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1.
Endocrinology ; 159(11): 3605-3614, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30204871

RESUMO

Metabolic feedback from the periphery to the brain results from a dynamic physiologic fluctuation of nutrients and hormones, including glucose and fatty acids, ghrelin, leptin, and insulin. The specific interactions between humoral factors and how they influence feeding is largely unknown. We hypothesized that acute glucose availability may alter how the brain responds to ghrelin, a hormonal signal of energy availability. Acute glucose administration suppressed a range of ghrelin-induced behaviors as well as gene expression changes in hypothalamic neuropeptide Y (NPY) and agouti-related peptide (AgRP) neurons after ghrelin administration. Knockdown of the energy-sensing molecule AMP-activated protein kinase (AMPK) in AgRP neurons resulted in loss of the glucose effect, and mice responded as though pretreated with saline. Conversely, 2-deoxyglucose (2-DG), which decreases glucose availability, potentiated ghrelin-induced feeding and increased hypothalamic NPY mRNA levels. AMPK knockdown did not alter the additive effect of 2-DG and ghrelin on feeding. Our findings support the idea that computation of energy status is dynamic, is informed by multiple signals, and responds to acute fluctuations in metabolic state. These observations are broadly relevant to the investigation of neuroendocrine control of feeding and highlight the underappreciated complexity of control within these systems.


Assuntos
Proteína Relacionada com Agouti/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Grelina/farmacologia , Glucose/farmacologia , Neurônios/efeitos dos fármacos , Neuropeptídeo Y/efeitos dos fármacos , RNA Mensageiro/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/metabolismo , Proteína Relacionada com Agouti/genética , Animais , Antimetabólitos/farmacologia , Núcleo Arqueado do Hipotálamo/citologia , Núcleo Arqueado do Hipotálamo/metabolismo , Desoxiglucose/farmacologia , Técnicas de Silenciamento de Genes , Hipotálamo/citologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Neurônios/metabolismo , Neuropeptídeo Y/genética , RNA Mensageiro/metabolismo
2.
Diabetes ; 66(2): 314-324, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27899482

RESUMO

The mediobasal hypothalamus (MBH) contains neurons capable of directly detecting metabolic signals such as glucose to control energy homeostasis. Among them, glucose-excited (GE) neurons increase their electrical activity when glucose rises. In view of previous work, we hypothesized that transient receptor potential canonical type 3 (TRPC3) channels are involved in hypothalamic glucose detection and the control of energy homeostasis. To investigate the role of TRPC3, we used constitutive and conditional TRPC3-deficient mouse models. Hypothalamic glucose detection was studied in vivo by measuring food intake and insulin secretion in response to increased brain glucose level. The role of TRPC3 in GE neuron response to glucose was studied by using in vitro calcium imaging on freshly dissociated MBH neurons. We found that whole-body and MBH TRPC3-deficient mice have increased body weight and food intake. The anorectic effect of intracerebroventricular glucose and the insulin secretory response to intracarotid glucose injection are blunted in TRPC3-deficient mice. TRPC3 loss of function or pharmacological inhibition blunts calcium responses to glucose in MBH neurons in vitro. Together, the results demonstrate that TRPC3 channels are required for the response to glucose of MBH GE neurons and the central effect of glucose on insulin secretion and food intake.


Assuntos
Peso Corporal/genética , Ingestão de Alimentos/genética , Metabolismo Energético/genética , Glucose/metabolismo , Hipotálamo/metabolismo , Insulina/metabolismo , Neurônios/metabolismo , Canais de Cátion TRPC/genética , Animais , Western Blotting , Jejum , Teste de Tolerância a Glucose , Homeostase , Hipotálamo/citologia , Secreção de Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Canais de Cátion TRPC/metabolismo
3.
Mol Cell Endocrinol ; 418 Pt 1: 9-16, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26261054

RESUMO

The maintenance of energy homeostasis requires the hypothalamic integration of nutrient feedback cues, such as glucose, fatty acids, amino acids, and metabolic hormones such as insulin, leptin and ghrelin. Although hypothalamic neurons are critical to maintain energy homeostasis research efforts have focused on feedback mechanisms in isolation, such as glucose alone, fatty acids alone or single hormones. However this seems rather too simplistic considering the range of nutrient and endocrine changes associated with different metabolic states, such as starvation (negative energy balance) or diet-induced obesity (positive energy balance). In order to understand how neurons integrate multiple nutrient or hormonal signals, we need to identify and examine potential intracellular convergence points or common molecular targets that have the ability to sense glucose, fatty acids, amino acids and hormones. In this review, we focus on the role of carnitine metabolism in neurons regulating energy homeostasis. Hypothalamic carnitine metabolism represents a novel means for neurons to facilitate and control both nutrient and hormonal feedback. In terms of nutrient regulation, carnitine metabolism regulates hypothalamic fatty acid sensing through the actions of CPT1 and has an underappreciated role in glucose sensing since carnitine metabolism also buffers mitochondrial matrix levels of acetyl-CoA, an allosteric inhibitor of pyruvate dehydrogenase and hence glucose metabolism. Studies also show that hypothalamic CPT1 activity also controls hormonal feedback. We hypothesis that hypothalamic carnitine metabolism represents a key molecular target that can concurrently integrate nutrient and hormonal information, which is critical to maintain energy homeostasis. We also suggest this is relevant to broader neuroendocrine research as it predicts that hormonal signaling in the brain varies depending on current nutrient status. Indeed, the metabolic action of ghrelin, leptin or insulin at POMC or NPY neurons may depend on appropriate nutrient-sensing in these neurons and we hypothesize carnitine metabolism is critical in the integrative processing. Future research is required to examine the neuron-specific effects of carnitine metabolism on concurrent nutrient- and hormonal-sensing in AgRP and POMC neurons.


