those in freshly isolated hNE cells in both magnitude and behaviour, demonstrating that conditional reprogramming culture is without effect on CFTR expression and function. For the cohort of subjects studied, CFTR-mediated whole-cell Cl- currents in hNE cells correlated well with CFTR-mediated transepithelial Cl- currents measured in vitro with the Ussing chamber technique, but not with those determined in vivo with the nasal potential difference assay. Nevertheless, they did correlate with the sweat Cl- concentration of study subjects. Thus, this study highlights the complexity of genotype-phenotype-CFTR function relationships, but emphasises the value of conditionally reprogrammed hNE cells in CFTR research and therapeutic testing. KEY POINTS: The genetic disease cystic fibrosis is caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel, which controls anion flow across epithelia lining ducts and tubes in the body. This study investigated CFTR function in nasal epithelial cells from people with cystic fibrosis and CFTR variants with a range of disease severity. CFTR function varied widely in nasal epithelial cells depending on the identity of CFTR variants, but was unaffected by conditional reprogramming culture, a cell culture technique used to grow large numbers of patient-derived cells. Assessment of CFTR function in vitro in nasal epithelial cells and epithelia, and in vivo in the nasal epithelium and sweat gland highlights the complexity of genotype-phenotype-CFTR function relationships.
{"title":"Correlating genotype with phenotype using CFTR-mediated whole-cell Cl<sup>-</sup> currents in human nasal epithelial cells.","authors":"Sabrina Noel, Nathalie Servel, Aurélie Hatton, Anita Golec, Mayuree Rodrat, Demi R S Ng, Hongyu Li, Iwona Pranke, Alexandre Hinzpeter, Aleksander Edelman, David N Sheppard, Isabelle Sermet-Gaudelus","doi":"10.1113/JP282143","DOIUrl":"https://doi.org/10.1113/JP282143","url":null,"abstract":"<p><p>Dysfunction of the epithelial anion channel cystic fibrosis transmembrane conductance regulator (CFTR) causes a wide spectrum of disease, including cystic fibrosis (CF) and CFTR-related diseases (CFTR-RDs). Here, we investigate genotype-phenotype-CFTR function relationships using human nasal epithelial (hNE) cells from a small cohort of non-CF subjects and individuals with CF and CFTR-RDs and genotypes associated with either residual or minimal CFTR function using electrophysiological techniques. Collected hNE cells were either studied directly with the whole-cell patch-clamp technique or grown as primary cultures at an air-liquid interface after conditional reprogramming. The properties of cAMP-activated whole-cell Cl<sup>-</sup> currents in freshly isolated hNE cells identified them as CFTR-mediated. Their magnitude varied between hNE cells from individuals within the same genotype and decreased in the rank order: non-CF > CFTR residual function > CFTR minimal function. CFTR-mediated whole-cell Cl<sup>-</sup> currents in hNE cells isolated from fully differentiated primary cultures were identical to those in freshly isolated hNE cells in both magnitude and behaviour, demonstrating that conditional reprogramming culture is without effect on CFTR expression and function. For the cohort of subjects studied, CFTR-mediated whole-cell Cl<sup>-</sup> currents in hNE cells correlated well with CFTR-mediated transepithelial Cl<sup>-</sup> currents measured in vitro with the Ussing chamber technique, but not with those determined in vivo with the nasal potential difference assay. Nevertheless, they did correlate with the sweat Cl<sup>-</sup> concentration of study subjects. Thus, this study highlights the complexity of genotype-phenotype-CFTR function relationships, but emphasises the value of conditionally reprogrammed hNE cells in CFTR research and therapeutic testing. KEY POINTS: The genetic disease cystic fibrosis is caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR), an ion channel, which controls anion flow across epithelia lining ducts and tubes in the body. This study investigated CFTR function in nasal epithelial cells from people with cystic fibrosis and CFTR variants with a range of disease severity. CFTR function varied widely in nasal epithelial cells depending on the identity of CFTR variants, but was unaffected by conditional reprogramming culture, a cell culture technique used to grow large numbers of patient-derived cells. Assessment of CFTR function in vitro in nasal epithelial cells and epithelia, and in vivo in the nasal epithelium and sweat gland highlights the complexity of genotype-phenotype-CFTR function relationships.</p>","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1515-1531"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39610887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-03-01Epub Date: 2022-01-24DOI: 10.1113/JP282622
Ivan Manzini
