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1.
Diabetes Obes Metab ; 25(6): 1534-1546, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36852745

RESUMO

AIM: To clarify the effects of glucose-dependent insulinotropic polypeptide (GIP) receptor agonists (GIPRAs) on feeding and body weight. MATERIALS AND METHODS: Acute and subchronic effects of subcutaneous GIPFA-085, a long-acting GIPRA, on blood glucose, food intake, body weight, respiratory exchange ratio and plasma leptin levels were measured in diet-induced obese (DIO) mice and/or functional leptin-deficient ob/ob mice. The effects of GIPFA-085 on the hypothalamic arcuate nucleus (ARC) neurons from lean and DIO mice were studied by measuring cytosolic Ca2+ concentration ([Ca2+ ]i ). RESULTS: Single bolus GIPFA-085 (30, 300 nmol/kg) dose-dependently reduced blood glucose in glucose tolerance tests, elevated plasma leptin levels at 0.5-6 hours and inhibited food intake at 2-24 hours after injection in DIO mice. Daily GIPFA-085 (300 nmol/kg) inhibited food intake and increased fat utilization on day 1, and reduced body weight gain on days 3-12 of treatment in DIO, but not ob/ob, mice. GIPFA-085 increased [Ca2+ ]i in the ARC leptin-responsive and proopiomelanocortin (POMC) neurons. GIPFA-085 and leptin cooperated to increase [Ca2+ ]i in ARC neurons and inhibit food intake. CONCLUSIONS: GIPFA-085 acutely inhibits feeding and increases lipid utilization, and sustainedly lowers body weight in DIO mice via mechanisms involving rises in leptin and activation of ARC leptin-responsive and POMC neurons. This study highlights the therapeutic potential of GIPRAs for treating obesity and diabetes.


Assuntos
Núcleo Arqueado do Hipotálamo , Leptina , Camundongos , Animais , Leptina/metabolismo , Pró-Opiomelanocortina/metabolismo , Pró-Opiomelanocortina/farmacologia , Pró-Opiomelanocortina/uso terapêutico , Glicemia , Obesidade/tratamento farmacológico , Obesidade/etiologia , Dieta , Peso Corporal , Receptores Acoplados a Proteínas G , Neurônios/metabolismo , Camundongos Endogâmicos C57BL
2.
J Endocrinol ; 252(3): 167-177, 2022 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-34854381

RESUMO

Recent evidence identifies a potent role for aerobic exercise to modulate the activity of hypothalamic neurons related to appetite; however, these studies have been primarily performed in male rodents. Since females have markedly different neuronal mechanisms regulating food intake, the current study aimed to determine the effects of acute treadmill exercise on hypothalamic neuron populations involved in regulating appetite in female mice. Mature, untrained female mice were exposed to acute sedentary, low- (10 m/min), moderate- (14 m/min), and high (18 m/min)-intensity treadmill exercise in a randomized crossover design. Mice were fasted 10 h before exercise, and food intake was monitored for 48 h after bouts. Immunohistochemical detection of cFOS was performed 3 h post-exercise to determine the changes in hypothalamic neuropeptide Y (NPY)/agouti-related peptide (AgRP), pro-opiomelanocortin (POMC), tyrosine hydroxylase (TH), and SIM1-expressing neuron activity concurrent with the changes in food intake. Additionally, stains for pSTAT3tyr705 and pERKthr202/tyr204 were performed to detect exercise-mediated changes in intracellular signaling. Briefly, moderate- and high-intensity exercises increased 24-h food intake by 5.9 and 19%, respectively, while low-intensity exercise had no effects. Furthermore, increases in NPY/AgRPARC, SIM1PVN, and TH neuron activity were observed 3 h after high-intensity exercise, with no effects on POMCARC neurons. While no effects of exercise on pERKthr202/tyr204 were observed, pSTAT3tyr705 was elevated specifically in NPY/AgRP neurons 3 h post-exercise. Overall, aerobic exercise increased the activity of several appetite-stimulating neuron populations in the hypothalamus of female mice, which may provide insight into previously reported sexual dimorphisms in post-exercise feeding.