Assuntos
Carnitina/metabolismo , Metabolismo Energético/fisiologia , Retroalimentação Fisiológica/fisiologia , Homeostase/fisiologia , Hipotálamo/metabolismo , Animais , Ácidos Graxos/metabolismo , Grelina/metabolismo , Glucose/metabolismo , Humanos , Leptina/metabolismo , Neurônios/metabolismo
4.
Endocrinology ; 155(7): 2411-22, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24742194

RESUMO

High-fat diet (HFD) feeding causes ghrelin resistance in arcuate neuropeptide Y (NPY)/Agouti-related peptide neurons. In the current study, we investigated the time course over which this occurs and the mechanisms responsible for ghrelin resistance. After 3 weeks of HFD feeding, neither peripheral nor central ghrelin increased food intake and or activated NPY neurons as demonstrated by a lack of Fos immunoreactivity or whole-cell patch-clamp electrophysiology. Pair-feeding studies that matched HFD calorie intake with chow calorie intake show that HFD exposure does not cause ghrelin resistance independent of body weight gain. We observed increased plasma leptin in mice fed a HFD for 3 weeks and show that leptin-deficient obese ob/ob mice are still ghrelin sensitive but become ghrelin resistant when central leptin is coadministered. Moreover, ob/ob mice fed a HFD for 3 weeks remain ghrelin sensitive, and the ability of ghrelin to induce action potential firing in NPY neurons was blocked by leptin. We also examined hypothalamic gliosis in mice fed a chow diet or HFD, as well as in ob/ob mice fed a chow diet or HFD and lean controls. HFD-fed mice exhibited increased glial fibrillary acidic protein-positive cells compared with chow-fed mice, suggesting that hypothalamic gliosis may underlie ghrelin resistance. However, we also observed an increase in hypothalamic gliosis in ob/ob mice fed a HFD compared with chow-fed ob/ob and lean control mice. Because ob/ob mice fed a HFD remain ghrelin sensitive, our results suggest that hypothalamic gliosis does not underlie ghrelin resistance. Further, pair-feeding a HFD to match the calorie intake of chow-fed controls did not increase body weight gain or cause central ghrelin resistance; thus, our evidence suggests that diet-induced hyperleptinemia, rather than diet-induced hypothalamic gliosis or HFD exposure, causes ghrelin resistance.


Assuntos
Resistência a Medicamentos/fisiologia , Grelina/farmacologia , Leptina/sangue , Neurônios/fisiologia , Potenciais de Ação/efeitos dos fármacos , Proteína Relacionada com Agouti/metabolismo , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/fisiologia , Dieta Hiperlipídica/efeitos adversos , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/etiologia , Gliose/fisiopatologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hipotálamo/metabolismo , Hipotálamo/patologia , Hipotálamo/fisiopatologia , Imuno-Histoquímica , Técnicas In Vitro , Leptina/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Camundongos Transgênicos , Microscopia de Fluorescência , Neurônios/metabolismo , Neuropeptídeo Y/genética , Neuropeptídeo Y/metabolismo , Obesidade/sangue , Obesidade/etiologia , Obesidade/fisiopatologia
5.
Endocrinology ; 155(3): 840-53, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24424063

RESUMO

In this study we examined fasted and refed cfos activation in cortical, brainstem, and hypothalamic brain regions associated with appetite regulation. We examined a number of time points during refeeding to gain insight into the temporal pattern of neuronal activation and changes in endocrine parameters associated with fasting and refeeding. In response to refeeding, blood glucose and plasma insulin returned to basal levels within 30 minutes, whereas plasma nonesterified fatty acids and leptin returned to basal levels after 1 and 2 hours, respectively. Within the hypothalamic arcuate nucleus (ARC), fasting increased cfos activation in ∼25% of neuropeptide Y neurons, which was terminated 1 hour after refeeding. Fasting had no effect on cfos activation in pro-opiomelanocortin neurons; however, 1 and 2 hours of refeeding significantly activated ∼20% of ARC pro-opiomelanocortin neurons. Acute refeeding (30, 60, and 120 minutes), but not fasting, increased cfos activation in the nucleus accumbens, the cingulate cortex (but not the insular cortex), the medial and lateral parabrachial nucleus, the nucleus of the solitary tract, the area postrema, the dorsal raphe, and the ventromedial nucleus of the hypothalamus. After 6 hours of refeeding, cfos activity was reduced in the majority of these regions compared with that at earlier time points. Our data indicate that acute refeeding, rather than long-term fasting, activates cortical, brainstem, and hypothalamic neural circuits associated with appetite regulation and reward processing. Although the hypothalamic ARC remains a critical sensory node detecting changes in the metabolic state and feedback during fasting and acute refeeding, our results also reveal the temporal pattern in cfos activation in cortical and brainstem areas implicated in the control of appetite and body weight regulation.


Assuntos
Tronco Encefálico/metabolismo , Córtex Cerebral/metabolismo , Ingestão de Alimentos/fisiologia , Privação de Alimentos , Hipotálamo/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Regulação do Apetite/fisiologia , Núcleo Arqueado do Hipotálamo/metabolismo , Glicemia/metabolismo , Peso Corporal , Ácidos Graxos/sangue , Regulação da Expressão Gênica , Giro do Cíngulo/metabolismo , Insulina/sangue , Leptina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , Pró-Opiomelanocortina/metabolismo , Núcleos da Rafe/metabolismo , Núcleo Solitário/metabolismo , Fatores de Tempo , Núcleo Hipotalâmico Ventromedial/metabolismo
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