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Leptin: Master Regulator of Biological Functions that Affects Breathing

Estelle B. Gauda, Silvia Conde, Mirian Bassi, Daniel B. Zoccal, Debora Simoes Almeida Colombari, Eduardo Colombari, Nikola Despotovic

10.1002/cphy.c190031

Source: Volume 10, Issue 3, July 2020

Published online: July 2020

Full Article on Wiley Online Library



Abstract

Obesity is a global epidemic in developed countries accounting for many of the metabolic and cardiorespiratory morbidities that occur in adults. These morbidities include type 2 diabetes, sleep‐disordered breathing (SDB), obstructive sleep apnea, chronic intermittent hypoxia, and hypertension. Leptin, produced by adipocytes, is a master regulator of metabolism and of many other biological functions including central and peripheral circuits that control breathing. By binding to receptors on cells and neurons in the brainstem, hypothalamus, and carotid body, leptin links energy and metabolism to breathing. In this comprehensive article, we review the central and peripheral locations of leptin's actions that affect cardiorespiratory responses during health and disease, with a particular focus on obesity, SDB, and its effects during early development. Obesity‐induced hyperleptinemia is associated with centrally mediated hypoventilation with decrease CO2 sensitivity. On the other hand, hyperleptinemia augments peripheral chemoreflexes to hypoxia and induces sympathoexcitation. Thus, “leptin resistance” in obesity is relative. We delineate the circuits responsible for these divergent effects, including signaling pathways. We review the unique effects of leptin during development on organogenesis, feeding behavior, and cardiorespiratory responses, and how undernutrition and overnutrition during critical periods of development can lead to cardiorespiratory comorbidities in adulthood. We conclude with suggestions for future directions to improve our understanding of leptin dysregulation and associated clinical diseases and possible therapeutic targets. Lastly, we briefly discuss the yin and the yang, specifically the contribution of relative adiponectin deficiency in adults with hyperleptinemia to the development of metabolic and cardiovascular disease. © 2020 American Physiological Society. Compr Physiol 10:1047‐1083, 2020.