Assuntos
Proteína Relacionada com Agouti/metabolismo , Hipotálamo/metabolismo , Neuropeptídeo Y/metabolismo , Condicionamento Físico Animal/fisiologia , Tirosina 3-Mono-Oxigenase/metabolismo , Animais , Feminino , Camundongos , Neurônios/enzimologia
3.
Cell Rep ; 37(2): 109800, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34644574

RESUMO

Hypothalamic pro-opiomelanocortin (POMC) neurons are known to trigger satiety. However, these neuronal cells encompass heterogeneous subpopulations that release γ-aminobutyric acid (GABA), glutamate, or both neurotransmitters, whose functions are poorly defined. Using conditional mutagenesis and chemogenetics, we show that blockade of the energy sensor mechanistic target of rapamycin complex 1 (mTORC1) in POMC neurons causes hyperphagia by mimicking a cellular negative energy state. This is associated with decreased POMC-derived anorexigenic α-melanocyte-stimulating hormone and recruitment of POMC/GABAergic neurotransmission, which is restrained by cannabinoid type 1 receptor signaling. Electrophysiology and optogenetic studies further reveal that pharmacological blockade of mTORC1 simultaneously activates POMC/GABAergic neurons and inhibits POMC/glutamatergic ones, implying that the functional specificity of these subpopulations relies on mTORC1 activity. Finally, POMC neurons with different neurotransmitter profiles possess specific molecular signatures and spatial distribution. Altogether, these findings suggest that mTORC1 orchestrates the activity of distinct POMC neurons subpopulations to regulate feeding behavior.


Assuntos
Regulação do Apetite , Comportamento Alimentar , Neurônios GABAérgicos/metabolismo , Ácido Glutâmico/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Inibição Neural , Núcleo Hipotalâmico Paraventricular/metabolismo , Pró-Opiomelanocortina/metabolismo , Animais , Masculino , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Pró-Opiomelanocortina/genética , Transdução de Sinais
4.
Front Endocrinol (Lausanne) ; 12: 705267, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220725

RESUMO

Emerging evidence identifies a potent role for aerobic exercise to modulate activity of neurons involved in regulating appetite; however, these studies produce conflicting results. These discrepancies may be, in part, due to methodological differences, including differences in exercise intensity and pre-exercise energy status. Consequently, the current study utilized a translational, well-controlled, within-subject, treadmill exercise protocol to investigate the differential effects of energy status and exercise intensity on post-exercise feeding behavior and appetite-controlling neurons in the hypothalamus. Mature, untrained male mice were exposed to acute sedentary, low (10m/min), moderate (14m/min), and high (18m/min) intensity treadmill exercise in a randomized crossover design. Fed and 10-hour-fasted mice were used, and food intake was monitored 48h. post-exercise. Immunohistochemical detection of cFOS was performed 1-hour post-exercise to determine changes in hypothalamic NPY/AgRP, POMC, tyrosine hydroxylase, and SIM1-expressing neuron activity concurrent with changes in food intake. Additionally, stains for pSTAT3tyr705 and pERKthr202/tyr204 were performed to detect exercise-mediated changes in intracellular signaling. Results demonstrated that fasted high intensity exercise suppressed food intake compared to sedentary trials, which was concurrent with increased anorexigenic POMC neuron activity. Conversely, fed mice experienced augmented post-exercise food intake, with no effects on POMC neuron activity. Regardless of pre-exercise energy status, tyrosine hydroxylase and SIM1 neuron activity in the paraventricular nucleus was elevated, as well as NPY/AgRP neuron activity in the arcuate nucleus. Notably, these neuronal changes were independent from changes in pSTAT3tyr705 and pERKthr202/tyr204 signaling. Overall, these results suggest fasted high intensity exercise may be beneficial for suppressing food intake, possibly due to hypothalamic POMC neuron excitation. Furthermore, this study identifies a novel role for pre-exercise energy status to differentially modify post-exercise feeding behavior and hypothalamic neuron activity, which may explain the inconsistent results from studies investigating exercise as a weight loss intervention.


Assuntos
Núcleo Arqueado do Hipotálamo/fisiologia , Metabolismo Energético , Comportamento Alimentar , Neurônios/fisiologia , Condicionamento Físico Animal , Pró-Opiomelanocortina/metabolismo , Animais , Hipotálamo/fisiologia , Masculino , Camundongos , Transdução de Sinais
5.
Int J Mol Sci ; 22(7)2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810547

RESUMO

The hypothalamic regulation of appetite governs whole-body energy balance. Satiety is regulated by endocrine factors including leptin, and impaired leptin signaling is associated with obesity. Despite the anorectic effect of leptin through the regulation of the hypothalamic feeding circuit, a distinct downstream mediator of leptin signaling in neuron remains unclear. Angiopoietin-like growth factor (AGF) is a peripheral activator of energy expenditure and antagonizes obesity. However, the regulation of AGF expression in brain and localization to mediate anorectic signaling is unknown. Here, we demonstrated that AGF is expressed in proopiomelanocortin (POMC)-expressing neurons located in the arcuate nucleus (ARC) of the hypothalamus. Unlike other brain regions, hypothalamic AGF expression is stimulated by leptin-induced signal transducers and activators of transcription 3 (STAT3) phosphorylation. In addition, leptin treatment to hypothalamic N1 cells significantly enhanced the promoter activity of AGF. This induction was abolished by the pretreatment of ruxolitinib, a leptin signaling inhibitor. These results indicate that hypothalamic AGF expression is induced by leptin and colocalized to POMC neurons.


