RESUMO
Heritable epigenetic mechanisms might contribute to the worldwide increase in the prevalence of obesity. Dalgaard et al. identify an epigenetic molecular switch that controls body weight control. The discovery suggests the existence of mammalian polyphenism in energy metabolism and might have implications for strategies to limit the obesity epidemic.
Assuntos
Epigênese Genética , Haploinsuficiência , Proteínas Nucleares/genética , Obesidade/genética , Proteínas Repressoras/genética , Magreza/genética , Animais , HumanosRESUMO
We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and circuit connectivity. Accordingly, astrocytic IR ablation reduces glucose-induced activation of hypothalamic pro-opio-melanocortin (POMC) neurons and impairs physiological responses to changes in glucose availability. Hypothalamus-specific knockout of astrocytic IRs, as well as postnatal ablation by targeting glutamate aspartate transporter (GLAST)-expressing cells, replicates such alterations. A normal response to altering directly CNS glucose levels in mice lacking astrocytic IRs indicates a role in glucose transport across the blood-brain barrier (BBB). This was confirmed in vivo in GFAP-IR KO mice by using positron emission tomography and glucose monitoring in cerebral spinal fluid. We conclude that insulin signaling in hypothalamic astrocytes co-controls CNS glucose sensing and systemic glucose metabolism via regulation of glucose uptake across the BBB.
Assuntos
Astrócitos/metabolismo , Glucose/metabolismo , Hipotálamo/metabolismo , Insulina/metabolismo , Transdução de Sinais , Sistema X-AG de Transporte de Aminoácidos/genética , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Animais , Barreira Hematoencefálica , Retículo Endoplasmático/metabolismo , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Homeostase , Camundongos , Mitocôndrias/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismoRESUMO
Diet-induced obesity can originate from the dysregulated activity of hypothalamic neuronal circuits, which are critical for the regulation of body weight and food intake. The exact mechanisms underlying such neuronal defects are not yet fully understood, but a maladaptive cross-talk between neurons and surrounding microglial is likely to be a contributing factor. Functional and anatomical connections between microglia and hypothalamic neuronal cells are at the core of how the brain orchestrates changes in the body's metabolic needs. However, such a melodious interaction may become maladaptive in response to prolonged diet-induced metabolic stress, thereby causing overfeeding, body weight gain, and systemic metabolic perturbations. From this perspective, we critically discuss emerging molecular and cellular underpinnings of microglia-neuron communication in the hypothalamic neuronal circuits implicated in energy balance regulation. We explore whether changes in this intercellular dialogue induced by metabolic stress may serve as a protective neuronal mechanism or contribute to disease establishment and progression. Our analysis provides a framework for future mechanistic studies that will facilitate progress into both the etiology and treatments of metabolic disorders.
Assuntos
Microglia/metabolismo , Neurônios/metabolismo , Obesidade/etiologia , Animais , Comunicação Celular , Citocinas/metabolismo , Dieta/efeitos adversos , Humanos , Rede Nervosa , Obesidade/imunologia , Obesidade/metabolismoRESUMO
Pharmacological blockers of the cannabinoid receptor type-1 (CB1) have been considered for a long time as the holy grail of obesity pharmacotherapy. These agents were hastily released in the clinical setting, due to their clear-cut therapeutic efficacy. However, the first generation of these drugs, which were able to target both the brain and peripheral tissues, had serious neuropsychiatric effects, leading authorities to ban their clinical use. New peripherally restricted CB1 blockers, characterized by low brain penetrance, have been developed over the past 10 years. In preclinical studies, these molecules seem to overcome the neuropsychiatric negative effects previously observed with brain-penetrant CB1 inhibitors, while retaining or even outperforming their efficacy. The mechanisms of action of these peripherally restricted compounds are only beginning to emerge, and a balanced discussion of the risk/benefits ratio associated to their possible clinical use is urgently needed, in order to avoid repeating past mistakes. Here, we will critically discuss the advantages and the possible hidden threats associated with the use of peripheral CB1 blockers for the pharmacotherapy of obesity and its associated metabolic complications. We will address whether this novel pharmacological approach might 'compete' with current pharmacotherapies for obesity and diabetes, while also conceptualizing future CB1-based pharmacological trends that may significantly lower the risk/benefits ratio associated with the use of these drugs.
Assuntos
Antagonistas de Receptores de Canabinoides/farmacologia , Obesidade/tratamento farmacológico , Animais , Antagonistas de Receptores de Canabinoides/efeitos adversos , Endocanabinoides , Humanos , Receptor CB1 de Canabinoide/antagonistas & inibidoresRESUMO
Diet-induced obesity and its metabolic comorbidities constitute an overwhelming health crisis and there is an urgent need for safe and effective pharmacological interventions. Being largely shelved for decades, scientists are now revisiting the anti-obesity virtues of leptin. Whereas it remains evident that leptin as a stand-alone therapy is not an effective approach, the potential for employing sensitising pharmacology to unleash the weight-lowering properties of leptin has injected new hope into the field. Fascinatingly, these leptin-sensitising agents seem to act via distinct metabolic pathways and may thus, in parallel with their clinical development, serve as important research tools to progress our understanding of the molecular, physiological and behavioural pathways underlying energy homeostasis and obesity pathophysiology. This review summarises a presentation given at the 'Is leptin coming back?' symposium at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by Thomas Meek and Gregory Morton, DOI: 10.1007/s00125-016-3898-3 , and by Gerald Shulman and colleagues, DOI: 10.1007/s00125-016-3909-4 ) and an overview by the Session Chair, Ulf Smith (DOI: 10.1007/s00125-016-3894-7 ).
