RESUMO
Neural regulation of energy expenditure is incompletely understood. By genetically disrupting GABAergic transmission in a cell-specific fashion, and by combining this with selective pharmacogenetic activation and optogenetic mapping techniques, we have uncovered an arcuate-based circuit that selectively drives energy expenditure. Specifically, mice lacking synaptic GABA release from RIP-Cre neurons have reduced energy expenditure, become obese and are extremely sensitive to high-fat diet-induced obesity, the latter due to defective diet-induced thermogenesis. Leptin's ability to stimulate thermogenesis, but not to reduce feeding, is markedly attenuated. Acute, selective activation of arcuate GABAergic RIP-Cre neurons, which monosynaptically innervate PVH neurons projecting to the NTS, rapidly stimulates brown fat and increases energy expenditure but does not affect feeding. Importantly, this response is dependent upon GABA release from RIP-Cre neurons. Thus, GABAergic RIP-Cre neurons in the arcuate selectively drive energy expenditure, contribute to leptin's stimulatory effect on thermogenesis, and protect against diet-induced obesity.
Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Metabolismo Energético , Neurônios GABAérgicos/metabolismo , Vias Neurais , Tecido Adiposo Marrom/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/citologia , Dieta , Integrases/metabolismo , Leptina/metabolismo , Camundongos , Obesidade/metabolismo , Núcleo Hipotalâmico Paraventricular/citologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/genética , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismoRESUMO
Light plays an essential role in a variety of physiological processes, including vision, mood, and glucose homeostasis. However, the intricate relationship between light and an animal's feeding behavior has remained elusive. Here, we found that light exposure suppresses food intake, whereas darkness amplifies it in male mice. Interestingly, this phenomenon extends its reach to diurnal male Nile grass rats and healthy humans. We further show that lateral habenula (LHb) neurons in mice respond to light exposure, which in turn activates 5-HT neurons in the dorsal Raphe nucleus (DRN). Activation of the LHbâ5-HTDRN circuit in mice blunts darkness-induced hyperphagia, while inhibition of the circuit prevents light-induced anorexia. Together, we discovered a light-responsive neural circuit that relays the environmental light signals to regulate feeding behavior in mice.
Assuntos
Comportamento Alimentar , Habenula , Luz , Animais , Masculino , Camundongos , Habenula/fisiologia , Comportamento Alimentar/fisiologia , Núcleo Dorsal da Rafe/fisiologia , Humanos , Camundongos Endogâmicos C57BL , Ingestão de Alimentos/fisiologia , Vias Neurais/fisiologia , Ratos , Neurônios Serotoninérgicos/fisiologia , Rede Nervosa/fisiologia , EscuridãoRESUMO
Diosgenin, an essential dietary steroidal sapogenin, possess multiple pharmacological activities. This study aimed to assess the effects of diosgenin on periodontitis and elucidate the mechanisms. Lipopolysaccharide (LPS)-stimulated human periodontal ligament stem cells (hPDLCs) and a Porphyromonas gingivalis (P.g) plus ligation-induced animal model were used for in vitro and in vivo studies, respectively. Inflammatory responses, nuclear factor κ-B (NF-κB) signaling and osteogenesis-related markers were measured both in LPS-stimulated hPDLSCs and in gingival tissue of periodontitis rats. Treatment with diosgenin significantly inhibited the production of tumor necrosis factor α (TNF-α), interleukin (IL)-1ß, and interleukin (IL)-6 and the activation of NF-κB pathway in LPS-stimulated hPDLSCs. Further, treatment with diosgenin enhanced the expression of osteoblast-related genes and increased the osteogenic differentiation capacity. Further, activation NF-κB pathway largely abolished the protective effects of diosgenin. Consistent with the in vitro studies, in vivo studies showed that administering diosgenin to periodontitis rats significantly lowered the levels of the TNF-α, IL-1ß, and IL-6 and the inflammatory transcription factor NF-κB in gingival tissue. In addition, osteoblast-related genes were promoted. Diosgenin attenuates periodontitis by adjusting NF-κB signaling to inhibit inflammatory effects and promoting osteogenesis, suggesting diosgenin might be developed as a therapeutic strategy for treating periodontitis in the future.