Assuntos
Proteínas Semelhantes a Angiopoietina/genética , Proteínas Semelhantes a Angiopoietina/metabolismo , Hipotálamo/metabolismo , Leptina/metabolismo , Transdução de Sinais , Proteína 6 Semelhante a Angiopoietina , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Encéfalo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Fosforilação , Pró-Opiomelanocortina/metabolismo , Fator de Transcrição STAT3/metabolismo
6.
Mol Metab ; 44: 101136, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33301986

RESUMO

OBJECTIVE: Our laboratory recently identified the centrally circulating α-klotho protein as a novel hypothalamic regulator of food intake and glucose metabolism in mice. The current study aimed to investigate novel molecular effectors of central α-klotho in the arcuate nucleus of the hypothalamus (ARC), while further deciphering its role regulating energy balance in both humans and mice. METHODS: Cerebrospinal fluid (CSF) was collected from 22 adults undergoing lower limb orthopedic surgeries, and correlations between body weight and α-klotho were determined using an α-klotho enzyme-linked immunosorbent assay (ELISA) kit. To investigate the effects of α-klotho on energy expenditure (EE), 2-day intracerebroventricular (ICV) treatment was performed in diet-induced obesity (DIO) mice housed in TSE Phenomaster indirect calorimetry metabolic cages. Immunohistochemical staining for cFOS and patch clamp electrophysiology were used to determine the effects of central α-klotho on proopiomelanocortin (POMC) and tyrosine hydroxylase (TH) neurons. Additional stainings were performed to determine novel roles for central α-klotho to regulate non-neuronal cell populations in the ARC. Lastly, ICV pretreatment with fibroblast growth factor receptor (FGFR) or PI3kinase inhibitors was performed to determine the intracellular signaling involved in α-klotho-mediated regulation of ARC nuclei. RESULTS: Obese/overweight human subjects had significantly lower CSF α-klotho concentrations compared to lean counterparts (1,044 ± 251 vs. 1616 ± 218 pmol/L, respectively). Additionally, 2 days of ICV α-klotho treatment increased EE in DIO mice. α-Klotho had no effects on TH neuron activity but elicited varied responses in POMC neurons, with 44% experiencing excitatory and 56% experiencing inhibitory effects. Inhibitor experiments identified an α-klotho→FGFR→PI3kinase signaling mechanism in the regulation of ARC POMC and NPY/AgRP neurons. Acute ICV α-klotho treatment also increased phosphorylated ERK in ARC astrocytes via FGFR signaling. CONCLUSION: Our human CSF data provide the first evidence that impaired central α-klotho function may be involved in the pathophysiology of obesity. Furthermore, results in mouse models identify ARC POMC neurons and astrocytes as novel molecular effectors of central α-klotho. Overall, the current study highlights prominent roles of α-klotho→FGFR→PI3kinase signaling in the homeostatic regulation of ARC neurons and whole-body energy balance.


Assuntos
Glucuronidase/metabolismo , Neurônios/metabolismo , Obesidade/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Peso Corporal , China , Metabolismo Energético/fisiologia , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Hipotálamo/metabolismo , Proteínas Klotho , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Pessoa de Meia-Idade , Pró-Opiomelanocortina/metabolismo , Transdução de Sinais/fisiologia , Adulto Jovem
7.
J Hazard Mater ; 402: 123926, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33254826

RESUMO

Bisphenol A (BPA), an environmental endocrine-disrupting compound, has been revealed associated with metabolic disorders such as obesity, prediabetes, and type 2 diabetes (T2D). However, its underlying mechanisms are still not fully understood. Here, we provide new evidence that BPA is a risk factor for T2D from a case-control study. To explore the detailed mechanisms, we used two types of diet models, standard diet (SD) and high-fat diet (HFD), to study the effects of long-term BPA exposure on prediabetes in 4-week-old mice. We found that BPA exposure for 12 weeks exacerbated HFD-induced prediabetic symptoms. Female mice showed increased body mass, serum insulin level, and impaired glucose tolerance, while male mice only exhibited impaired glucose tolerance. No change was found in SD-fed mice. Besides, BPA exposure enhanced astrocyte-dependent hypothalamic inflammation in both male and female mice, which impaired proopiomelanocortin (POMC) neuron functions. Moreover, eliminating inflammation by toll-like receptor 4 (TLR4) knockout significantly abolished the effects of BPA on the hypothalamus and diet-induced prediabetes. Taken together, our data establish a key role for TLR4-dependent hypothalamic inflammation in regulating the effects of BPA on prediabetes.


