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A Tale of Three Systems: Toward a Neuroimmunoendocrine Model of Obesity.
The prevalence of obesity is on the rise. What was once considered a simple disease of energy imbalance is now recognized as a complex condition perpetuated by neuro- and immunopathologies. In this review, we summarize the current knowledge of the neuroimmunoendocrine mechanisms underlying obesity. We examine the pleiotropic effects of leptin action in addition to its established role in the modulation of appetite, and we discuss the neural circuitry mediating leptin action and how this is altered with obesity, both centrally (leptin resistance) and in adipose tissues (sympathetic neuropathy). Finally, we dissect the numerous causal and consequential roles of adipose tissue macrophages in obesity and highlight recent key studies demonstrating their direct role in organismal energy homeostasis.
The sympathetic nervous system in the 21st century: Neuroimmune interactions in metabolic homeostasis and obesity.
The sympathetic nervous system maintains metabolic homeostasis by orchestrating the activity of organs such as the pancreas, liver, and white and brown adipose tissues. From the first renderings by Thomas Willis to contemporary techniques for visualization, tracing, and functional probing of axonal arborizations within organs, our understanding of the sympathetic nervous system has started to grow beyond classical models. In the present review, we outline the evolution of these findings and provide updated neuroanatomical maps of sympathetic innervation. We offer an autonomic framework for the neuroendocrine loop of leptin action, and we discuss the role of immune cells in regulating sympathetic terminals and metabolism. We highlight potential anti-obesity therapeutic approaches that emerge from the modern appreciation of SNS as a neural network vis a vis the historical fear of sympathomimetic pharmacology, while shifting focus from post- to pre-synaptic targeting. Finally, we critically appraise the field and where it needs to go.
Central nicotine induces browning through hypothalamic κ opioid receptor.
Increased body weight is a major factor that interferes with smoking cessation. Nicotine, the main bioactive compound in tobacco, has been demonstrated to have an impact on energy balance, since it affects both feeding and energy expenditure at the central level. Among the central actions of nicotine on body weight, much attention has been focused on its effect on brown adipose tissue (BAT) thermogenesis, though its effect on browning of white adipose tissue (WAT) is unclear. Here, we show that nicotine induces the browning of WAT through a central mechanism and that this effect is dependent on the κ opioid receptor (KOR), specifically in the lateral hypothalamic area (LHA). Consistent with these findings, smokers show higher levels of uncoupling protein 1 (UCP1) expression in WAT, which correlates with smoking status. These data demonstrate that central nicotine-induced modulation of WAT browning may be a target against human obesity.
Mediation of the Acute Stress Response by the Skeleton.
We hypothesized that bone evolved, in part, to enhance the ability of bony vertebrates to escape danger in the wild. In support of this notion, we show here that a bone-derived signal is necessary to develop an acute stress response (ASR). Indeed, exposure to various types of stressors in mice, rats (rodents), and humans leads to a rapid and selective surge of circulating bioactive osteocalcin because stressors favor the uptake by osteoblasts of glutamate, which prevents inactivation of osteocalcin prior to its secretion. Osteocalcin permits manifestations of the ASR to unfold by signaling in post-synaptic parasympathetic neurons to inhibit their activity, thereby leaving the sympathetic tone unopposed. Like wild-type animals, adrenalectomized rodents and adrenal-insufficient patients can develop an ASR, and genetic studies suggest that this is due to their high circulating osteocalcin levels. We propose that osteocalcin defines a bony-vertebrate-specific endocrine mediation of the ASR.
Obesity: a neuroimmunometabolic perspective.
Neuroimmunology and immunometabolism are burgeoning topics of study, but the intersection of these two fields is scarcely considered. This interplay is particularly prevalent within adipose tissue, where immune cells and the sympathetic nervous system (SNS) have an important role in metabolic homeostasis and pathology, namely in obesity. In the present Review, we first outline the established reciprocal adipose-SNS relationship comprising the neuroendocrine loop facilitated primarily by adipose tissue-derived leptin and SNS-derived noradrenaline. Next, we review the extensive crosstalk between adipocytes and resident innate immune cells as well as the changes that occur in these secretory and signalling pathways in obesity. Finally, we discuss the effect of SNS adrenergic signalling in immune cells and conclude with exciting new research demonstrating an immutable role for SNS-resident macrophages in modulating SNS-adipose crosstalk. We posit that the latter point constitutes the existence of a new field - neuroimmunometabolism.