RESUMO
Obesity is a serious global health problem because of its increasing prevalence and comorbidities, but its treatments are limited. The serotonin 2C receptor (5-HT2CR), a G-protein-coupled receptor, activates proopiomelanocortin (POMC) neurons in the arcuate nucleus of hypothalamus (ARH) to reduce appetite and weight gain. However, several 5-HT analogs targeting this receptor, e.g., lorcaserin (Lor), suffer from diminished efficacy to reduce weight after prolonged administration. Here, we show that barbadin (Bar), a novel ß-arrestin/ß2-adaptin inhibitor, can prevent 5-HT2CR internalization in cells and potentiate long-term effects of Lor to reduce appetite and body weight in male mice. Mechanistically, we demonstrate that Bar co-treatment can effectively maintain the sensitivity of the 5-HT2CR in POMCARH neurons, despite prolonged Lor exposure, thereby allowing these neurons to be activated through opening the transient receptor potential cation (TRPC) channels. Thus, our results prove the concept that inhibition of 5-HT2CR desensitization can be a valid strategy to improve the long-term weight loss effects of Lor or other 5-HT2CR agonists, and also provide an intellectual framework to develop effective long-term management of weight by targeting 5-HT2CR desensitization.SIGNIFICANCE STATEMENT By demonstrating that the combination of barbadin (Bar) with a G-protein-coupled receptor (GPCR) agonist can provide prolonged weight-lowering benefits in a preclinical setting, our work should call for additional efforts to validate Bar as a safe and effective medicine or to use Bar as a lead compound to develop more suitable compounds for obesity treatment. These results prove the concept that inhibition of serotonin 2C receptor (5-HT2CR) desensitization can be a valid strategy to improve the long-term weight loss effects of lorcaserin (Lor) or other 5-HT2CR agonists. Since GPCRs represent a major category as therapeutic targets for various human diseases and desensitization of GPCRs is a common issue, our work may provide a conceptual framework to enhance effects of a broad range of GPCR medicines.
Assuntos
Benzazepinas/farmacologia , Neurônios/efeitos dos fármacos , Pirimidinas/farmacologia , Receptor 5-HT2C de Serotonina/metabolismo , Redução de Peso/efeitos dos fármacos , Animais , Apetite/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pró-Opiomelanocortina/metabolismo , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , TempoRESUMO
Obesity is primarily a consequence of consuming calories beyond energetic requirements, but underpinning drivers have not been fully defined. 5-Hydroxytryptamine (5-HT) neurons in the dorsal Raphe nucleus (5-HTDRN) regulate different types of feeding behavior, such as eating to cope with hunger or for pleasure. Here, we observed that activation of 5-HTDRN to hypothalamic arcuate nucleus (5-HTDRN â ARH) projections inhibits food intake driven by hunger via actions at ARH 5-HT2C and 5-HT1B receptors, whereas activation of 5-HTDRN to ventral tegmental area (5-HTDRN â VTA) projections inhibits non-hunger-driven feeding via actions at 5-HT2C receptors. Further, hunger-driven feeding gradually activates ARH-projecting 5-HTDRN neurons via inhibiting their responsiveness to inhibitory GABAergic inputs; non-hunger-driven feeding activates VTA-projecting 5-HTDRN neurons through reducing a potassium outward current. Thus, our results support a model whereby parallel circuits modulate feeding behavior either in response to hunger or to hunger-independent cues.
Assuntos
Fome , Serotonina , Núcleo Dorsal da Rafe , Neurônios/fisiologia , Área Tegmentar Ventral/fisiologiaRESUMO
The current obesity epidemic mainly results from high-fat high-caloric diet (HFD) feeding and may also be contributed by chronic stress; however, the neural basis underlying stress-related diet-induced obesity remains unknown. Corticotropin-releasing hormone (CRH) neurons in the paraventricular hypothalamus (PVH), a known body weight-regulating region, represent one key group of stress-responsive neurons. Here, we found that HFD feeding blunted PVH CRH neuron response to nutritional challenges as well as stress stimuli and dexamethesone, which normally produce rapid activation and inhibition on these neurons, respectively. We generated mouse models with the activity of these neurons clamped at high or low levels, both of which showed HFD-mimicking, blunted PVH CRH neuron responsiveness. Strikingly, both models developed rapid HFD-induced obesity, associated with HFD-mimicking, reduced diurnal rhythmicity in feeding and energy expenditure. Thus, blunted responsiveness of PVH CRH neurons, but not their absolute activity levels, underlies HFD-induced obesity and may also contribute to stress-induced obesity.
