Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK

Copyright © 2014 Elsevier Inc. All rights reserved.Peer reviewedPublisher PD

Cholinergic neurons in the dorsomedial hypothalamus regulate mouse brown adipose tissue metabolism.

OBJECTIVE: Brown adipose tissue (BAT) thermogenesis is critical in maintaining body temperature. The dorsomedial hypothalamus (DMH) integrates cutaneous thermosensory signals and regulates adaptive thermogenesis. Here, we study the function and synaptic connectivity of input from DMH cholinergic neurons to sympathetic premotor neurons in the raphe pallidus (Rpa). METHODS: In order to selectively manipulate DMH cholinergic neuron activity, we generated transgenic mice expressing channelrhodopsin fused to yellow fluorescent protein (YFP) in cholinergic neurons (choline acetyltransferase (ChAT)-Cre::ChR2-YFP) with the Cre-LoxP technique. In addition, we used an adeno-associated virus carrying the Cre recombinase gene to delete the floxed Chat gene in the DMH. Physiological studies in response to optogenetic stimulation of DMH cholinergic neurons were combined with gene expression and immunocytochemical analyses. RESULTS: A subset of DMH neurons are ChAT-immunopositive neurons. The activity of these neurons is elevated by warm ambient temperature. A phenotype-specific neuronal tracing shows that DMH cholinergic neurons directly project to serotonergic neurons in the Rpa. Optical stimulation of DMH cholinergic neurons decreases BAT activity, which is associated with reduced body core temperature. Furthermore, elevated DMH cholinergic neuron activity decreases the expression of BAT uncoupling protein 1 (Ucp1) and peroxisome proliferator-activated receptor γ coactivator 1 α (Pgc1α) mRNAs, markers of BAT activity. Injection of M2-selective muscarinic receptor antagonists into the 4th ventricle abolishes the effect of optical stimulation. Single cell qRT-PCR analysis of retrogradely identified BAT-projecting neurons in the Rpa shows that all M2 receptor-expressing neurons contain tryptophan hydroxylase 2. In animals lacking the Chat gene in the DMH, exposure to warm temperature reduces neither BAT Ucp1 nor Pgc1α mRNA expression. CONCLUSION: DMH cholinergic neurons directly send efferent signals to sympathetic premotor neurons in the Rpa. Elevated cholinergic input to this area reduces BAT activity through activation of M2 mAChRs on serotonergic neurons. Therefore, the direct DMH(ACh)-Rpa(5-HT) pathway may mediate physiological heat-defense responses to elevated environmental temperature.We thank Althea Cavanaugh and Licheng Wu for technical supports. This work was supported by NIDDK (RO1DK092246) to Y.-H.J. and New York obesity nutrition research center to J.H.J.This is the final published version. It first appeared at http://www.sciencedirect.com/science/article/pii/S2212877815000617

Central Serotonergic Neurons Activate and Recruit Thermogenic Brown and Beige Fat and Regulate Glucose and Lipid Homeostasis

SummaryThermogenic brown and beige adipocytes convert chemical energy to heat by metabolizing glucose and lipids. Serotonin (5-HT) neurons in the CNS are essential for thermoregulation and accordingly may control metabolic activity of thermogenic fat. To test this, we generated mice in which the human diphtheria toxin receptor (DTR) was selectively expressed in central 5-HT neurons. Treatment with diphtheria toxin (DT) eliminated 5-HT neurons and caused loss of thermoregulation, brown adipose tissue (BAT) steatosis, and a >50% decrease in uncoupling protein 1 (Ucp1) expression in BAT and inguinal white adipose tissue (WAT). In parallel, blood glucose increased 3.5-fold, free fatty acids 13.4-fold, and triglycerides 6.5-fold. Similar BAT and beige fat defects occurred in Lmx1bf/fePet1Cre mice in which 5-HT neurons fail to develop in utero. We conclude 5-HT neurons play a major role in regulating glucose and lipid homeostasis, in part through recruitment and metabolic activation of brown and beige adipocytes

Central Control of Brown Adipose Tissue Thermogenesis

Thermogenesis, the production of heat energy, is an essential component of the homeostatic repertoire to maintain body temperature during the challenge of low environmental temperature and plays a key role in elevating body temperature during the febrile response to infection. Mitochondrial oxidation in brown adipose tissue (BAT) is a significant source of neurally regulated metabolic heat production in many species from mouse to man. BAT thermogenesis is regulated by neural networks in the central nervous system which responds to feedforward afferent signals from cutaneous and core body thermoreceptors and to feedback signals from brain thermosensitive neurons to activate BAT sympathetic nerve activity. This review summarizes the research leading to a model of the feedforward reflex pathway through which environmental cold stimulates BAT thermogenesis and includes the influence on this thermoregulatory network of the pyrogenic mediator, prostaglandin E2, to increase body temperature during fever. The cold thermal afferent circuit from cutaneous thermal receptors, through second-order thermosensory neurons in the dorsal horn of the spinal cord ascends to activate neurons in the lateral parabrachial nucleus which drive GABAergic interneurons in the preoptic area (POA) to inhibit warm-sensitive, inhibitory output neurons of the POA. The resulting disinhibition of BAT thermogenesis-promoting neurons in the dorsomedial hypothalamus activates BAT sympathetic premotor neurons in the rostral ventromedial medulla, including the rostral raphe pallidus, which provide excitatory, and possibly disinhibitory, inputs to spinal sympathetic circuits to drive BAT thermogenesis. Other recently recognized central sites influencing BAT thermogenesis and energy expenditure are also described