Ferritin regulates organismal energy balance and thermogenesis.
OBJECTIVE: The ferritin heavy/heart chain (FTH) gene encodes the ferroxidase component of the iron (Fe) sequestering ferritin complex, which plays a central role in the regulation of cellular Fe metabolism. Here we tested the hypothesis that ferritin regulates organismal Fe metabolism in a manner that impacts energy balance and thermal homeostasis. METHODS: We developed a mouse strain, referred herein as FthR26 fl/fl, expressing a tamoxifen-inducible Cre recombinase under the control of the Rosa26 (R26) promoter and carrying two LoxP (fl) sites: one at the 5'end of the Fth promoter and another the 3' end of the first Fth exon. Tamoxifen administration induces global deletion of Fth in adult FthR26Δ/Δ mice, testing whether FTH is required for maintenance of organismal homeostasis. RESULTS: Under standard nutritional Fe supply, Fth deletion in adult FthR26Δ/Δ mice led to a profound deregulation of organismal Fe metabolism, oxidative stress, inflammation, and multi-organ damage, culminating in death. Unexpectedly, Fth deletion was also associated with a profound atrophy of white and brown adipose tissue as well as with collapse of energy expenditure and thermogenesis. This was attributed mechanistically to mitochondrial dysfunction, as assessed in the liver and in adipose tissue. CONCLUSION: The FTH component of ferritin acts as a master regulator of organismal Fe homeostasis, coupling nutritional Fe supply to organismal redox homeostasis, energy expenditure and thermoregulation.
Deletion of iRhom2 protects against diet-induced obesity by increasing thermogenesis.
OBJECTIVE: Obesity is the result of positive energy balance. It can be caused by excessive energy consumption but also by decreased energy dissipation, which occurs under several conditions including when the development or activation of brown adipose tissue (BAT) is impaired. Here we evaluated whether iRhom2, the essential cofactor for the Tumour Necrosis Factor (TNF) sheddase ADAM17/TACE, plays a role in the pathophysiology of metabolic syndrome. METHODS: We challenged WT versus iRhom2 KO mice to positive energy balance by chronic exposure to a high fat diet and then compared their metabolic phenotypes. We also carried out ex vivo assays with primary and immortalized mouse brown adipocytes to establish the autonomy of the effect of loss of iRhom2 on thermogenesis and respiration. RESULTS: Deletion of iRhom2 protected mice from weight gain, dyslipidemia, adipose tissue inflammation, and hepatic steatosis and improved insulin sensitivity when challenged by a high fat diet. Crucially, the loss of iRhom2 promotes thermogenesis via BAT activation and beige adipocyte recruitment, enabling iRhom2 KO mice to dissipate excess energy more efficiently than WT animals. This effect on enhanced thermogenesis is cell-autonomous in brown adipocytes as iRhom2 KOs exhibit elevated UCP1 levels and increased mitochondrial proton leak. CONCLUSION: Our data suggest that iRhom2 is a negative regulator of thermogenesis and plays a role in the control of adipose tissue homeostasis during metabolic disease.
The structure of Orco and its impact on our understanding of olfaction.
Zufall and Domingos discuss the significance of the recent structure of the insect odorant co-receptor Orco to the field of olfaction.
Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects.
Anti-obesity drugs in the amphetamine (AMPH) class act in the brain to reduce appetite and increase locomotion. They are also characterized by adverse cardiovascular effects with origin that, despite absence of any in vivo evidence, is attributed to a direct sympathomimetic action in the heart. Here, we show that the cardiac side effects of AMPH originate from the brain and can be circumvented by PEGylation (PEGyAMPH) to exclude its central action. PEGyAMPH does not enter the brain and facilitates SNS activity via theβ2-adrenoceptor, protecting mice against obesity by increasing lipolysis and thermogenesis, coupled to higher heat dissipation, which acts as an energy sink to increase energy expenditure without altering food intake or locomotor activity. Thus, we provide proof-of-principle for a novel class of exclusively peripheral anti-obesity sympathofacilitators that are devoid of any cardiovascular and brain-related side effects.
