RESUMEN
Urbanization stands out as a significant anthropogenic factor, exerting selective pressures on ecosystems and biotic components. A notable outcome of urbanization is thermal heterogeneity where the emergence of Urban Heat Islands is characterized by elevated air and surface temperatures compared to adjacent rural areas. Investigating the influence of thermal heterogeneity on urban animals could offer insights into how temperature variations can lead to phenotypic shifts. Urban pigeons (Columba livia) serve as an excellent model for studying urban thermal effects, given the melanism variations, which are associated with the pleiotropy of the melanocortin system. To examine the development of physiological plasticity in response to urban thermal variations, we conducted a study on pigeons in Santiago, Chile, during the rainy season. We assessed the influence of habitat on physiological traits related to metabolism and antioxidant capacities, which are theoretically affected by feather coloration. Our findings reveal that variations in melanism significantly impact pigeon physiology, affecting both antioxidant capacities and the mitochondrial activity of red blood cells. It was found that higher urban temperatures, from both the current sampling month and the prior sampling month (from CRU TS dataset), were negatively and strongly associated with lower antioxidant and metabolic activities. This suggests that elevated urban temperatures likely benefit the energetic budgets of pigeon populations and mitigate the negative effects of oxidative metabolism, with differential effects depending on feather colorations.
Asunto(s)
Columbidae , Melanosis , Animales , Columbidae/fisiología , Ciudades , Plumas , Antioxidantes , Ecosistema , Calor , Estrés OxidativoRESUMEN
The arcuate nucleus (ARH) is an important hypothalamic area for the homeostatic control of feeding and other metabolic functions. In the ARH, proopiomelanocortin- (POMC) and agouti-related peptide (AgRP)-expressing neurons play a key role in the central regulation of metabolism. These neurons are influenced by circulating factors, such as leptin and growth hormone (GH). The objective of the present study was to determine whether a direct action of GH on ARH neurons regulates the density of POMC and AgRP axonal projections to major postsynaptic targets. We studied POMC and AgRP axonal projections to the hypothalamic paraventricular (PVH), lateral (LHA) and dorsomedial (DMH) nuclei in leptin receptor (LepR)-deficient mice (Leprdb/db), GH-deficient mice (Ghrhrlit/lit) and in mice carrying specific ablations of GH receptor (GHR) either in LepR- or AgRP-expressing cells. Leprdb/db mice presented reduction in the density of POMC innervation to the PVH compared to wild-type and Ghrhrlit/lit mice. Additionally, both Leprdb/db and Ghrhrlit/lit mice showed reduced AgRP fiber density in the PVH, LHA and DMH. LepR GHR knockout mice showed decreased density of POMC innervation in the PVH and DMH, compared to control mice, whereas a reduction in the density of AgRP innervation was observed in all areas analyzed. Conversely, AgRP-specific ablation of GHR led to a significant reduction in AgRP projections to the PVH, LHA and DMH, without affecting POMC innervation. Our findings indicate that GH has direct trophic effects on the formation of POMC and AgRP axonal projections and provide additional evidence that GH regulates hypothalamic neurocircuits controlling energy homeostasis.
Asunto(s)
Núcleo Arqueado del Hipotálamo , Receptores de Somatotropina , Proteína Relacionada con Agouti/metabolismo , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Hipotálamo/metabolismo , Leptina/metabolismo , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Proopiomelanocortina/metabolismo , Receptores de Somatotropina/genéticaRESUMEN
Several hypothalamic neuronal populations are directly responsive to growth hormone (GH) and central GH action regulates glucose and energy homeostasis. However, the potential role of GH signaling in proopiomelanocortin (POMC) neurons has not been studied yet. Thus, we investigated whether POMC neurons are responsive to GH and if ablation of GH receptor (GHR) or STAT5 in POMC cells leads to metabolic imbalances. Approximately 60% of POMC neurons of the arcuate nucleus exhibited STAT5 phosphorylation after intracerebroventricular GH injection. Ablation of GHR or STAT5 in POMC cells did not affect energy or glucose homeostasis. However, glucoprivic hyperphagia was blunted in male and female GHR knockout mice, and in male POMC-specific STAT5 knockout mice. Additionally, the absence of GHR in POMC neurons decreased glycemia during prolonged food restriction in male mice. Thus, GH action in POMC neurons regulates glucoprivic hyperphagia as well as blood glucose levels during prolonged food restriction.