Figure 1. Figure 1. Intracellular signaling pathways activated when leptin binds to the long form of the leptin receptor (Ob‐Rb) in cells in the arcuate nucleus that express POMC and AgRP. Janus kinase (JAK2) associates with the receptor via the box1 motif. The long isoform leptin (L) receptor (Ob‐Rb) contains four important tyrosine residues (Tyr974, Tyr985, Tyr1077, and Tyr1138). These phosphorylated tyrosine residues provide docking sites for signaling proteins. Tyr1138 recruits the transcription factor STAT3, which is subsequently phosphorylated by JAK2, dimerizes, and translocates to the nucleus, where it induces SOCS3 and POMC (pro‐opiomelanocortin) expression, while repressing AgRP (agouti‐related peptide). SOCS proteins inhibit signaling by binding to phosphorylated JAK proteins or interacting directly with tyrosine‐phosphorylated receptors. The ability of SOCS3 to inhibit leptin‐stimulated phosphorylation of JAK2 and ERK provides a negative feedback mechanism on the leptin signaling system. Grb‐2, growth factor receptor binding‐2; STAT3, signal transducer and activator of transcription; SOCS, suppressor of cytokine signaling. Adapted, with permission, from Fruhbeck G, 2006 111.
Figure 2. Figure 2. The medullary respiratory network with pulmonary and pontine feedbacks. General schematic diagram representing the respiratory network with two interacting feedback. This schematic shows the interactions between different populations of respiratory neurons within major brain areas involved in the control of breathing, such as the CO2‐sensitive cells in the hypothalamus, Raphe and RTN/pFRG, the pons, the ventral respiratory group (BötzC, PBC and VRG), the NTS and the peripheral inputs and efferents. Abbreviations: BötzC, Bötzinger complex; PBC, pre‐Bötzinger complex; RTN/pFRG, retrotrapezoid nucleus/parafacial respiratory group; SAR, slowly adapting receptors; RAR, rapidly adapting receptors. Adapted, with permission, from Gauda E and Martin R, 2018 120.
Figure 3. Figure 3. The effect of central leptin administration on food intake and breathing. (A) Daily food intake during control period (C1–C3) and during lateral ventricle (LV) treatment (t1–t6) with PBS (control), (LEP, 5 μg/day), MC3/4R antagonist SHU‐9119 (SHU, 0.6 nmol/day), or SHU‐9119 + leptin for 7 days in rats. (B) Basal ventilation and ventilatory response to 7% CO2 after LV treatments in rats. (C) Ventilatory responses in mice: wild‐type, leptin receptor deletion in the entire brain (LepR/Nestin‐cre), leptin receptor deletion in POMC neurons (LepR/POMC‐cre) and mice with MC4R deficiency (MC4R−/−). Adapted, with permission, from Bassi M, et al., 2015 30.
Figure 4. Figure 4. Anatomical localization of serotonin (SERT) and Ob‐R mRNA expression in the rostral brainstem of the monkey. Plates represent sections containing five regions of Raphe nuclei included in the analysis: CLi (A), rostral DR (rDR; B), rostral MR (rMR; B), caudal DR (cDR; C), and caudal MR (cMR; C). Symbols represent the locations of cells containing SERT mRNA (gray triangles), Ob‐R mRNA (empty inverted triangles), or both SERT/Ob‐R mRNAs (black circles). Aq, cerebral aqueduct; CG, central gray; C3, oculomotor nucleus; mlf, medial longitudinal fasciculus; xscp, decussation of superior cerebellar peduncle; IC, inferior colliculus; scp, superior cerebellar peduncle; 4V, fourth ventricle; LC, locus coeruleus. Adapted, with permission, from Finn PD, et al., 2001 102.
Figure 5. Figure 5. Schematic diagram depicting the interrelationship between weight‐dependent and physiological‐dependent mechanisms on metabolic and cardiorespiratory responses in obesity. While weight‐dependent mechanisms are a function of the physical increase in body mass or fat mass (e.g., increased mechanical load, narrowed airway), physiology‐dependent mechanisms are physiological changes coincident with obesity or diabetes which go on to influence chemosensitivity and sleep apnea either directly or via action on sympathetic activity, inflammation, or other mechanisms. Adapted, with permission, from Framnes SN and Arble DM, 2018 107.
Figure 6. Figure 6. (A) Schematic model of interactions between respiratory network and sympathetic nervous system. The brain stem respiratory nuclei generate the coordinated inspiratory and expiratory motor activities responsible to control upper airway resistance and respiratory movements. It has been suggested that the respiratory neurons interact with presympathetic neurons of rostral ventrolateral medulla (RVLM), generating the respiratory oscillations in the sympathetic activity. In addition to these central mechanisms, the peripheral afferent inputs, like those from pulmonary stretch receptors, arterial baroreceptors, and peripheral chemoreceptors, may interact with respiratory and sympathetic neurons and also contribute to respiratory‐sympathetic coupling. (B) Illustration shows the pattern of raw and integrated (∫) activities of thoracic sympathetic (tSN), abdominal (AbN), and phrenic nerves (PN) as well as the magnitude of perfusion pressure (PP) of control and chronic intermittent hypoxia (CIH) rats. Note that in control rats the amplitude of AbN activity is low, indicating that the respiratory pattern is composed of active inspiration (active I) and passive expiration (passive E). On the other hand, in CIH rats the AbN exhibits an addition burst during the late part of expiration (late‐E), indicating that not only inspiration but also expiration are active in CIH rats (active I/active E). In addition, as a consequence of the active expiratory pattern, the tSN exhibits a correlated peak of discharge during late‐E. EXP indicates expiratory neurons; INSP, inspiratory neurons; SYMP, presympathetic neurons; IML, intermediolateral column; PMN, phrenic motor neurons; AMN, abdominal motor neurons. Adapted, with permission, from Moraes DJ, et al., 2012 239.
Figure 7. Figure 7. Effect of HFD on ventilation in rats. Rats fed with high‐fat diet (HFD) during 12 weeks have high variation of the respiratory frequency (fR) and abdominal expiratory motor activity (ABD) during hypercapnia (10% of CO2) compared to standard diet (SD) fed rats. The activity of the diaphragm muscle (DIA) was similar among the groups (SD n = 14 and HFD n = 13). * Different from SD and # different from basal condition, P < 0.05. Adapted, with permission, from Speretta GF, et al., 2018 350