The sympathetic neuro-adipose connection and the control of body weight.
In recent decades, obesity has become a global public health crisis irrespective of age or gender [20]. But according to historic records, concerns over appropriate maintenance of body size have been long established. For more than to 2 millennia, the main therapeutic approach to curb excess weight has been to recommend dietary restrictions and regular exercise (Haslam, 2016). Nevertheless, more contemporary studies indicate that the employment of such approaches in the treatment of severely obese patients causes metabolic adaptions which impair their long-term success in weight management [8]. These evidences highlight thus, the urgency in the search for a more comprehensive knowledge of the mechanisms that underlie the control of body weight, which would be essential for the development of effective strategies for the treatment of obesity and its comorbidities. Importantly, the discovery of the hormone leptin [33]and the use of novel techniques in targeted transgenesis [32] have enabled progress in defining some of the key players and the molecular mechanisms that are involved in the processes that control body size homeostasis and energy balance, and how obesity may disrupt leptin's feedback loop and lead to the pathology of metabolic syndrome. On the light of such findings, here we review how the sympathetic nervous system modulates adipose tissue metabolism downstream of leptin's action on the CNS, with particular focus on how this system may be disrupted in the context of excess adiposity, plus highlight the potential clinical implications arising from a better understanding of the physiologic control of the sympathetic neuro-adipose connection.
Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine.
The cellular mechanism(s) linking macrophages to norepinephrine (NE)-mediated regulation of thermogenesis have been a topic of debate. Here we identify sympathetic neuron-associated macrophages (SAMs) as a population of cells that mediate clearance of NE via expression of solute carrier family 6 member 2 (SLC6A2), an NE transporter, and monoamine oxidase A (MAOA), a degradation enzyme. Optogenetic activation of the sympathetic nervous system (SNS) upregulates NE uptake by SAMs and shifts the SAM profile to a more proinflammatory state. NE uptake by SAMs is prevented by genetic deletion of Slc6a2 or inhibition of the encoded transporter. We also observed an increased proportion of SAMs in the SNS of two mouse models of obesity. Genetic ablation of Slc6a2 in SAMs increases brown adipose tissue (BAT) content, causes browning of white fat, increases thermogenesis, and leads to substantial and sustained weight loss in obese mice. We further show that this pathway is conserved, as human sympathetic ganglia also contain SAMs expressing the analogous molecular machinery for NE clearance, which thus constitutes a potential target for obesity treatment.
Cellular and molecular basis of decision-making.
People think they are in control of their own decisions: what to eat or drink, whom to marry or pick a fight with, where to live, what to buy. Behavioural economists and neurophysiologists have long studied decision-making behaviours. However, these behaviours have only recently been studied through the light of molecular genetics. Here, we review recent research in mice, Drosophila melanogaster and Caenorhabditis elegans, that analyses the molecular and cellular mechanisms underlying decision-making. These studies interrogate decision-making about food, sexual behaviour, aggression or foraging strategies, and add molecular and cell biology understanding onto the consilience of brain and decision.
Hypothalamic melanin concentrating hormone neurons communicate the nutrient value of sugar.
Sugars that contain glucose, such as sucrose, are generally preferred to artificial sweeteners owing to their post-ingestive rewarding effect, which elevates striatal dopamine (DA) release. While the post-ingestive rewarding effect, which artificial sweeteners do not have, signals the nutrient value of sugar and influences food preference, the neural circuitry that mediates the rewarding effect of glucose is unknown. In this study, we show that optogenetic activation of melanin-concentrating hormone (MCH) neurons during intake of the artificial sweetener sucralose increases striatal dopamine levels and inverts the normal preference for sucrose vs sucralose. Conversely, animals with ablation of MCH neurons no longer prefer sucrose to sucralose and show reduced striatal DA release upon sucrose ingestion. We further show that MCH neurons project to reward areas and are required for the post-ingestive rewarding effect of sucrose in sweet-blind Trpm5(-/-) mice. These studies identify an essential component of the neural pathways linking nutrient sensing and food reward. DOI: http://dx.doi.org/10.7554/eLife.01462.001.