Assuntos
Obesidade , Hormônios Liberadores de Hormônios Hipofisários , Animais , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Hipotálamo/metabolismo , Camundongos , Neurônios/metabolismo , Obesidade/etiologiaRESUMO
Atypical food intake is a primary cause of obesity and other eating and metabolic disorders. Insight into the neural control of feeding has previously focused mainly on signalling mechanisms associated with the hypothalamus, the major centre in the brain that regulates body weight homeostasis. However, roles of non-canonical central nervous system signalling mechanisms in regulating feeding behaviour have been largely uncharacterized. Acetylcholine has long been proposed to influence feeding owing in part to the functional similarity between acetylcholine and nicotine, a known appetite suppressant. Nicotine is an exogenous agonist for acetylcholine receptors, suggesting that endogenous cholinergic signalling may play a part in normal physiological regulation of feeding. However, it remains unclear how cholinergic neurons in the brain regulate food intake. Here we report that cholinergic neurons of the mouse basal forebrain potently influence food intake and body weight. Impairment of cholinergic signalling increases food intake and results in severe obesity, whereas enhanced cholinergic signalling decreases food consumption. We found that cholinergic circuits modulate appetite suppression on downstream targets in the hypothalamus. Together our data reveal the cholinergic basal forebrain as a major modulatory centre underlying feeding behaviour.
Assuntos
Regulação do Apetite/fisiologia , Prosencéfalo Basal/citologia , Prosencéfalo Basal/fisiologia , Neurônios Colinérgicos/metabolismo , Comportamento Alimentar/fisiologia , Resposta de Saciedade/fisiologia , Acetilcolina/metabolismo , Animais , Peso Corporal/fisiologia , Morte Celular , Colina O-Acetiltransferase/deficiência , Agonistas Colinérgicos , Neurônios Colinérgicos/patologia , Ingestão de Alimentos/fisiologia , Ingestão de Alimentos/psicologia , Comportamento Alimentar/psicologia , Feminino , Homeostase , Hiperfagia/enzimologia , Hiperfagia/genética , Hiperfagia/patologia , Hipotálamo/citologia , Hipotálamo/fisiologia , Masculino , Camundongos , Camundongos Knockout , Modelos Neurológicos , Nicotina/metabolismo , Obesidade/enzimologia , Obesidade/genética , Obesidade/patologia , Receptores Colinérgicos/metabolismoRESUMO
The current epidemic of obesity and its associated metabolic syndromes imposes unprecedented challenges to our society. Despite intensive research focus on obesity pathogenesis, an effective therapeutic strategy to treat and cure obesity is still lacking. The obesity development is due to a disturbed homeostatic control of feeding and energy expenditure, both of which are controlled by an intricate neural network in the brain. Given the inherent complexity of brain networks in controlling feeding and energy expenditure, the understanding of brain-based pathophysiology for obesity development is limited. One key limiting factor in dissecting neural pathways for feeding and energy expenditure is unavailability of techniques that can be used to effectively reduce the complexity of the brain network to a tractable paradigm, based on which a strong hypothesis can be tested. Excitingly, emerging techniques have been involved to be able to link specific groups of neurons and neural pathways to behaviors (i.e., feeding and energy expenditure). In this chapter, novel techniques especially those based on animal models and viral vector approaches will be discussed. We hope that this chapter will provide readers with a basis that can help to understand the literatures using these techniques and with a guide to apply these exciting techniques to investigate brain mechanisms underlying feeding and energy expenditure.