Figure 8. Figure 8. Schematic diagram depicting of main central nervous system (CNS) sites of leptin action to modulate ventilation including proopiomelanocortin (POMC) neurons. Upper panel: Leptin activates leptin receptors (LRs) in the ARC nucleus causing inhibition of neuropeptide Y/agouti‐related peptide (NPY/AgRP) and depolarization of POMC neurons leading to the release of alpha melanocyte‐stimulating hormone (α‐MSH) which, in turn, activates the melanocortin 3 and 4 receptors (MC3/4R) mainly in the arcuate nucleus (ARC) as well as in the others nuclei located in brainstem such as nucleus of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM). The evoked responses induced by leptin in the CNS are a reduction in the food intake, increase in renal sympathetic activity (RSNA), increase in arterial pressure and in the ventilation. Lower panel: LepR/POMC‐cre mice are obese and have reduced hypercapnic ventilatory response (HCVR). Abbreviations: AP, arterial pressure; BötC, Bötzinger complex; DMV, dorsal motor nucleus of the vagus; 7N, facial nucleus; KF, Kölliker Fuse; LC, locus coeruleus; NA, nucleus ambiguous; PBN, parabrachial nucleus; PVN, paraventricular nucleus of the hypothalamus; pre‐BötC, pre‐Bötzinger complex; RTN/pFRG, retrotrapezoid nucleus/parafacial respiratory group; and VRG, ventral respiratory group. Modified, with permission, from Bassi M, et al., 2015 28.
Figure 9. Figure 9. Schematic diagram showing the effect of leptin deficiency on the ontogeny of projections of the ARH through the hypothalamus during development. Left panel (wild‐type WT) and right panel leptin deficient (Lepob/Lepob) on postnatal day (P) P6, P12, P16, and adults (P60). Leptin deficiency permanently disrupts the formation of projections from the arcuate nucleus to each major target nucleus. The relative size of each pathway is roughly proportional to the thickness of the lines associated with it. AVPV, anteroventral periventricular nucleus; MPN, medial preoptic nucleus; DMH, dorsomedial hypothalamus; PVH, periventricular hypothalamic nuclei; and LHA, lateral hypothalamic area. Leptin deficient mice are slow to develop and have a reduced number of projections from the ARH to other key areas of the hypothalamus that regulate feeding behavior. Adapted, with permission, from Bouret SG and Simerly RB, 2004 42.
Figure 10. Figure 10. Serum leptin concentrations in cord blood (ng/mL) according to gestational age (weeks) in fetuses and newborns. Blue symbol represents values obtained from fetuses and newborns with normal growth; red circles, represents values from fetuses and newborns with IUGR. Modified, with permission, from Jaquet D, et al., 1998 168.
Figure 11. Figure 11. Overnutrition and excessive adiposity during pregnancy and lactation alter the fetal programming leading to obesity and hypertension. The altered leptin signaling in the hypothalamus promotes a selective leptin resistance in which the anorexic effects of leptin are lost, whilst the pressor effect of leptin is enhanced. Adapted, with permission, from Taylor PD, et al., 2014 364.
Figure 12. Figure 12. Schematic representation of some stimuli that activate carotid body (CB) chemoreceptors and the responses elicited by the carotid body. Decreased arterial oxygen pressure (PO2), increased carbon dioxide arterial pressure (PCO2), angiotensin II (ANG II), leptin, and insulin are examples of stimuli that activate the CB. In general, these stimuli originate type 1 CB cell depolarization, increase in intracellular Ca2+ and the release of neurotransmitters that act on the CB sensitive nerve, the carotid sinus nerve (CSN), to increase its activity aiming its integration at the central nervous system level to produce respiratory, cardiovascular, renal, and endocrine responses.
Figure 13. Figure 13. Diagram representing the involvement of carotid body in leptin effects in the control of breathing and on sympathetic overactivation that participates in genesis of insulin resistance and hypertension. Hyperleptinemia produced by adipose tissue dysfunction induced by dysmetabolism, obesity and/or by chronic intermittent hypoxia originates an increase in carotid body sensitization that is on the basis of increased spontaneous ventilation, increased hypoxic ventilatory response, and augmented sympathetic activity.
Figure 14. Figure 14. Graphic depiction of types of bariatric surgery. Printed, with permission, from Gletsu‐Miller N and Wright BN, 2013 126.
Figure 15. Figure 15. Schematic showing adiponectin signaling in macrophages, liver, endothelial and muscle cells. Adiponectin is produced by adipose tissue, the agonist to the transcription factor PPARγ will increase the production of adiponectin and decrease BMI, while oxidative stress, angiotensin II, testosterone, IL‐6, TNFα, will inhibit the production of adiponectin. Adiponectin binding to adiponectin receptors on (i) macrophages inhibits the production of NF‐κB and SR‐A thereby inhibiting the production of TNFα, and foam cells, (ii) liver cells increases metabolism and blocks TNFα production, (iii) endothelial cells promoting NO production, and inhibiting synthesis of chemokines, (iv) muscle cells inhibits the production of TNF and promotes growth and proliferation. m‐TOR, mammalian target of rapamycin; SR‐A, scavenger receptors‐A; AMPK, AMP‐activated protein kinase; SRF, serum response element; COX‐2, cyclooxygenase‐2; VCAM‐1, vascular cell adhesion protein 1; PPARγ, peroxisome proliferator‐activated receptor gamma; BMI, body mass index; IL, Interleukin. Adapted, with permission, from Summer R, et al., 2011 359.
Figure 16. Figure 16. Low‐power photomicrograph, using Hoffman contrast microscopy, of an organotypic slice of the carotid body 24 h in culture. Fat cells are in close proximity to the CB in vivo. Tissue was removed from a Sprague Dawley rat at 2 weeks postnatal age. CB, carotid body; CA, carotid artery. Arrows depict fat cells (FC). Adapted, with permission, from Kwak DJ, et al., 2006 187.