Sympathetic neuro-adipose connections mediate leptin-driven lipolysis.
Leptin is a hormone produced by the adipose tissue that acts in the brain, stimulating white fat breakdown. We find that the lipolytic effect of leptin is mediated through the action of sympathetic nerve fibers that innervate the adipose tissue. Using intravital two-photon microscopy, we observe that sympathetic nerve fibers establish neuro-adipose junctions, directly "enveloping" adipocytes. Local optogenetic stimulation of sympathetic inputs induces a local lipolytic response and depletion of white adipose mass. Conversely, genetic ablation of sympathetic inputs onto fat pads blocks leptin-stimulated phosphorylation of hormone-sensitive lipase and consequent lipolysis, as do knockouts of dopamine β-hydroxylase, an enzyme required for catecholamine synthesis. Thus, neuro-adipose junctions are necessary and sufficient for the induction of lipolysis in white adipose tissue and are an efferent effector of leptin action. Direct activation of sympathetic inputs to adipose tissues may represent an alternative approach to induce fat loss, circumventing central leptin resistance. PAPERCLIP.
Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons.
Ventral tegmental area (VTA) dopamine neurons in the brain's reward circuit have a crucial role in mediating stress responses, including determining susceptibility versus resilience to social-stress-induced behavioural abnormalities. VTA dopamine neurons show two in vivo patterns of firing: low frequency tonic firing and high frequency phasic firing. Phasic firing of the neurons, which is well known to encode reward signals, is upregulated by repeated social-defeat stress, a highly validated mouse model of depression. Surprisingly, this pathophysiological effect is seen in susceptible mice only, with no apparent change in firing rate in resilient individuals. However, direct evidence--in real time--linking dopamine neuron phasic firing in promoting the susceptible (depression-like) phenotype is lacking. Here we took advantage of the temporal precision and cell-type and projection-pathway specificity of optogenetics to show that enhanced phasic firing of these neurons mediates susceptibility to social-defeat stress in freely behaving mice. We show that optogenetic induction of phasic, but not tonic, firing in VTA dopamine neurons of mice undergoing a subthreshold social-defeat paradigm rapidly induced a susceptible phenotype as measured by social avoidance and decreased sucrose preference. Optogenetic phasic stimulation of these neurons also quickly induced a susceptible phenotype in previously resilient mice that had been subjected to repeated social-defeat stress. Furthermore, we show differences in projection-pathway specificity in promoting stress susceptibility: phasic activation of VTA neurons projecting to the nucleus accumbens (NAc), but not to the medial prefrontal cortex (mPFC), induced susceptibility to social-defeat stress. Conversely, optogenetic inhibition of the VTA-NAc projection induced resilience, whereas inhibition of the VTA-mPFC projection promoted susceptibility. Overall, these studies reveal novel firing-pattern- and neural-circuit-specific mechanisms of depression.
Leptin regulates the reward value of nutrient.
We developed an assay for quantifying the reward value of nutrient and used it to analyze the effects of metabolic state and leptin. In this assay, mice chose between two sippers, one of which dispensed water and was coupled to optogenetic activation of dopaminergic (DA) neurons and the other of which dispensed natural or artificial sweeteners. This assay measured the reward value of sweeteners relative to lick-induced optogenetic activation of DA neurons. Mice preferred optogenetic stimulation of DA neurons to sucralose, but not to sucrose. However, the mice preferred sucralose plus optogenetic stimulation versus sucrose. We found that food restriction increased the value of sucrose relative to sucralose plus optogenetic stimulation, and that leptin decreased it. Our data suggest that leptin suppresses the ability of sucrose to drive taste-independent DA neuronal activation and provide new insights into the mechanism of leptin's effects on food intake.