Assuntos
Metabolismo Energético , Comportamento Alimentar , Vias Neurais , Obesidade/fisiopatologia , Animais , Encéfalo/fisiopatologia , Técnicas Genéticas , Humanos , Modelos AnimaisRESUMO
Non-alcoholic fatty liver disease (NAFLD) has become a global health problem. However, there is no approved therapy for NAFLD. Farnesoid X receptor (FXR) is a potential drug target for treatment of NAFLD. In an attempt to screen FXR agonists, we found that cycloastragenol (CAG), a natural occurring compound in Astragali Radix, stimulated FXR transcription activity. In animal studies, we demonstrated that CAG treatment resulted in obvious reduction of high-fat diet induced lipid accumulation in liver accompanied by lowered blood glucose, serum triglyceride levels and hepatic bile acid pool size. The stimulation of FXR signalling by CAG treatment in DIO mice was confirmed via gene expression and western blot analysis. Molecular docking data further supported the interaction of CAG and FXR. In addition, CAG alleviated hepatic steatosis in methionine and choline deficient L-amino acid diet (MCD) induced non-alcoholic steatohepatitis (NASH) mice. Our data suggest that CAG ameliorates NAFLD via the enhancement of FXR signalling.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Citoplasmáticos e Nucleares/agonistas , Sapogeninas/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Animais , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Células Hep G2 , Humanos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Sapogeninas/farmacologiaRESUMO
The hypothalamus is critical for feeding and body weight regulation. Prevailing studies focus on hypothalamic neurons that are defined by selectively expressing transcription factors or neuropeptides including those expressing proopiomelanocortin (POMC) and agouti-related peptides (AgRP). The Cre expression driven by the pancreas-duodenum homeobox 1 promoter is abundant in several hypothalamic nuclei but not in AgRP or POMC neurons. Using this line, we generated mice with disruption of GABA release from a major subset of non-POMC, non-AgRP GABAergic neurons in the hypothalamus. These mice exhibited a reduction in postweaning feeding and growth, and disrupted hyperphagic responses to NPY. Disruption of GABA release severely diminished GABAergic input to the paraventricular hypothalamic nucleus (PVH). Furthermore, disruption of GABA-A receptor function in the PVH also reduced postweaning feeding and blunted NPY-induced hyperphagia. Given the limited knowledge on postweaning feeding, our results are significant in identifying GABA release from a major subset of less appreciated hypothalamic neurons as a key mediator for postweaning feeding and NPY hyperphagia, and the PVH as one major downstream site that contributes significantly to the GABA action. Significance statement: Prevalent studies on feeding in the hypothalamus focus on well characterized, selective groups neurons [e.g., proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons], and as a result, the role of the majority of other hypothalamic neurons is largely neglected. Here, we demonstrated an important role for GABAergic projections from non-POMC non-AgRP neurons to the paraventricular hypothalamic nucleus in promoting postweaning (mainly nocturnal) feeding and mediating NPY-induced hyperphagia. Thus, these results signify an importance to study those yet to be defined hypothalamic neurons in the regulation of energy balance and reveal a neural basis for postweaning (nocturnal) feeding and NPY-mediated hyperphagia.
Assuntos
Comportamento Alimentar/fisiologia , Neurônios GABAérgicos/fisiologia , Hiperfagia/fisiopatologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Proteína Relacionada com Agouti/biossíntese , Animais , Hipotálamo/citologia , Hipotálamo/fisiologia , Hibridização In Situ , Camundongos , Camundongos Mutantes , Neuropeptídeo Y/metabolismo , Técnicas de Cultura de Órgãos , Núcleo Hipotalâmico Paraventricular/citologia , Técnicas de Patch-Clamp , Pró-Opiomelanocortina/biossínteseRESUMO
Lesions of the lateral hypothalamus (LH) cause hypophagia. However, activation of glutamatergic neurons in LH inhibits feeding. These results suggest a potential importance for other LH neurons in stimulating feeding. Our current study in mice showed that disruption of GABA release from adult LH GABAergic neurons reduced feeding. LH GABAergic neurons project extensively to the paraventricular hypothalamic nucleus (PVH), and optogenetic stimulation of GABAergic LH â PVH fibers induced monosynaptic IPSCs in PVH neurons, and potently increased feeding, which depended on GABA release. In addition, disruption of GABA-A receptors in the PVH reduced feeding. Thus, we have identified a new feeding pathway in which GABAergic projections from the LH to the PVH promote feeding.