Figure 1. Intracellular signaling pathways activated when leptin binds to the long form of the leptin receptor (Ob‐Rb) in cells in the arcuate nucleus that express POMC and AgRP. Janus kinase (JAK2) associates with the receptor via the box1 motif. The long isoform leptin (L) receptor (Ob‐Rb) contains four important tyrosine residues (Tyr974, Tyr985, Tyr1077, and Tyr1138). These phosphorylated tyrosine residues provide docking sites for signaling proteins. Tyr1138 recruits the transcription factor STAT3, which is subsequently phosphorylated by JAK2, dimerizes, and translocates to the nucleus, where it induces SOCS3 and POMC (pro‐opiomelanocortin) expression, while repressing AgRP (agouti‐related peptide). SOCS proteins inhibit signaling by binding to phosphorylated JAK proteins or interacting directly with tyrosine‐phosphorylated receptors. The ability of SOCS3 to inhibit leptin‐stimulated phosphorylation of JAK2 and ERK provides a negative feedback mechanism on the leptin signaling system. Grb‐2, growth factor receptor binding‐2; STAT3, signal transducer and activator of transcription; SOCS, suppressor of cytokine signaling. Adapted, with permission, from Fruhbeck G, 2006 111.


Figure 2. The medullary respiratory network with pulmonary and pontine feedbacks. General schematic diagram representing the respiratory network with two interacting feedback. This schematic shows the interactions between different populations of respiratory neurons within major brain areas involved in the control of breathing, such as the CO2‐sensitive cells in the hypothalamus, Raphe and RTN/pFRG, the pons, the ventral respiratory group (BötzC, PBC and VRG), the NTS and the peripheral inputs and efferents. Abbreviations: BötzC, Bötzinger complex; PBC, pre‐Bötzinger complex; RTN/pFRG, retrotrapezoid nucleus/parafacial respiratory group; SAR, slowly adapting receptors; RAR, rapidly adapting receptors. Adapted, with permission, from Gauda E and Martin R, 2018 120.


