Efectos centrales de MCH sobre el metabolismo periférico

El sistema nervioso central juega un papel fundamental en la regulación del balance energético puesto que controla la ingesta, el gasto energético y el uso de los sustratos metabólicos. La hormona concentradora de melanina (MCH), es un neuropéptido orexigénico de especial relevancia en la regulación del balance energético. La MCH, secretada por el hipotálamo lateral, favorece la ingesta y la adiposidad de tejidos periféricos. Hasta el momento, se desconoce cómo MCH modula el metabolismo periférico, así como los circuitos centrales a través de los cuales ejerce su acción. En este estudio se establece que los efectos centrales de la hormona MCH modulan el metabolismo lipídico periférico. La administración central de MCH en modelos murinos (rata y ratón) estimula la absorción y deposición de lípidos en el tejido adiposo blanco e hígado, independientemente de sus efectos orexigénicos o cambios en el gasto energético. Es decir, se demuestra el efecto de MCH en el sistema nervioso central, sobre el cambio en la partición nutricional y en el uso de los sustratos metabólicos. Estas acciones centrales se ejecutan en la periferia mediante dos rutas diferenciadas: el sistema nervioso simpático media la acción de MCH sobre el metabolismo lipídico del tejido adiposo blanco; mientras que el sistema nervioso parasimpático media las acciones de MCH sobre el metabolismo lipídico del hígado, mediando el estrés del retículo endoplasmático. Los efectos centrales de MCH sobre el tejido adiposo blanco e hígado, se ejecutan en áreas independientes del hipotálamo; concretamente en el núcleo arcuato y núcleo lateral respectivamente. La acción de MCH en núcleo lateral del hipotálamo, sobre el metabolismo hepático del ER-stress y lípidos, esta mediado por el sistema opioide: concretamente el sistema kappa opioide. La inhibición genética de KOR en el LHA mejora la esteatosis hepática inducida por dieta y MCH, mientras que su sobre-expresión en dicho núcleo incrementa la acumulación lipídica en hígado mediante la activación del ER-stress hepático. Esta modulación hepática por el sistema MCH-KOR en el LHA, es relevante por el hecho de que tanto la inhibición del MCH-R1 como de KOR, reduce la esteatohepatitis inducida por la dieta MCD. En este trabajo se demuestra a través de qué circuitos hipotalámicos la MCH regula el metabolismo lipídico de hígado y grasa; así como que el sistema nervioso autónomo media la transmisión de la información desde el hipotálamo a dichos tejidos. Así mismo, se establecen los mecanismos moleculares a través de los cuales MCH modula el metabolismo lipídico del hígado y de la grasa. Finalmente, se muestra como la acción central de MCH y el sistema opioide, actúan como moduladores del desarrollo de la esteatosis hepática

Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis

© 2021 The Authors.Appropriate cristae remodeling is a determinant of mitochondrial function and bioenergetics and thus represents a crucial process for cellular metabolic adaptations. Here, we show that mitochondrial cristae architecture and expression of the master cristae-remodeling protein OPA1 in proopiomelanocortin (POMC) neurons, which are key metabolic sensors implicated in energy balance control, is affected by fluctuations in nutrient availability. Genetic inactivation of OPA1 in POMC neurons causes dramatic alterations in cristae topology, mitochondrial Ca2+ handling, reduction in alpha-melanocyte stimulating hormone (α-MSH) in target areas, hyperphagia, and attenuated white adipose tissue (WAT) lipolysis resulting in obesity. Pharmacological blockade of mitochondrial Ca2+ influx restores α-MSH and the lipolytic program, while improving the metabolic defects of mutant mice. Chemogenetic manipulation of POMC neurons confirms a role in lipolysis control. Our results unveil a novel axis that connects OPA1 in POMC neurons with mitochondrial cristae, Ca2+ homeostasis, and WAT lipolysis in the regulation of energy balance.This work was supported by Agencia Estatal de Investigación y Fondo Social Europeo, Proyecto BFU2016-76973-R FEDER (C.V.A.); AG052005, AG052986, AG051459, DK111178 from NIH and NKFI-KKP-126998 from Hungarian National Research, Development and Innovation Office (T.L.H.); MR/P009824/2 from Medical Research Council UK (G.D.); and Ayudas Fundación BBVA a Investigadores y Creadores Culturales (2015), European Research Council (ERC) under the European Union’s Horizon 2020 Research And Innovation Program (grant agreement 725004) and CERCA Programme/Generalitat de Catalunya (M.C.). A.O. is supported by a Miguel Servet contract (CP19/00083) from Instituto de Salud Carlos III and co-financed by FEDER

Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca2+ homeostasis with adipose tissue lipolysis

Appropriate cristae remodeling is a determinant of mitochondrial function and bioenergetics and thus represents a crucial process for cellular metabolic adaptations. Here, we show that mitochondrial cristae architecture and expression of the master cristae-remodeling protein OPA1 in proopiomelanocortin (POMC) neurons, which are key metabolic sensors implicated in energy balance control, is affected by fluctuations in nutrient availability. Genetic inactivation of OPA1 in POMC neurons causes dramatic alterations in cristae topology, mitochondrial Ca2+ handling, reduction in alpha-melanocyte stimulating hormone (α-MSH) in target areas, hyperphagia, and attenuated white adipose tissue (WAT) lipolysis resulting in obesity. Pharmacological blockade of mitochondrial Ca2+ influx restores α-MSH and the lipolytic program, while improving the metabolic defects of mutant mice. Chemogenetic manipulation of POMC neurons confirms a role in lipolysis control. Our results unveil a novel axis that connects OPA1 in POMC neurons with mitochondrial cristae, Ca2+ homeostasis, and WAT lipolysis in the regulation of energy balance

Hypothalamic pregnenolone mediates recognition memory in the context of metabolic disorders

Obesity and type-2 diabetes are associated with cognitive dysfunction. Since the hypothalamus is implicated in energy balance control and memory disorders, we hypothesized that specific neurons in this brain region are at the interface of metabolism and cognition. Acute obesogenic diet administration in mice impaired recognition memory due to defective production of the neurosteroid-precursor pregnenolone in the hypothalamus. Genetic interference with pregnenolone synthesis by Star deletion in hypothalamic POMC, but not AgRP neurons, deteriorated recognition memory independently of metabolic disturbances. Our data suggested that pregnenolone's effects on cognitive function were mediated via an autocrine mechanism on POMC neurons, influencing hippocampal long-term potentiation. The relevance of central pregnenolone on cognition was also confirmed in metabolically-unhealthy obese patients. Our data reveals an unsuspected role for POMC neuron-derived neurosteroids in cognition. These results provide the basis for a framework to investigate new facets of POMC neuron biology with implications for cognitive disorders

Mitochondrial Dynamics Mediated by Mitofusin 1 Is Required for POMC Neuron Glucose-Sensing and Insulin Release Control.

Proopiomelanocortin (POMC) neurons are critical sensors of nutrient availability implicated in energy balance and glucose metabolism control. However, the precise mechanisms underlying nutrient sensing in POMC neurons remain incompletely understood. We show that mitochondrial dynamics mediated by Mitofusin 1 (MFN1) in POMC neurons couple nutrient sensing with systemic glucose metabolism. Mice lacking MFN1 in POMC neurons exhibited defective mitochondrial architecture remodeling and attenuated hypothalamic gene expression programs during the fast-to-fed transition. This loss of mitochondrial flexibility in POMC neurons bidirectionally altered glucose sensing, causing abnormal glucose homeostasis due to defective insulin secretion by pancreatic β cells. Fed mice lacking MFN1 in POMC neurons displayed enhanced hypothalamic mitochondrial oxygen flux and reactive oxygen species generation. Central delivery of antioxidants was able to normalize the phenotype. Collectively, our data posit MFN1-mediated mitochondrial dynamics in POMC neurons as an intrinsic nutrient-sensing mechanism and unveil an unrecognized link between this subset of neurons and insulin release