Assuntos
Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Animais , Compostos Benzidrílicos/toxicidade , Estudos de Casos e Controles , Feminino , Hipotálamo/metabolismo , Inflamação/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fenóis , Estado Pré-Diabético/induzido quimicamente , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
8.
Proc Natl Acad Sci U S A ; 117(33): 20149-20158, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32747560

RESUMO

The C2 domain containing protein extended synaptotagmin (E-Syt) plays important roles in both lipid homeostasis and the intracellular signaling; however, its role in physiology remains largely unknown. Here, we show that hypothalamic E-Syt3 plays a critical role in diet-induced obesity (DIO). E-Syt3 is characteristically expressed in the hypothalamic nuclei. Whole-body or proopiomelanocortin (POMC) neuron-specific ablation of E-Syt3 ameliorated DIO and related comorbidities, including glucose intolerance and dyslipidemia. Conversely, overexpression of E-Syt3 in the arcuate nucleus moderately promoted food intake and impaired energy expenditure, leading to increased weight gain. Mechanistically, E-Syt3 ablation led to increased processing of POMC to α-melanocyte-stimulating hormone (α-MSH), increased activities of protein kinase C and activator protein-1, and enhanced expression of prohormone convertases. These findings reveal a previously unappreciated role for hypothalamic E-Syt3 in DIO and related metabolic disorders.


Assuntos
Regulação da Expressão Gênica/fisiologia , Obesidade/induzido quimicamente , Obesidade/genética , Sinaptotagminas/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Predisposição Genética para Doença , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Pró-Proteína Convertase 1/genética , Pró-Proteína Convertase 1/metabolismo , Pró-Proteína Convertase 2/genética , Pró-Proteína Convertase 2/metabolismo , Sinaptotagminas/genética
9.
Adv Nutr ; 11(6): 1489-1509, 2020 11 16.
Artigo em Inglês | MEDLINE | ID: mdl-32623461

RESUMO

Although excessive consumption of deep-fried foods is regarded as 1 of the most important epidemiological factors of lifestyle diseases such as Alzheimer's disease, type 2 diabetes, and obesity, the exact mechanism remains unknown. This review aims to discuss whether heated cooking oil-derived peroxidation products cause cell degeneration/death for the occurrence of lifestyle diseases. Deep-fried foods cooked in ω-6 PUFA-rich vegetable oils such as rapeseed (canola), soybean, sunflower, and corn oils, already contain or intrinsically generate "hydroxynonenal" by peroxidation. As demonstrated previously, hydroxynonenal promotes carbonylation of heat-shock protein 70.1 (Hsp70.1), with the resultant impaired ability of cells to recycle damaged proteins and stabilize the lysosomal membrane. Until now, the implication of lysosomal/autophagy failure due to the daily consumption of ω-6 PUFA-rich vegetable oils in the progression of cell degeneration/death has not been reported. Since the "calpain-cathepsin hypothesis" was formulated as a cause of ischemic neuronal death in 1998, its relevance to Alzheimer's neuronal death has been suggested with particular attention to hydroxynonenal. However, its relevance to cell death of the hypothalamus, liver, and pancreas, especially related to appetite/energy control, is unknown. The hypothalamus senses information from both adipocyte-derived leptin and circulating free fatty acids. Concentrations of circulating fatty acid and its oxidized form, especially hydroxynonenal, are increased in obese and/or aged subjects. As overactivation of the fatty acid receptor G-protein coupled receptor 40 (GPR40) in response to excessive or oxidized fatty acids in these subjects may lead to the disruption of Ca2+ homeostasis, it should be evaluated whether GPR40 overactivation contributes to diverse cell death. Here, we describe the molecular implication of ω-6 PUFA-rich vegetable oil-derived hydroxynonenal in lysosomal destabilization leading to cell death. By oxidizing Hsp70.1, both the dietary PUFA- (exogenous) and the membrane phospholipid- (intrinsic) peroxidation product "hydroxynonenal," when combined, may play crucial roles in the occurrence of diverse lifestyle diseases including Alzheimer's disease.


Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Óleos de Plantas , Ácidos Graxos Ômega-3 , Ácidos Graxos Ômega-6 , Humanos , Estilo de Vida , Fatores de Risco
10.
Mol Metab ; 36: 100963, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32283518

RESUMO

OBJECTIVE: Maternal unbalanced nutritional habits during embryonic development and perinatal stages perturb hypothalamic neuronal programming of the offspring, thus increasing obesity-associated diabetes risk. However, the underlying molecular mechanisms remain largely unknown. In this study we sought to determine the translatomic signatures associated with pro-opiomelanocortin (POMC) neuron malprogramming in maternal obesogenic conditions. METHODS: We used the RiboTag mouse model to specifically profile the translatome of POMC neurons during neonatal (P0) and perinatal (P21) life and its neuroanatomical, functional, and physiological consequences. RESULTS: Maternal high-fat diet (HFD) exposure did not interfere with offspring's hypothalamic POMC neuron specification, but significantly impaired their spatial distribution and axonal extension to target areas. Importantly, we established POMC neuron-specific translatome signatures accounting for aberrant neuronal development and axonal growth. These anatomical and molecular alterations caused metabolic dysfunction in early life and adulthood. CONCLUSIONS: Our study provides fundamental insights on the molecular mechanisms underlying POMC neuron malprogramming in obesogenic contexts.


Assuntos
Obesidade/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Pró-Opiomelanocortina/metabolismo , Animais , DNA/genética , Metilação de DNA , Dieta Hiperlipídica , Feminino , Estudo de Associação Genômica Ampla , Hipotálamo/metabolismo , Masculino , Camundongos , Neurogênese/genética , Neurônios/metabolismo , Obesidade/metabolismo , Gravidez/genética , Gravidez/metabolismo , Pró-Opiomelanocortina/fisiologia
11.
Exp Cell Res ; 389(1): 111848, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31954693

RESUMO

Loss of neuron homeostasis in the arcuate nucleus (ARC) is responsible for diet-induced-obesity (DIO). We previously reported that loss of Rb1 gene compromised the homeostasis of anorexigenic POMC neurons in ARC and induced obesity in mice. To evaluate the development of DIO, we propose to analyze the transcriptomic alteration of POMC neurons in mice following high fat diet (HFD) feeding. We isolated these neurons from established DIO mice and performed transcriptomic profiling using RNA-seq. In total, 1066 genes (628 upregulated and 438 downregulated) were identified as differentially expressed genes (DEGs). Pathway enrichment analysis with these DEGs further revealed that "cell cycle," "apoptosis," "chemokine signaling," and "sphingolipid metabolism" pathways were correlated with DIO development. Moreover, we validated that the pRb protein, a key regulator of "cell cycle pathway," was inactivated by phosphorylation in POMC neurons by HFD feeding. Importantly, the reversal of deregulated cell cycle by stereotaxic delivering of the unphosphorylated pRbΔP in ARC significantly meliorated the DIO. Collectively, our study provides insights into the mechanisms related to the loss of homeostasis of POMC neurons in DIO, and suggests pRb phosphorylation as a potential intervention target to treat DIO.


Assuntos
Dieta Hiperlipídica , Neurônios/metabolismo , Obesidade/genética , Pró-Opiomelanocortina/metabolismo , Transcriptoma , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/patologia , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Obesos , Camundongos Transgênicos , Neurônios/patologia , Obesidade/etiologia , Obesidade/patologia , Pró-Opiomelanocortina/genética
12.
Mol Neurobiol ; 57(2): 896-909, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31578706

RESUMO

Feeding behavior regulation is a complex process, which depends on the central integration of different signals, such as glucose, leptin, and ghrelin. Recent studies have shown that glial cells known as tanycytes that border the basal third ventricle (3V) detect glucose and then use glucose-derived signaling to inform energy status to arcuate nucleus (ARC) neurons to regulate feeding behavior. Monocarboxylate transporters (MCT) 1 and MCT4 are localized in the cellular processes of tanycytes, which could facilitate monocarboxylate release to orexigenic and anorexigenic neurons. We hypothesize that MCT1 and MCT4 inhibitions could alter the metabolic communication between tanycytes and ARC neurons, affecting feeding behavior. We have previously shown that MCT1 knockdown rats eat more and exhibit altered satiety parameters. Here, we generate MCT4 knockdown rats and MCT1-MCT4 double knockdown rats using adenovirus-mediated transduction of a shRNA into the 3V. Feeding behavior was evaluated in MCT4 and double knockdown animals, and neuropeptide expression in response to intracerebroventricular glucose administration was measured. MCT4 inhibition produced a decrease in food intake, contrary to double knockdown. MCT4 inhibition was accompanied by a decrease in eating rate and mean meal size and an increase in mean meal duration, parameters that are not changed in the double knockdown animals with exception of eating rate. Finally, we observed a loss in glucose regulation of orexigenic neuropeptides and abnormal expression of anorexigenic neuropeptides in response to fasting when these transporters are inhibited. Taken together, these results indicate that MCT1 and MCT4 expressions in tanycytes play a role in feeding behavior regulation.