Figure 3. The effect of central leptin administration on food intake and breathing. (A) Daily food intake during control period (C1–C3) and during lateral ventricle (LV) treatment (t1–t6) with PBS (control), (LEP, 5 μg/day), MC3/4R antagonist SHU‐9119 (SHU, 0.6 nmol/day), or SHU‐9119 + leptin for 7 days in rats. (B) Basal ventilation and ventilatory response to 7% CO2 after LV treatments in rats. (C) Ventilatory responses in mice: wild‐type, leptin receptor deletion in the entire brain (LepR/Nestin‐cre), leptin receptor deletion in POMC neurons (LepR/POMC‐cre) and mice with MC4R deficiency (MC4R−/−). Adapted, with permission, from Bassi M, et al., 2015 30.


Figure 4. Anatomical localization of serotonin (SERT) and Ob‐R mRNA expression in the rostral brainstem of the monkey. Plates represent sections containing five regions of Raphe nuclei included in the analysis: CLi (A), rostral DR (rDR; B), rostral MR (rMR; B), caudal DR (cDR; C), and caudal MR (cMR; C). Symbols represent the locations of cells containing SERT mRNA (gray triangles), Ob‐R mRNA (empty inverted triangles), or both SERT/Ob‐R mRNAs (black circles). Aq, cerebral aqueduct; CG, central gray; C3, oculomotor nucleus; mlf, medial longitudinal fasciculus; xscp, decussation of superior cerebellar peduncle; IC, inferior colliculus; scp, superior cerebellar peduncle; 4V, fourth ventricle; LC, locus coeruleus. Adapted, with permission, from Finn PD, et al., 2001 102.


Figure 5. Schematic diagram depicting the interrelationship between weight‐dependent and physiological‐dependent mechanisms on metabolic and cardiorespiratory responses in obesity. While weight‐dependent mechanisms are a function of the physical increase in body mass or fat mass (e.g., increased mechanical load, narrowed airway), physiology‐dependent mechanisms are physiological changes coincident with obesity or diabetes which go on to influence chemosensitivity and sleep apnea either directly or via action on sympathetic activity, inflammation, or other mechanisms. Adapted, with permission, from Framnes SN and Arble DM, 2018 107.