Amino acids and hypertension in adults

Accumulating evidence suggests a potential role of dietary protein among nutritional factors interfering with the regulation of blood pressure. Dietary protein source (plant versus animal protein), and especially, protein composition in terms of amino acids has been postulated to interfere with mechanisms underlying the development of hypertension. Recently, mounting interest has been directed at amino acids in hypertension focusing on habitual dietary intake and their circulating levels regardless of single amino acid dietary supplementation. The aim of the present review was to summarize epidemiological evidence concerning the connection between amino acids and hypertension. Due to the large variability in methodologies used for assessing amino acid levels and heterogeneity in the results obtained, it was not possible to draw robust conclusions. Indeed, some classes of amino acids or individual amino acids showed non-causative association with blood pressure as well as the incidence of hypertension, but the evidence was far from being conclusive. Further research should be prompted for a thorough understanding of amino acid effects and synergistic actions of different amino acid classes on blood pressure regulation

Participação dos receptores nicotínicos na neurotransmissão da resposta cárdio-vagal do baroreflexo e do reflexo BEZOLD-JARISCH no núcleo ambíguo de ratos anestesiados

Estudos imunohistoquímicos têm demonstrado que o núcleo ambíguo (NA) desempenha um papel predominante no controle cárdio-vagal, devido sua projeção direta para o coração, via nervo vago. Estudos anteriores mostraram através do bloqueio com ácido kinurênico, que os receptores de aminoácido excitatório dos neurônios do NA possuem grande importância na mediação da resposta cronotrópica negativa do barorreflexo (BRF) e reflexo Bezold-Jarisch (RBJ). Entretanto, outros aspectos ainda precisam ser melhores esclarecidos, como por exemplo, o papel dos receptores colinérgicos nicotínicos na mediação desta resposta reflexa bradicárdica, assim como a possível influência destes receptores sobre as respostas induzidas pelo L-Glutamato (L-Glu) no NA. O objetivo deste estudo foi avaliar a participação dos receptores colinérgicos nicotínicos na modulação das respostas cardiovasculares induzidas pela ativação do BRF e do RBJ e estudar uma possível interação entre a neurotransmissão glutamatérgica e colinérgica nicotínica ao nível do NA. Foram utilizados ratos Wistar, anestesiados com uretana, paralisados com succinilcolina e ventilados artificialmente. Os animais foram submetidos à cateterização das artéria e veia femorais, para permitir os registros cardiovasculares e administração de drogas, respectivamente, e ao bloqueio da manifestação da atividade simpática cardíaca, através do antagonista β-adrenérgico atenolol. Foram feitas microinjeções no NA com as seguintes coordenadas: ântero-posterior = nível do óbex, lateral ±1,7 mm da linha média e dorso-ventral = -1,4 a -1,8 mm da superfície do óbex. As drogas utilizadas neste estudo foram: L-Glu (5 nmol/50 nL), nicotina (0,5; 1; 5 e 10 mM), α-bungarotoxina (1 µM), DH-β-E (100 µM) e solução controle (salina, NaCl 0,9%). O BRF foi induzido pela infusão contínua da fenilefrina (50 µg/mL/min) e o RBJ pela injeção endovenosa de fenilbiguanida (10 µg/Kg). Os resultados mostraram discretas respostas hipotensoras e bradicardia consistente às microinjeções de L-Glu no NA. As microinjeções de nicotina promoveram significativas respostas bradicárdicas nas doses de 1 e 5 mM e respostas pressoras discretas. Na dose de 10 mM, tanto as respostas bradicárdicas como as pressoras não foram mais observadas. A microinjeção unilateral de DH-β-E no NA não causou alterações significativas nas respostas para o L-Glu e a nicotina, no entanto, microinjeção unilateral de α-bungarotoxina no NA atenuou as respostas bradicárdicas induzidas pelo L-Glu e a nicotina no mesmo sítio. Em relação aos reflexos cardiovasculares, observamos que o bloqueio com α-bungarotoxina atenuou significativamente o BRF, enquanto que apenas a resposta bradicárdica do RBJ foi atenuada. Os resultados obtidos no presente estudo confirmam que o NA desempenha um importante papel na modulação das respostas cardiovasculares. Sugerem ainda que as subunidades α7 dos receptores colinérgicos nicotínicos do NA, ao nível do óbex, participam da modulação das respostas reflexas cárdio-vagais do BRF e RBJ em ratos anestesiados. Em relação à neurotransmissão glutamatérgicas, nossos resultados mostraram que os receptores colinérgicos nicotínicos interferem nas respostas cardiovasculares glutamatérgicas. No entanto, estudos adicionais são necessários para elucidar esta interação, seja interferindo na liberação do L-Glu a partir de projeções provenientes do NTS (nucleus of tractus solitarius) ou diretamente nos receptores de aminoácidos excitatórios no NA