Assuntos
Ingestão de Alimentos/fisiologia , Comportamento Alimentar/fisiologia , Hipotálamo/metabolismo , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/metabolismo , Simportadores/metabolismo , Animais , Regulação do Apetite/fisiologia , Jejum/fisiologia , Neuroglia/metabolismo , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Ratos , Ratos Sprague-Dawley
13.
Adv Exp Med Biol ; 1090: 183-198, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30390291

RESUMO

In organism, energy homeostasis is a biological process that involves the coordinated homeostatic regulation of energy intake (food intake) and energy expenditure. The human brain, particularly the hypothalamic proopiomelanocortin (POMC)- and agouti-related protein/neuropeptide Y (AgRP/NPY)-expressing neurons in the arcuate nucleus, plays an essential role in regulating energy homeostasis. The regulation process is mainly dependent upon peripheral hormones such as leptin and insulin, as well as nutrients such as glucose, amino acids, and fatty acids. Although many studies have attempted to illustrate the exact mechanisms of glucose and hormones action on these neurons, we still cannot clearly see the full picture of this regulation action. Therefore, in this review we will mainly discuss those established theories and recent progresses in this area, demonstrating the possible physiological mechanism by which glucose, leptin, and insulin affect neuronal excitability of POMC and AgRP neurons. In addition, we will also focus on some important ion channels which are expressed by POMC and AgRP neurons, such as KATP channels and TRPC channels, and explain how these channels are regulated by peripheral hormones and nutrients and thus regulate energy homeostasis.


Assuntos
Fenômenos Eletrofisiológicos , Metabolismo Energético , Neurônios/fisiologia , Nutrientes , Proteína Relacionada com Agouti/fisiologia , Núcleo Arqueado do Hipotálamo/citologia , Glucose/fisiologia , Homeostase , Humanos , Insulina/fisiologia , Leptina/fisiologia , Neuropeptídeo Y/fisiologia , Pró-Opiomelanocortina/fisiologia
14.
Cell Rep ; 25(2): 278-287.e4, 2018 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-30304668

RESUMO

Leptin acts on hypothalamic pro-opiomelanocortin (POMC) neurons to regulate glucose homeostasis, but the precise mechanisms remain unclear. Here, we demonstrate that leptin-induced depolarization of POMC neurons is associated with the augmentation of a voltage-gated calcium (CaV) conductance with the properties of the "R-type" channel. Knockdown of the pore-forming subunit of the R-type (CaV2.3 or Cacna1e) conductance in hypothalamic POMC neurons prevented sustained leptin-induced depolarization. In vivo POMC-specific Cacna1e knockdown increased hepatic glucose production and insulin resistance, while body weight, feeding, or leptin-induced suppression of food intake were not changed. These findings link Cacna1e function to leptin-mediated POMC neuron excitability and glucose homeostasis and may provide a target for the treatment of diabetes.


Assuntos
Canais de Cálcio Tipo R/metabolismo , Cálcio/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Glucose/metabolismo , Leptina/farmacologia , Fígado/metabolismo , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismo , Animais , Canais de Cálcio Tipo R/genética , Proteínas de Transporte de Cátions/genética , Células Cultivadas , Homeostase , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/efeitos dos fármacos
15.
Cell Rep ; 23(6): 1728-1741, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29742429

RESUMO

Anorexigenic pro-opiomelanocortin (Pomc)/alpha-melanocyte stimulating hormone (αMSH) neurons of the hypothalamic melanocortin system function as key regulators of energy homeostasis, also controlling somatic growth across different species. However, the mechanisms of melanocortin-dependent growth control still remain ill-defined. Here, we reveal a thus-far-unrecognized structural and functional connection between Pomc neurons and the somatotropic hypothalamo-pituitary axis. Excessive feeding of larval zebrafish causes leptin resistance and reduced levels of the hypothalamic satiety mediator pomca. In turn, this leads to reduced activation of hypophysiotropic somatostatin (Sst)-neurons that express the melanocortin receptor Mc4r, elevated growth hormone (GH) expression in the pituitary, and enhanced somatic growth. Mc4r expression and αMSH responsiveness are conserved in Sst-expressing hypothalamic neurons of mice. Thus, acquired leptin resistance and attenuation of pomca transcription in response to excessive caloric intake may represent an ancient mechanism to promote somatic growth when food resources are plentiful.