Figure 6. (A) Schematic model of interactions between respiratory network and sympathetic nervous system. The brain stem respiratory nuclei generate the coordinated inspiratory and expiratory motor activities responsible to control upper airway resistance and respiratory movements. It has been suggested that the respiratory neurons interact with presympathetic neurons of rostral ventrolateral medulla (RVLM), generating the respiratory oscillations in the sympathetic activity. In addition to these central mechanisms, the peripheral afferent inputs, like those from pulmonary stretch receptors, arterial baroreceptors, and peripheral chemoreceptors, may interact with respiratory and sympathetic neurons and also contribute to respiratory‐sympathetic coupling. (B) Illustration shows the pattern of raw and integrated (∫) activities of thoracic sympathetic (tSN), abdominal (AbN), and phrenic nerves (PN) as well as the magnitude of perfusion pressure (PP) of control and chronic intermittent hypoxia (CIH) rats. Note that in control rats the amplitude of AbN activity is low, indicating that the respiratory pattern is composed of active inspiration (active I) and passive expiration (passive E). On the other hand, in CIH rats the AbN exhibits an addition burst during the late part of expiration (late‐E), indicating that not only inspiration but also expiration are active in CIH rats (active I/active E). In addition, as a consequence of the active expiratory pattern, the tSN exhibits a correlated peak of discharge during late‐E. EXP indicates expiratory neurons; INSP, inspiratory neurons; SYMP, presympathetic neurons; IML, intermediolateral column; PMN, phrenic motor neurons; AMN, abdominal motor neurons. Adapted, with permission, from Moraes DJ, et al., 2012 239.


Figure 7. Effect of HFD on ventilation in rats. Rats fed with high‐fat diet (HFD) during 12 weeks have high variation of the respiratory frequency (fR) and abdominal expiratory motor activity (ABD) during hypercapnia (10% of CO2) compared to standard diet (SD) fed rats. The activity of the diaphragm muscle (DIA) was similar among the groups (SD n = 14 and HFD n = 13). * Different from SD and # different from basal condition, P < 0.05. Adapted, with permission, from Speretta GF, et al., 2018 350


Figure 8. Schematic diagram depicting of main central nervous system (CNS) sites of leptin action to modulate ventilation including proopiomelanocortin (POMC) neurons. Upper panel: Leptin activates leptin receptors (LRs) in the ARC nucleus causing inhibition of neuropeptide Y/agouti‐related peptide (NPY/AgRP) and depolarization of POMC neurons leading to the release of alpha melanocyte‐stimulating hormone (α‐MSH) which, in turn, activates the melanocortin 3 and 4 receptors (MC3/4R) mainly in the arcuate nucleus (ARC) as well as in the others nuclei located in brainstem such as nucleus of the solitary tract (NTS) and rostral ventrolateral medulla (RVLM). The evoked responses induced by leptin in the CNS are a reduction in the food intake, increase in renal sympathetic activity (RSNA), increase in arterial pressure and in the ventilation. Lower panel: LepR/POMC‐cre mice are obese and have reduced hypercapnic ventilatory response (HCVR). Abbreviations: AP, arterial pressure; BötC, Bötzinger complex; DMV, dorsal motor nucleus of the vagus; 7N, facial nucleus; KF, Kölliker Fuse; LC, locus coeruleus; NA, nucleus ambiguous; PBN, parabrachial nucleus; PVN, paraventricular nucleus of the hypothalamus; pre‐BötC, pre‐Bötzinger complex; RTN/pFRG, retrotrapezoid nucleus/parafacial respiratory group; and VRG, ventral respiratory group. Modified, with permission, from Bassi M, et al., 2015 28.


Figure 9. Schematic diagram showing the effect of leptin deficiency on the ontogeny of projections of the ARH through the hypothalamus during development. Left panel (wild‐type WT) and right panel leptin deficient (Lepob/Lepob) on postnatal day (P) P6, P12, P16, and adults (P60). Leptin deficiency permanently disrupts the formation of projections from the arcuate nucleus to each major target nucleus. The relative size of each pathway is roughly proportional to the thickness of the lines associated with it. AVPV, anteroventral periventricular nucleus; MPN, medial preoptic nucleus; DMH, dorsomedial hypothalamus; PVH, periventricular hypothalamic nuclei; and LHA, lateral hypothalamic area. Leptin deficient mice are slow to develop and have a reduced number of projections from the ARH to other key areas of the hypothalamus that regulate feeding behavior. Adapted, with permission, from Bouret SG and Simerly RB, 2004 42.