Asunto(s)
Proteínas Portadoras/fisiología , Glucosa/metabolismo , Hiperfagia/patología , Neuronas/metabolismo , Proopiomelanocortina/metabolismo , Factor de Transcripción STAT5/fisiología , Animales , Núcleo Arqueado del Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/patología , Femenino , Hiperfagia/metabolismo , Masculino , Ratones , Ratones NoqueadosRESUMEN
The central melanocortin system is composed of neurons that express either the proopiomelanocortin (POMC) or the agouti-related protein (AgRP). POMC is cleaved in bioactive peptides, including the α-melanocyte-stimulating hormone (α-MSH). α-MSH activates the melanocortin-4 receptor (MC4R) inducing satiety, whereas AgRP acts as an inverse agonist of MC4R. However, only limited information is available regarding possible area-specific differences in the interaction between α-MSH and AgRP terminals on MC4R-expressing cells. Therefore, the objective of the present study was to compare the distribution pattern of α-MSH and AgRP terminals on the perikarya of MC4R-expressing neurons. We performed a triple-label immunofluorescence reaction in brain series of MC4R-reporter mice to visualize MC4R-expressing neurons together with AgRP and α-MSH terminals. POMC and AgRP neurons project to areas that contain MC4R-expressing cells, although several brain nuclei exhibit AgRP and α-MSH terminals, but they do no express MC4R, while other brain areas contain MC4R-expressing cells and receive no apparent innervation of AgRP and POMC neurons. AgRP terminals make more presumptive appositions than α-MSH on the soma of MC4R-expressing neurons of the medial preoptic area and paraventricular nucleus of the hypothalamus (Pa). Additionally, a higher percentage of MC4R cells receive at least one presumptive apposition from AgRP terminals in the median preoptic nucleus and Pa, compared to α-MSH appositions. Thus, our study revealed area-specific differences in the interaction between α-MSH and AgRP terminals and the soma of MC4R-expressing neurons. These findings provide new insights about the relationship between first- and second-order neurons of the central melanocortin system.
Asunto(s)
Proteína Relacionada con Agouti/metabolismo , Receptor de Melanocortina Tipo 4/metabolismo , alfa-MSH/metabolismo , Animales , Axones/metabolismo , Encéfalo/metabolismo , Ingestión de Alimentos/fisiología , Metabolismo Energético/fisiología , Hipotálamo/metabolismo , Leptina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas/metabolismo , Núcleo Hipotalámico Paraventricular/metabolismoRESUMEN
Leptin regulates energy balance and also exhibits neurotrophic effects during critical developmental periods. However, the actual role of leptin during development is not yet fully understood. To uncover the importance of leptin in early life, the present study restored leptin signaling either at the fourth or tenth week of age in mice formerly null for the leptin receptor (LepR) gene. We found that some defects previously considered irreversible due to neonatal deficiency of leptin signaling, including the poor development of arcuate nucleus neural projections, were recovered by LepR reactivation in adulthood. However, LepR deficiency in early life led to irreversible obesity via suppression of energy expenditure. LepR reactivation in adulthood also led to persistent reduction in hypothalamic Pomc, Cartpt and Prlh mRNA expression and to defects in the reproductive system and brain growth. Our findings revealed that early defects in leptin signaling cause permanent metabolic, neuroendocrine and developmental problems.