Publications of the Space Physiology and Countermeasures Program, Cardiopulmonary Discipline: 1980-1990

A 10-year cumulative bibliography of publications resulting from research supported by the Cardiopulmonary Discipline of the Space Physiology and Countermeasures Program of NASA's Life Sciences Division is provided. Primary subjects included in this bibliography are Fluid Shifts, Cardiovascular Fitness, Cardiovascular Physiology, and Pulmonary Physiology. General physiology references are also included. Principal investigators whose research tasks resulted in publication are identified. Publications are identified by a record number corresponding with their entry in the Life Sciences Bibliographic Database, maintained at the George Washington University

The Potential Mechanisms of High-Velocity, Low-Amplitude, Controlled Vertebral Thrusts on Neuroimmune Function:A Narrative Review

The current COVID-19 pandemic has necessitated the need to find healthcare solutions that boost or support immunity. There is some evidence that high-velocity, low-amplitude (HVLA) controlled vertebral thrusts have the potential to modulate immune mediators. However, the mechanisms of the link between HVLA controlled vertebral thrusts and neuroimmune function and the associated potential clinical implications are less clear. This review aims to elucidate the underlying mechanisms that can explain the HVLA controlled vertebral thrust--neuroimmune link and discuss what this link implies for clinical practice and future research needs. A search for relevant articles published up until April 2021 was undertaken. Twenty-three published papers were found that explored the impact of HVLA controlled vertebral thrusts on neuroimmune markers, of which eighteen found a significant effect. These basic science studies show that HVLA controlled vertebral thrust influence the levels of immune mediators in the body, including neuropeptides, inflammatory markers, and endocrine markers. This narravtive review discusses the most likely mechanisms for how HVLA controlled vertebral thrusts could impact these immune markers. The mechanisms are most likely due to the known changes in proprioceptive processing that occur within the central nervous system (CNS), in particular within the prefrontal cortex, following HVLA spinal thrusts. The prefrontal cortex is involved in the regulation of the autonomic nervous system, the hypothalamic–pituitary–adrenal axis and the immune system. Bi-directional neuro-immune interactions are affected by emotional or pain-related stress. Stress-induced sympathetic nervous system activity also alters vertebral motor control. Therefore, there are biologically plausible direct and indirect mechanisms that link HVLA controlled vertebral thrusts to the immune system, suggesting HVLA controlled vertebral thrusts have the potential to modulate immune function. However, it is not yet known whether HVLA controlled vertebral thrusts have a clinically relevant impact on immunity. Further research is needed to explore the clinical impact of HVLA controlled vertebral thrusts on immune function

Tratamento com ÔMEGA-3 nas respostas cardiovasculares produzidas pela ativação do quimiorreflexo em ratos com sepse

FAPEMIG - Fundação de Amparo a Pesquisa do Estado de Minas GeraisTrabalho de Conclusão de Curso (Graduação)O sistema cardiovascular é imprescindível nos processos de controle da homeostase que inclui a manutenção das concentrações de gases no sangue (O 2 e CO 2 ). Distúrbios patológicos podem afetar esse controle, como exemplo, a sepse; que produz uma resposta inflamatória sistêmica. Em ratos, a sepse pode ser induzida por uma técnica conhecida como ligação e perfuração do ceco (CLP), que por sua vez abole as respostas cardiovasculares da ativação do quimiorreflexo. Admitindo o Ômega-3 como um ácido graxo importante e por ser imunorregulador em processos inflamatórios, o estudo tem como objetivo verificar se uma dieta rica em Ômega-3 poderia restaurar as respostas cardiovasculares do quimiorreflexo em ratos submetidos à CLP. Ratos pós-desmame foram tratados por 60 dias com Ômega-3 (ou solução controle) tanto subcutaneamente quanto pelo método da gavagem [gv (infusão oral)]. Após 60 dias, artéria e veia femoral foram canuladas para registro dos parâmetros cardiovasculares e injeção de drogas, respectivamente. Alguns ratos foram submetidos à cirurgia CLP (indução da sepse) enquanto outros cirurgia fictícia (sem sepse). As respostas cardiovasculares do quimiorreflexo foram produzidas em ratos não anestesiados através da injeção endovenosa de Cianeto de potássio. Os resultados confirmaram que a sepse abole as respostas cardiovasculares do quimiorreflexo e estas respostas não são recuperadas em ratos tratados cronicamente com Ômega-3. Além disso, os tratamentos com Ômega-3 em ratos sem sepse também atenuaram as respostas cardiovasculares do quimiorreflexo