Assuntos
Dieta , Hormônio do Crescimento/metabolismo , Crescimento e Desenvolvimento/efeitos dos fármacos , Leptina/farmacologia , Pró-Opiomelanocortina/metabolismo , Somatostatina/metabolismo , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Humanos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Larva/efeitos dos fármacos , Larva/fisiologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibição Neural/efeitos dos fármacos , Adeno-Hipófise/efeitos dos fármacos , Adeno-Hipófise/metabolismo , Peixe-Zebra , alfa-MSH/metabolismo
16.
Neurochem Res ; 43(4): 821-837, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29397535

RESUMO

The pro-opiomelanocortin (POMC)-expressing neurons of the hypothalamic arcuate nucleus (ARC) are involved in the control of food intake and metabolic processes. It is assumed that, in addition to leptin, the activity of these neurons is regulated by serotonin and dopamine, but only subtype 2C serotonin receptors (5-HT2CR) was identified earlier on the POMC-neurons. The aim of this work was a comparative study of the localization and number of leptin receptors (LepR), types 1 and 2 dopamine receptors (D1R, D2R), 5-HT1BR and 5-HT2CR on the POMC-neurons and the expression of the genes encoding them in the ARC of the normal and diet-induced obese (DIO) rodents and the agouti mice (A y /a) with the melanocortin obesity. As shown by immunohistochemistry (IHC), all the studied receptors were located on the POMC-immunopositive neurons, and their IHC-content was in agreement with the expression of their genes. In DIO rats the number of D1R and D2R in the POMC-neurons and their expression in the ARC were reduced. In DIO mice the number of D1R and D2R did not change, while the number of LepR and 5-HT2CR was increased, although to a small extent. In the POMC-neurons of agouti mice the number of LepR, D2R, 5-HT1BR and 5-HT2CR was increased, and the D1R number was reduced. Thus, our data demonstrates for the first time the localization of different types of the serotonin and dopamine receptors on the POMC-neurons and a specific pattern of the changes of their number and expression in the DIO and melanocortin obesity.


Assuntos
Hipotálamo/metabolismo , Obesidade/metabolismo , Pró-Opiomelanocortina/biossíntese , Receptores Dopaminérgicos/biossíntese , Receptores para Leptina/biossíntese , Receptores de Serotonina/biossíntese , Animais , Feminino , Hipotálamo/química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/química , Neurônios/metabolismo , Pró-Opiomelanocortina/análise , Ratos , Ratos Wistar , Receptores Dopaminérgicos/análise , Receptores para Leptina/análise , Receptores de Serotonina/análise , Roedores
17.
Elife ; 62017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28762947

RESUMO

Satiety-signaling, pro-opiomelanocortin (POMC)-expressing neurons in the arcuate nucleus of the hypothalamus play a pivotal role in the regulation of energy homeostasis. Recent studies reported altered mitochondrial dynamics and decreased mitochondria- endoplasmic reticulum contacts in POMC neurons during diet-induced obesity. Since mitochondria play a crucial role in Ca2+ signaling, we investigated whether obesity alters Ca2+ handling of these neurons in mice. In diet-induced obesity, cellular Ca2+ handling properties including mitochondrial Ca2+ uptake capacity are impaired, and an increased resting level of free intracellular Ca2+ is accompanied by a marked decrease in neuronal excitability. Experimentally increasing or decreasing intracellular Ca2+ concentrations reproduced electrophysiological properties observed in diet-induced obesity. Taken together, we provide the first direct evidence for a diet-dependent deterioration of Ca2+ homeostasis in POMC neurons during obesity development resulting in impaired function of these critical energy homeostasis-regulating neurons.


Assuntos
Potenciais de Ação , Núcleo Arqueado do Hipotálamo/fisiologia , Cálcio/metabolismo , Homeostase , Mitocôndrias/metabolismo , Neurônios/fisiologia , Animais , Dieta , Metabolismo Energético , Camundongos , Neurônios/química , Obesidade , Pró-Opiomelanocortina/análise
18.
Elife ; 62017 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-28632132

RESUMO

In the arcuate nucleus of the hypothalamus (ARH) satiety signaling (anorexigenic) pro-opiomelanocortin (POMC)-expressing and hunger signaling (orexigenic) agouti-related peptide (AgRP)-expressing neurons are key components of the neuronal circuits that control food intake and energy homeostasis. Here, we assessed whether the catecholamine noradrenalin directly modulates the activity of these neurons in mice. Perforated patch clamp recordings showed that noradrenalin changes the activity of these functionally antagonistic neurons in opposite ways, increasing the activity of the orexigenic NPY/AgRP neurons and decreasing the activity of the anorexigenic POMC neurons. Cell type-specific transcriptomics and pharmacological experiments revealed that the opposing effect on these neurons is mediated by the activation of excitatory α1A - and ß- adrenergic receptors in NPY/AgRP neurons, while POMC neurons are inhibited via α2A - adrenergic receptors. Thus, the coordinated differential modulation of the key hypothalamic neurons in control of energy homeostasis assigns noradrenalin an important role to promote feeding.