Asunto(s)
Envejecimiento/genética , Regulación del Desarrollo de la Expresión Génica , Leptina/genética , Obesidad/genética , Receptores de Leptina/genética , Envejecimiento/metabolismo , Proteína Relacionada con Agouti/genética , Proteína Relacionada con Agouti/metabolismo , Animales , Animales Recién Nacidos , Núcleo Arqueado del Hipotálamo/crecimiento & desarrollo , Núcleo Arqueado del Hipotálamo/metabolismo , Núcleo Arqueado del Hipotálamo/patología , Metabolismo Energético/genética , Femenino , Gónadas/crecimiento & desarrollo , Gónadas/metabolismo , Gónadas/patología , Hipotálamo/crecimiento & desarrollo , Hipotálamo/metabolismo , Hipotálamo/patología , Leptina/metabolismo , Masculino , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Neuronas/patología , Obesidad/metabolismo , Obesidad/patología , Proopiomelanocortina/genética , Proopiomelanocortina/metabolismo , Hormona Liberadora de Prolactina/genética , Hormona Liberadora de Prolactina/metabolismo , Receptores de Leptina/deficiencia , Transducción de SeñalRESUMEN
Excessive alcohol intake induces an inflammatory response in the brain, via TNFα, TLR4 and NF-κB signaling pathways. It has been proposed that neuroinflammation would play a very important role in the development of alcohol addiction. In addition to stimulating the synthesis of inflammatory mediators such as IL-6, IL-1ß and TNFα, NF-κB is capable of reducing the anti-inflammatory activity of PPARα and PPARγ. Reciprocally, PPARα, PPARγ and melanocortin 4 receptor (MC4R) can decrease the proinflammatory activity of NF-κB, establishing an interplay of inactivations between such nuclear factors and receptors. In this review, we hypothesize that one of the mechanisms by which alcohol produces neuroinflammation is through NF-κB-mediated decrease in PPARα and PPARγ anti-inflammatory activities; in addition, ethanol negatively affects MC4R activity, decreasing the ability of this receptor to activate PPARγ. PPARα, PPARγ and MC4R can be pharmacologically activated by synthetic ligands (fibrates, thiazolidinediones and synthetic peptides, respectively); in this context, we propose that the administration of such ligands would decrease neuroinflammation produced by alcohol intake. The advantage of this approach is that fibrates and thiazolidinediones are FDA-approved drugs that have been used for years in other clinical conditions, and now may offer a new perspective for the treatment of alcoholism.
Asunto(s)
Consumo de Bebidas Alcohólicas/fisiopatología , Inflamación/etiología , Melanocortinas/metabolismo , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Receptores Toll-Like/metabolismo , Animales , Antiinflamatorios/uso terapéutico , Etanol/efectos adversos , Humanos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , LigandosRESUMEN
UNLABELLED: Melanocortin receptors (MC3/4R) mediate most of the metabolic and cardiovascular actions of leptin. AIM: Here, we tested if MC4R also contributes to leptin's effects on respiratory function. METHODS: After control measurements, male Holtzman rats received daily microinjections of leptin, SHU9119 (MC3/4R antagonist) or SHU9119 combined with leptin infused into the brain lateral ventricle for 7 days. On the 6th day of treatment, tidal volume (VT ), respiratory frequency (fR ) and pulmonary ventilation (VE ) were measured by whole-body plethysmography during normocapnia or hypercapnia (7% CO2 ). Baseline mean arterial pressure (MAP), heart rate (HR) and metabolic rate were also measured. VE , VT and fR were also measured in mice with leptin receptor deletion in the entire central nervous system (LepR/Nestin-cre) or only in proopiomelanocortin neurones (LepR/POMC-cre) and in MC4R knockout (MC4R(-/-) ) and wild-type mice. RESULTS: Leptin (5 µg day(-1) ) reduced body weight (~17%) and increased ventilatory response to hypercapnia, whereas SHU9119 (0.6 nmol day(-1) ) increased body weight (~18%) and reduced ventilatory responses compared with control-PBS group (Lep: 2119 ± 90 mL min(-1) kg(-1) and SHU9119: 997 ± 67 mL min(-1) kg(-1) , vs. PBS: 1379 ± 91 mL min(-1) kg(-1) ). MAP increased after leptin treatment (130 ± 2 mmHg) compared to PBS (106 ± 3 mmHg) or SHU9119 alone (109 ± 3 mmHg). SHU9119 prevented the effects of leptin on body weight, MAP (102 ± 3 mmHg) and ventilatory response to hypercapnia (1391 ± 137 mL min(-1) kg(-1) ). The ventilatory response to hypercapnia was attenuated in the LepR/Nestin-cre, LepR/POMC-cre and MC4R(-/-) mice. CONCLUSION: These results suggest that central MC4R mediate the effects of leptin on respiratory response to hypercapnia.