Assuntos
Ingestão de Alimentos/fisiologia , Neurônios GABAérgicos/fisiologia , Região Hipotalâmica Lateral/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Animais , Neurônios GABAérgicos/metabolismo , Região Hipotalâmica Lateral/citologia , Potenciais Pós-Sinápticos Inibidores , Camundongos , Vias Neurais/citologia , Vias Neurais/fisiologia , Núcleo Hipotalâmico Paraventricular/citologiaRESUMO
AIMS/HYPOTHESIS: Pan-peroxisome proliferator-activated receptor (PPAR) agonists have long been sought as therapeutics against the metabolic syndrome, but current PPAR agonists show limited efficacy and adverse effects. Natural herbs provide a structurally untapped resource to prevent and treat complicated metabolic syndrome. METHODS: Natural PPAR agonists were screened using reporter gene, competitive binding and 3T3-L1 pre-adipocyte differentiation assays in vitro. The effects on metabolic phenotypes were verified in db/db and diet-induced obese mice. In addition, potentially synergistic actions of bavachinin (BVC, a novel natural pan-PPAR agonist from the fruit of the traditional Chinese glucose-lowering herb malaytea scurfpea) and synthetic PPAR agonists were studied through nuclear magnetic resonance, molecular docking, reporter gene assays and mouse studies. RESULTS: BVC exhibited glucose-lowering properties without inducing weight gain and hepatotoxicity. Importantly, BVC synergised with thiazolidinediones, which are synthetic PPAR-γ agonists, and fibrates, which are PPAR-α agonists, to induce PPAR transcriptional activity, as well as to lower glucose and triacylglycerol levels in db/db mice. We further found that BVC occupies a novel alternative binding site in addition to the canonical site of synthetic agonists of PPAR, and that the synthetic PPAR-γ agonist rosiglitazone can block BVC binding to this canonical site but not to the alternative site. CONCLUSIONS/INTERPRETATION: This is the first report of a synergistic glucose- and lipid-lowering effect of BVC and synthetic agonists induced by unique binding with PPAR-γ or -α. This combination may improve the efficacy and decrease the toxicity of marketed drugs for use as adjunctive therapy to treat the metabolic syndrome.
Assuntos
Flavonoides/uso terapêutico , Obesidade/tratamento farmacológico , Obesidade/metabolismo , PPAR alfa/agonistas , Células 3T3-L1 , Animais , Sítios de Ligação , Glicemia/efeitos dos fármacos , Sinergismo Farmacológico , Feminino , Flavonoides/administração & dosagem , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Obesidade/sangue , PPAR gama , Tiazolidinedionas/uso terapêutico , Triglicerídeos/sangueRESUMO
BACKGROUND/AIMS: Apolipoprotein A-IV (apoA-IV) in the brain potently suppresses food intake. However, the mechanisms underlying its anorexigenic effects remain to be identified. METHODS: We first examined the effects of apoA-IV on cellular activities in hypothalamic neurons that co-express agouti-related peptide (AgRP) and neuropeptide Y (NPY) and in neurons that express pro-opiomelanocortin (POMC). We then compared anorexigenic effects of apoA-IV in wild-type mice and in mutant mice lacking melanocortin 4 receptors (MC4Rs; the receptors of AgRP and the POMC gene product). Finally, we examined expression of apoA-IV in mouse hypothalamus and quantified its protein levels at fed versus fasted states. RESULTS: We demonstrate that apoA-IV inhibited the firing rate of AgRP/NPY neurons. The decreased firing was associated with hyperpolarized membrane potential and decreased miniature excitatory postsynaptic current. We further used c-fos immunoreactivity to show that intracerebroventricular (i.c.v.) injections of apoA-IV abolished the fasting-induced activation of AgRP/NPY neurons in mice. Further, we found that apoA-IV depolarized POMC neurons and increased their firing rate. In addition, genetic deletion of MC4Rs blocked anorexigenic effects of i.c.v. apoA-IV. Finally, we detected endogenous apoA-IV in multiple neural populations in the mouse hypothalamus, including AgRP/NPY neurons, and food deprivation suppressed hypothalamic apoA-IV protein levels. CONCLUSION: Our findings support a model where central apoA-IV inhibits AgRP/NPY neurons and activates POMC neurons to activate MC4Rs, which in turn suppresses food intake.