Most animals have an olfactory system (OS) whose anatomy, organization and functioning are remarkably similar. The OS is responsible for the sense of smell, through which animals gather information about the chemical composition of the environment (Manzini et al. 2022). In most species, the sense of smell conveys essential information for finding suitable food, avoiding predators, orienting themselves in space and increasing reproductive success. This also applies to humans, where it is crucial for the enjoyment of food and strongly influences general well-being (Boesveldt & Parma, 2021). The OS also senses and responds to endogenous signals that change depending on the metabolic status. The activation of receptors expressed in cells of the OS by specific hormones and nutritional signalling molecules can influence the functioning of the OS and thus modulate the sense of smell (Fadool & Kolling, 2020). It has long been known that obesity, that is, an excessive body fat accumulation, negatively affects our health and leads to a progressive decline of several organ systems (Tchernof & Després, 2013). More recent studies have linked obesity to cellular and molecular disruption of the OS. It has been reported that obese animals have both a smaller number of olfactory sensory neurons (OSNs) and associated projections to the olfactory bulb (OB), reduced expression of olfactory receptors, lesser amounts of olfactory G-proteins and weaker odorant-induced receptor potentials. On the level of the OB, the first relay centre of the OS, obesity alters the functioning of projection neurons, neurons that transmit olfactory information to higher olfactory centres. Together, this leads to an impaired sense of smell (Fadool & Kolling, 2020). The apparent link between obesity and the alterations of the OS has been challenged by ground-breaking results obtained using transgenic mouse lines. While genetically obese animals that consumed a nutrient-balanced diet retained an intact OS, animals genetically resistant to obesity still exhibited a reduction of OSNs when fed a diet containing a higher amount of fat. These results led to the hypothesis that excess fat in the diet rather than obesity could trigger alterations of the OS (Fadool & Kolling, 2020). In the current issue of The Journal of Physiology, Chelette and coworkers (2022) have examined this hypothesis in detail and provided compelling evidence that excess fat in the diet rather than the development of obesity is the cause for loss of OSNs and associated projections to the OB. To decouple diet-induced obesity from dietary fat consumption, the authors developed a sophisticated pair-feeding method that allowed feeding a moderately high-fat (MHF) diet while keeping the total calories the same as in a nutrient-balanced (but lower fat) control diet. Using this feeding method and a transgenic mouse line in which a specific subpopulation of OSNs can be readily visualized, the authors elegantly demonstrated the follo
{"title":"Diet-induced disruption of the olfactory system: not only obesity is to blame.","authors":"Ivan Manzini","doi":"10.1113/JP282622","DOIUrl":"https://doi.org/10.1113/JP282622","url":null,"abstract":"Most animals have an olfactory system (OS) whose anatomy, organization and functioning are remarkably similar. The OS is responsible for the sense of smell, through which animals gather information about the chemical composition of the environment (Manzini et al. 2022). In most species, the sense of smell conveys essential information for finding suitable food, avoiding predators, orienting themselves in space and increasing reproductive success. This also applies to humans, where it is crucial for the enjoyment of food and strongly influences general well-being (Boesveldt & Parma, 2021). The OS also senses and responds to endogenous signals that change depending on the metabolic status. The activation of receptors expressed in cells of the OS by specific hormones and nutritional signalling molecules can influence the functioning of the OS and thus modulate the sense of smell (Fadool & Kolling, 2020). It has long been known that obesity, that is, an excessive body fat accumulation, negatively affects our health and leads to a progressive decline of several organ systems (Tchernof & Després, 2013). More recent studies have linked obesity to cellular and molecular disruption of the OS. It has been reported that obese animals have both a smaller number of olfactory sensory neurons (OSNs) and associated projections to the olfactory bulb (OB), reduced expression of olfactory receptors, lesser amounts of olfactory G-proteins and weaker odorant-induced receptor potentials. On the level of the OB, the first relay centre of the OS, obesity alters the functioning of projection neurons, neurons that transmit olfactory information to higher olfactory centres. Together, this leads to an impaired sense of smell (Fadool & Kolling, 2020). The apparent link between obesity and the alterations of the OS has been challenged by ground-breaking results obtained using transgenic mouse lines. While genetically obese animals that consumed a nutrient-balanced diet retained an intact OS, animals genetically resistant to obesity still exhibited a reduction of OSNs when fed a diet containing a higher amount of fat. These results led to the hypothesis that excess fat in the diet rather than obesity could trigger alterations of the OS (Fadool & Kolling, 2020). In the current issue of The Journal of Physiology, Chelette and coworkers (2022) have examined this hypothesis in detail and provided compelling evidence that excess fat in the diet rather than the development of obesity is the cause for loss of OSNs and associated projections to the OB. To decouple diet-induced obesity from dietary fat consumption, the authors developed a sophisticated pair-feeding method that allowed feeding a moderately high-fat (MHF) diet while keeping the total calories the same as in a nutrient-balanced (but lower fat) control diet. Using this feeding method and a transgenic mouse line in which a specific subpopulation of OSNs can be readily visualized, the authors elegantly demonstrated the follo","PeriodicalId":501632,"journal":{"name":"The Journal of Physiology","volume":" ","pages":"1273-1274"},"PeriodicalIF":5.5,"publicationDate":"2022-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39799491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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