Assuntos
Proteína Relacionada com Agouti/metabolismo , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Norepinefrina/metabolismo , Pró-Opiomelanocortina/metabolismo , Animais , Perfilação da Expressão Gênica , Camundongos , Técnicas de Patch-Clamp
19.
J Neurosci ; 35(38): 13171-82, 2015 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-26400946

RESUMO

It remains largely unknown whether and how hunger states control activity-dependent synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). We here report that both LTP and LTD of excitatory synaptic strength within the appetite control circuits residing in hypothalamic arcuate nucleus (ARC) behave in a manner of hunger states dependence and cell type specificity. For instance, we find that tetanic stimulation induces LTP at orexigenic agouti-related protein (AgRP) neurons in ad libitum fed mice, whereas it induces LTD in food-deprived mice. In an opposite direction, the same induction protocol induces LTD at anorexigenic pro-opiomelanocortin (POMC) neurons in fed mice but weak LTP in deprived mice. Mechanistically, we also find that food deprivation increases the expressions of NR2C/NR2D/NR3-containing NMDA receptors (NMDARs) at AgRP neurons that contribute to the inductions of LTD, whereas it decreases their expressions at POMC neurons. Collectively, our data reveal that hunger states control the directions of activity-dependent synaptic plasticity by switching NMDA receptor subpopulations in a cell type-specific manner, providing insights into NMDAR-mediated interactions between energy states and associative memory. Significance statement: Based on the experiments performed in this study, we demonstrate that activity-dependent synaptic plasticity is also under the control of energy states by regulating NMDAR subpopulations in a cell type-specific manner. We thus propose a reversible memory configuration constructed from energy states-dependent cell type-specific bidirectional conversions of LTP and LTD. Together with the distinct functional roles played by NMDAR signaling in the control of food intake and energy states, these findings reveal a new reciprocal interaction between energy states and associative memory, one that might serve as a target for therapeutic treatments of the energy-related memory disorders or vice versa.


Assuntos
Núcleo Arqueado do Hipotálamo/citologia , Fome , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Complexo Relacionado com a AIDS/metabolismo , Proteína Relacionada com Agouti/metabolismo , Animais , Compostos de Diazônio/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas In Vitro , Camundongos , Camundongos Transgênicos , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/classificação , Neurônios/efeitos dos fármacos , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Piridinas/farmacologia , Transcriptoma , Valina/análogos & derivados , Valina/farmacologia , Zinco/farmacologia
20.
Mol Metab ; 4(6): 471-82, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26042201

RESUMO

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is a potent regulator of neuronal development, and the Bdnf gene produces two populations of transcripts with either a short or long 3' untranslated region (3' UTR). Deficiencies in BDNF signaling have been shown to cause severe obesity in humans; however, it remains unknown how BDNF signaling impacts the organization of neuronal circuits that control energy balance. METHODS: We examined the role of BDNF on survival, axonal projections, and synaptic inputs of neurons in the arcuate nucleus (ARH), a structure critical for the control of energy balance, using Bdnf (klox/klox) mice, which lack long 3' UTR Bdnf mRNA and develop severe hyperphagic obesity. RESULTS: We found that a small fraction of neurons that express the receptor for BDNF, TrkB, also expressed proopiomelanocortin (POMC) or neuropeptide Y (NPY)/agouti-related protein (AgRP) in the ARH. Bdnf(klox/klox) mice had normal numbers of POMC, NPY, and TrkB neurons in the ARH; however, retrograde labeling revealed a drastic reduction in the number of ARH axons that project to the paraventricular hypothalamus (PVH) in these mice. In addition, fewer POMC and AgRP axons were found in the dorsomedial hypothalamic nucleus (DMH) and the lateral part of PVH, respectively, in Bdnf (klox/klox) mice. Using immunohistochemistry, we examined the impact of BDNF deficiency on inputs to ARH neurons. We found that excitatory inputs onto POMC and NPY neurons were increased and decreased, respectively, in Bdnf (klox/klox) mice, likely due to a compensatory response to marked hyperphagia displayed by the mutant mice. CONCLUSION: This study shows that the majority of TrkB neurons in the ARH are distinct from known neuronal populations and that BDNF plays a critical role in directing projections from these neurons to the DMH and PVH. We propose that hyperphagic obesity due to BDNF deficiency is in part attributable to impaired axonal growth of TrkB-expressing ARH neurons.

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