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

Bardoxolone methyl prevents fat deposition and inflammation in brown adipose tissue and enhances sympathetic activity in mice fed a high-fat diet

Obesity results in changes in brown adipose tissue (BAT) morphology, leading to fat deposition, inflammation, and alterations in sympathetic nerve activity. Bardoxolone methyl (BARD) has been extensively studied for the treatment of chronic diseases. We present for the first time the effects of oral BARD treatment on BAT morphology and associated changes in the brainstem. Three groups (n = 7) of C57BL/6J mice were fed either a high-fat diet (HFD), a high-fat diet supplemented with BARD (HFD/BARD), or a low-fat diet (LFD) for 21 weeks. BARD was administered daily in drinking water. Interscapular BAT, and ventrolateral medulla (VLM) and dorsal vagal complex (DVC) in the brainstem, were collected for analysis by histology, immunohistochemistry and Western blot. BARD prevented fat deposition in BAT, demonstrated by the decreased accumulation of lipid droplets. When administered BARD, HFD mice had lower numbers of F4/80 and CD11c macrophages in the BAT with an increased proportion of CD206 macrophages, suggesting an anti-inflammatory effect. BARD increased phosphorylation of tyrosine hydroxylase in BAT and VLM. In the VLM, BARD increased energy expenditure proteins, including beta 3-adrenergic receptor (β3-AR) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Overall, oral BARD prevented fat deposition and inflammation in BAT, and stimulated sympathetic nerve activity. © 2015 by the authors; licensee MDPI, Basel, SwitzerlandThis article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/4.0/). Copy acquired from MDPI: http://www.mdpi.com/2072-6643/7/6/4705

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

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

The role of ionotropic glutamate receptors in the dorsomedial hypothalamus in the increase in core body temperature evoked by interoceptive and exteroceptive stresses in rats

Indiana University-Purdue University Indianapolis (IUPUI)Brain responds to an array of diverse challenges that are defined as either exteroceptive stress, involving cognitive processing of sensory information from the external environment and or interoceptive stress, detected through sensory neural or chemical cues from the internal environment. The physiological response to most stresses consists of autonomic responses that are essential for animal survival in the face of a threatening circumstance. However, it is known that exposition to continuous situations of stress is involved in the development of a series of diseases such as hypertension, myocardial infarction and panic syndrome. Several studies have shown that cells in a specific area of the brain, the dorsomedial hypothalamus (DMH), are involved in the response produced during emotional stress. However, the role of glutamatergic transmission in the DMH in the increase in body temperature induced by experimental stress has not been examined. Research findings thus far indicate that neurons in the DMH play a role in thermoregulation and that local glutamate receptors may be involved. The hypothesis of this thesis is that activity at ionotropic glutamate receptors in the DMH is necessary for the thermogenic response induced by experimental stress. In the present work, microinjections of kynurenate, an excitatory amino acid antagonist, NBQX (2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione), an AMPA/kainate receptor antagonist, DL-2-amino-5-phosphonovaleric acid (APV), an NMDA receptor antagonist, and a mixture of NBQX and APV, were delivered to the DMH before exposure to experimental stress. The stress paradigms used include models for exteroceptive stress and interoceptive stress. The results show that inhibition of both NMDA and non-NMDA receptors is necessary to abolish the thermogenic response produced by all stress paradigms tested. Furthermore, there appears to be a difference in the degree of attenuation of the thermogenic response produced by either inhibition of NMDA receptors or non-NMDA receptors. Together these results support a definite role for ionotropic glutamate receptors within DMH region in the thermogenic response to stress. These results also finally show that the DMH is involved in all the major physiological stress responses including increase in plasma ACTH, increase in heart rate, blood pressure and now temperature as well

Role of the hypothalamic paraventricular nucleus in the cardiovascular responses to elevations in body temperature

The hypothalamic paraventricular nucleus (PVN) is known to be a major integrative region within the forebrain. It is composed of functionally different subgroups of neurons, including the parvocellular neurons that project to important autonomic targets in the brainstem e.g. the rostral ventrolateral medulla (RVLM) and the intermediolateral cell column (IML) of the spinal cord, where the sympathetic preganglionic motor-neurons are located. These regions are critical in cardiovascular regulation; hence, these projections are likely to mediate the effects of the PVN on sympathetic nerve activity and hence may contribute to the cardiovascular changes induced by physiological stimuli such as elevations in body temperature. The neurotransmitter such as nitric oxide (NO) is important in cardiovascular regulation and it is now emerging as a major focus of investigation in thermoregulation. One of the most striking accumulations of NO containing-neurons is in the PVN where it appears to be playing an important role in cardiovascular regulation and body fluid homeostasis. The results of the work show; 1. That spinally-projecting and nitrergic neurons in the PVN may contribute to the central pathways activated by exposure to a hot environment. 2. Suggests that nitrergic neurons and spinally- projecting neurons in the brainstem may make a small contribution to the central pathways mediating the reflex responses initiated by hyperthermia. 3. The present study also illustrates that these PVN neurons projecting to the RVLM may make a smaller contribution than the spinal-projecting neurons in the PVN to the cardiovascular responses initiated by heat. 4. The results of my studies showed that the microinjection of muscimol to inhibit the neuronal activity in the PVN abolished the reflex decrease in renal blood flow following an elevation of core body temperature. In addition, this effect was specific to the PVN, since microinjections of muscimol into areas outside the PVN were not effective. These findings demonstrate that the PVN is critical for this reflex cardiovascular response initiated by hyperthermia. In conclusion, PVN is critical for the reflex decrease in renal blood flow during elevations in core body temperature. We hypothesise that projections from the PVN to the spinal cord and the RVLM contribute to the reflex cardiovascular responses. Additionally, nitrergic neurons in the PVN may contribute but the physiological role of those neurons in the reflex responses elicited by hyperthermia needs to be investigated

Neurophysiological and metabolic regulation of spontaneous and synthetic torpor: a translational perspective

Torpor is an energy-saving physiological state characterized by a transient and reversible decrease in metabolic rate and core temperature, which occurs in different species in conditions of scarce food availability. At present, the mechanism underlying torpor occurrence is unknown. The attempt to imitate natural torpor is pursued in clinical practice, in order to overcome the severe side effects that follow the induction of therapeutic hypothermia. Several attempts to induce a torpor-like state (synthetic torpor) by manipulating central nervous activity have been made in rodents. Most promising are the activation of central adenosine type-1 receptors and the pharmacological inhibition of the Raphe Pallidus (RPa). Aims of the present project were: i) to unravel the neural pathway of spontaneous torpor in mice, a species that enters daily torpor spontaneously; ii) to understand the possible mechanism of metabolic rate reduction in spontaneous and synthetic torpor, in mice and rats, respectively, by evaluating mitochondrial activity during deep hypothermia; iii) to explore the possibility to induce synthetic torpor in a large mammal, the swine, by the central manipulation of the RPa. In summary, the results showed that: i) Paraventricular and Dorsomedial Hypothalamic nuclei showed a specific neural activation at the entrance in torpor; ii) liver mitochondria showed a reduction in maximum respiration rate in spontaneous, but not in synthetic torpor, while no major changes occurred in kidney and brain; iii) central manipulation of the RPa in swine induced physiological modifications similar to those observed in rats