Figure 10. Serum leptin concentrations in cord blood (ng/mL) according to gestational age (weeks) in fetuses and newborns. Blue symbol represents values obtained from fetuses and newborns with normal growth; red circles, represents values from fetuses and newborns with IUGR. Modified, with permission, from Jaquet D, et al., 1998 168.


Figure 11. Overnutrition and excessive adiposity during pregnancy and lactation alter the fetal programming leading to obesity and hypertension. The altered leptin signaling in the hypothalamus promotes a selective leptin resistance in which the anorexic effects of leptin are lost, whilst the pressor effect of leptin is enhanced. Adapted, with permission, from Taylor PD, et al., 2014 364.


Figure 12. Schematic representation of some stimuli that activate carotid body (CB) chemoreceptors and the responses elicited by the carotid body. Decreased arterial oxygen pressure (PO2), increased carbon dioxide arterial pressure (PCO2), angiotensin II (ANG II), leptin, and insulin are examples of stimuli that activate the CB. In general, these stimuli originate type 1 CB cell depolarization, increase in intracellular Ca2+ and the release of neurotransmitters that act on the CB sensitive nerve, the carotid sinus nerve (CSN), to increase its activity aiming its integration at the central nervous system level to produce respiratory, cardiovascular, renal, and endocrine responses.


Figure 13. Diagram representing the involvement of carotid body in leptin effects in the control of breathing and on sympathetic overactivation that participates in genesis of insulin resistance and hypertension. Hyperleptinemia produced by adipose tissue dysfunction induced by dysmetabolism, obesity and/or by chronic intermittent hypoxia originates an increase in carotid body sensitization that is on the basis of increased spontaneous ventilation, increased hypoxic ventilatory response, and augmented sympathetic activity.


Figure 14. Graphic depiction of types of bariatric surgery. Printed, with permission, from Gletsu‐Miller N and Wright BN, 2013 126.


Figure 15. Schematic showing adiponectin signaling in macrophages, liver, endothelial and muscle cells. Adiponectin is produced by adipose tissue, the agonist to the transcription factor PPARγ will increase the production of adiponectin and decrease BMI, while oxidative stress, angiotensin II, testosterone, IL‐6, TNFα, will inhibit the production of adiponectin. Adiponectin binding to adiponectin receptors on (i) macrophages inhibits the production of NF‐κB and SR‐A thereby inhibiting the production of TNFα, and foam cells, (ii) liver cells increases metabolism and blocks TNFα production, (iii) endothelial cells promoting NO production, and inhibiting synthesis of chemokines, (iv) muscle cells inhibits the production of TNF and promotes growth and proliferation. m‐TOR, mammalian target of rapamycin; SR‐A, scavenger receptors‐A; AMPK, AMP‐activated protein kinase; SRF, serum response element; COX‐2, cyclooxygenase‐2; VCAM‐1, vascular cell adhesion protein 1; PPARγ, peroxisome proliferator‐activated receptor gamma; BMI, body mass index; IL, Interleukin. Adapted, with permission, from Summer R, et al., 2011 359.


Figure 16. Low‐power photomicrograph, using Hoffman contrast microscopy, of an organotypic slice of the carotid body 24 h in culture. Fat cells are in close proximity to the CB in vivo. Tissue was removed from a Sprague Dawley rat at 2 weeks postnatal age. CB, carotid body; CA, carotid artery. Arrows depict fat cells (FC). Adapted, with permission, from Kwak DJ, et al., 2006 187.
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Article Title: Leptin: Master Regulator of Biological Functions that Affects Breathing
 

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Estelle B. Gauda, Silvia Conde, Mirian Bassi, Daniel B. Zoccal, Debora Simoes Almeida Colombari, Eduardo Colombari, Nikola Despotovic. Leptin: Master Regulator of Biological Functions that Affects Breathing. Compr Physiol 2020, 10: 1047-1083. doi: 10.1002/cphy.c190031