Assuntos
Apolipoproteína A-V/farmacologia , Núcleo Arqueado do Hipotálamo/citologia , Regulação da Expressão Gênica/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismo , 6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Proteína Relacionada com Agouti/genética , Proteína Relacionada com Agouti/metabolismo , Animais , Apolipoproteína A-V/metabolismo , Bicuculina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , GABAérgicos/farmacologia , Regulação da Expressão Gênica/genética , Técnicas In Vitro , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Bloqueadores dos Canais de Sódio/farmacologia , Tetrodotoxina/farmacologia , Valina/análogos & derivados , Valina/farmacologiaRESUMO
The melanocortin receptor 4 (MC4R) plays a major role in body weight regulation and its agonist MTII has been widely used to study the role of MC4Rs in energy expenditure promotion and feeding reduction. Unexpectedly, we observed that intraperitoneal (i.p.) administration of MTII induced a rapid reduction in both body temperature and energy expenditure, which was independent of its effect on feeding and followed by a prolonged increase in energy expenditure. The rapid reduction was at least partly mediated by brain neurons since intracerebroventricular (icv) administration of alpha melanocyte-stimulating hormone, an endogenous melanocortin receptor agonist, produced a similar response. In addition, the body temperature-lowering effect of MTII was independent of the presence of MC4Rs, but in a similar fashion to the previously shown effect on body temperature by 5'AMP. Moreover, ß-adrenergic receptors (ß-ARs) were required for the recovery from low body temperature induced by MTII and further pharmacological studies showed that the MTII's effect on body temperature may be partially mediated by the vasopressin V1a receptors. Collectively, our results reveal a previously unappreciated role for the melanocortin pathway in rapidly lowering body temperature.
Assuntos
Temperatura Corporal/efeitos dos fármacos , Peptídeos Cíclicos/farmacologia , Receptor Tipo 4 de Melanocortina/agonistas , alfa-MSH/análogos & derivados , Animais , Temperatura Corporal/fisiologia , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Camundongos , Camundongos Knockout , Receptor Tipo 4 de Melanocortina/deficiência , Receptor Tipo 4 de Melanocortina/fisiologia , Receptores Adrenérgicos beta/deficiência , Receptores Adrenérgicos beta/genética , Receptores Adrenérgicos beta/fisiologia , Receptores de Vasopressinas/fisiologia , alfa-MSH/farmacologiaRESUMO
Dopaminergic (DA) neurons are known to play a key role in controlling behaviors. While DA neurons in other brain regions are extensively characterized, those in zona incerta (ZITH or A13) receive much less attention and their function remains to be defined. Here it is shown that optogenetic stimulation of these neurons elicited intensive self-grooming behaviors and promoted place preference, which can be enhanced by training but cannot be converted into contextual memory. Interestingly, the same stimulation increased DA release to periaqueductal grey (PAG) neurons and local PAG antagonism of DA action reduced the elicited self-grooming. In addition, A13 neurons increased their activity in response to various external stimuli and during natural self-grooming episodes. Finally, monosynaptic retrograde tracing showed that the paraventricular hypothalamus represents one of the major upstream brain regions to A13 neurons. Taken together, these results reveal that A13 neurons are one of the brain sites that promote appetitive self-grooming involving DA release to the PAG.
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Maladaptation in balancing internal energy needs and external threat cues may result in eating disorders. However, brain mechanisms underlying such maladaptations remain elusive. Here, we identified that the basal forebrain (BF) sends glutamatergic projections to glutamatergic neurons in the ventral tegmental area (VTA) in mice. Glutamatergic neurons in both regions displayed correlated responses to various stressors. Notably, in vivo manipulation of BF terminals in the VTA revealed that the glutamatergic BF â VTA circuit reduces appetite, increases locomotion, and elicits avoidance. Consistently, activation of VTA glutamatergic neurons reduced body weight, blunted food motivation, and caused hyperactivity with behavioral signs of anxiety, all hallmarks of typical anorexia symptoms. Importantly, activation of BF glutamatergic terminals in the VTA reduced dopamine release in the nucleus accumbens. Collectively, our results point to overactivation of the glutamatergic BF â VTA circuit as a potential cause of anorexia-like phenotypes involving reduced dopamine release.
Assuntos
Prosencéfalo Basal , Área Tegmentar Ventral , Camundongos , Animais , Área Tegmentar Ventral/fisiologia , Dopamina/fisiologia , Anorexia , Fenótipo , Neurônios Dopaminérgicos/fisiologiaRESUMO
Circadian rhythms are internal biological rhythms driving temporal tissue-specific, metabolic programs. Loss of the circadian transcription factor BMAL1 in the paraventricular nucleus (PVN) of the hypothalamus reveals its importance in metabolic rhythms, but its functions in individual PVN cells are poorly understood. Here, loss of BMAL1 in the PVN results in arrhythmicity of processes controlling energy balance and alters peripheral diurnal gene expression. BMAL1 chromatin immunoprecipitation sequencing (ChIP-seq) and single-nucleus RNA sequencing (snRNA-seq) reveal its temporal regulation of target genes, including oxytocin (OXT), and restoring circulating OXT peaks in BMAL1-PVN knockout (KO) mice rescues absent activity rhythms. While glutamatergic neurons undergo day/night changes in expression of genes involved in cell morphogenesis, astrocytes and oligodendrocytes show gene expression changes in cytoskeletal organization and oxidative phosphorylation. Collectively, our findings show diurnal gene regulation in neuronal and non-neuronal PVN cells and that BMAL1 contributes to diurnal OXT secretion, which is important for systemic diurnal rhythms.
Assuntos
Fatores de Transcrição ARNTL , Relógios Circadianos , Ritmo Circadiano , Camundongos Knockout , Neurônios , Núcleo Hipotalâmico Paraventricular , Animais , Fatores de Transcrição ARNTL/metabolismo , Fatores de Transcrição ARNTL/genética , Núcleo Hipotalâmico Paraventricular/metabolismo , Relógios Circadianos/genética , Camundongos , Neurônios/metabolismo , Ritmo Circadiano/fisiologia , Ocitocina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Regulação da Expressão Gênica , Astrócitos/metabolismo , Oligodendroglia/metabolismoRESUMO
Obesity results from excessive caloric input associated with overeating and presents a major public health challenge. The hypothalamus has received significant attention for its role in governing feeding behavior and body weight homeostasis. However, extrahypothalamic brain circuits also regulate appetite and consumption by altering sensory perception, motivation, and reward. We recently discovered a population of basal forebrain cholinergic (BFc) neurons that regulate appetite suppression. Through viral tracing methods in the mouse model, we found that BFc neurons densely innervate the basolateral amygdala (BLA), a limbic structure involved in motivated behaviors. Using channelrhodopsin-assisted circuit mapping, we identified cholinergic responses in BLA neurons following BFc circuit manipulations. Furthermore, in vivo acetylcholine sensor and genetically encoded calcium indicator imaging within the BLA (using GACh3 and GCaMP, respectively) revealed selective response patterns of activity during feeding. Finally, through optogenetic manipulations in vivo, we found that increased cholinergic signaling from the BFc to the BLA suppresses appetite and food intake. Together, these data support a model in which cholinergic signaling from the BFc to the BLA directly influences appetite and feeding behavior.
Assuntos
Prosencéfalo Basal , Complexo Nuclear Basolateral da Amígdala , Camundongos , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Prosencéfalo Basal/fisiologia , Neurônios Colinérgicos/fisiologia , Colinérgicos , Ingestão de Alimentos/fisiologiaRESUMO
Feeding behaviour is influenced by two primary factors: homoeostatic needs driven by hunger and hedonic desires for pleasure even in the absence of hunger. While efficient homoeostatic feeding is vital for survival, excessive hedonic feeding can lead to adverse consequences such as obesity and metabolic dysregulations. However, the neurobiological mechanisms that orchestrate homoeostatic versus hedonic food consumption remain largely unknown. Here we show that GABAergic proenkephalin (Penk) neurons in the diagonal band of Broca (DBB) of male mice respond to food presentation. We further demonstrate that a subset of DBBPenk neurons that project to the paraventricular nucleus of the hypothalamus are preferentially activated upon food presentation during fasting periods and transmit a positive valence to facilitate feeding. On the other hand, a separate subset of DBBPenk neurons that project to the lateral hypothalamus are preferentially activated when detecting a high-fat high-sugar (HFHS) diet and transmit a negative valence to inhibit food consumption. Notably, when given free choice of chow and HFHS diets, mice with the whole DBBPenk population ablated exhibit reduced consumption of chow but increased intake of the HFHS diet, resulting in accelerated development of obesity and metabolic disturbances. Together, we identify a molecularly defined neural population in male mice that is crucial for the maintenance of energy balance by facilitating homoeostatic feeding while suppressing hedonic overeating.
RESUMO
Obesity is a growing global health epidemic with limited effective therapeutics. Serotonin (5-HT) is one major neurotransmitter which remains an excellent target for new weight-loss therapies, but there remains a gap in knowledge on the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using a closed-loop optogenetic feeding paradigm, we showed that the 5-HTDRNâarcuate nucleus (ARH) circuit plays an important role in regulating meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HTDRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response to GABAergic inputs can be enhanced by hunger. Additionally, deletion of the GABAA receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the instrumental role of dopaminergic inputs via dopamine receptor D2 in 5-HTDRN neurons in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HTDRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, which allows for the initiation of a meal.