Assuntos
Leptina/uso terapêutico , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Humanos , Leptina/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Complex interactions between periphery and the brain regulate food intake in mammals. Cannabinoid type-1 (CB1) receptor antagonists are potent hypophagic agents, but the sites where this acute action is exerted and the underlying mechanisms are not fully elucidated. To dissect the mechanisms underlying the hypophagic effect of CB1 receptor blockade, we combined the acute injection of the CB1 receptor antagonist rimonabant with the use of conditional CB1-knockout mice, as well as with pharmacological modulation of different central and peripheral circuits. Fasting/refeeding experiments revealed that CB1 receptor signaling in many specific brain neurons is dispensable for the acute hypophagic effects of rimonabant. CB1 receptor antagonist-induced hypophagia was fully abolished by peripheral blockade of ß-adrenergic transmission, suggesting that this effect is mediated by increased activity of the sympathetic nervous system. Consistently, we found that rimonabant increases gastrointestinal metabolism via increased peripheral ß-adrenergic receptor signaling in peripheral organs, including the gastrointestinal tract. Blockade of both visceral afferents and glutamatergic transmission in the nucleus tractus solitarii abolished rimonabant-induced hypophagia. Importantly, these mechanisms were specifically triggered by lipid-deprivation, revealing a nutrient-specific component acutely regulated by CB1 receptor blockade. Finally, peripheral blockade of sympathetic neurotransmission also blunted central effects of CB1 receptor blockade, such as fear responses and anxiety-like behaviors. These data demonstrate that, independently of their site of origin, important effects of CB1 receptor blockade are expressed via activation of peripheral sympathetic activity. Thus, CB1 receptors modulate bidirectional circuits between the periphery and the brain to regulate feeding and other behaviors.
Assuntos
Ansiedade/metabolismo , Regulação do Apetite , Encéfalo/metabolismo , Transtornos da Alimentação e da Ingestão de Alimentos/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Sistema Nervoso Simpático/metabolismo , Transmissão Sináptica , Animais , Ansiedade/genética , Ansiedade/patologia , Ansiedade/fisiopatologia , Encéfalo/patologia , Encéfalo/fisiopatologia , Transtornos da Alimentação e da Ingestão de Alimentos/genética , Transtornos da Alimentação e da Ingestão de Alimentos/fisiopatologia , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/patologia , Trato Gastrointestinal/fisiopatologia , Camundongos , Camundongos Knockout , Receptor CB1 de Canabinoide/genética , Sistema Nervoso Simpático/patologia , Sistema Nervoso Simpático/fisiopatologiaRESUMO
BACKGROUND: Cumulative data indicate that the endocannabinoid system plays a major role in feeding behavior and energy balance. Genetic silencing of cannabinoid receptor type 1 (CB1) reduces body weight gain, independently of food intake. METHODS: In this work, we investigated whether the hypothalamic neuropeptide expression pattern supports the absence of the anorexigenic response observed under constitutive CB1 ablation, by using neuronal CB1 conditional null mice (CamK-CB1-KO) and whole body CB1 null mice (CB1-KO). RESULTS: Our data showed that both CB1 null models display a marked decrease in proopiomelanocortin (POMC) and cocaine-amphetamine-regulated transcript (CART) expression in the arcuate nucleus of the hypothalamus (ARC). CONCLUSIONS: This evidence suggests that a lack of hypophagia is associated with the suppression of ARC anorexigenic neuropeptides and that behavioral changes in food intake (or lack thereof) after constitutive CB1 ablation are likely mediated by impaired melanocortin and CART signaling in the hypothalamus.
Assuntos
Anorexia/metabolismo , Núcleo Arqueado do Hipotálamo/metabolismo , Comportamento Alimentar/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Pró-Opiomelanocortina/metabolismo , Receptor CB1 de Canabinoide/fisiologia , Animais , Comportamento Animal , Peso Corporal , Antagonistas de Receptores de Canabinoides/farmacologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/deficiência , Receptor CB1 de Canabinoide/genéticaRESUMO
The mineralocorticoid receptor (MR) controls adipocyte function, but its role in the conversion of white adipose tissue (WAT) into thermogenic fat has not been elucidated. We investigated responses to the MR antagonists spironolactone (spiro; 20 mg/kg/d) and drospirenone (DRSP; 6 mg/kg/d) in C57BL/6 mice fed a high-fat (HF) diet for 90 d. DRSP and spiro curbed HF diet-induced impairment in glucose tolerance, and prevented body weight gain and white fat expansion. Notably, either MR antagonist induced up-regulation of brown adipocyte-specific transcripts and markedly increased protein levels of uncoupling protein 1 (UCP1) in visceral and inguinal fat depots when compared with the HF diet group. Positron emission tomography and magnetic resonance spectroscopy confirmed acquisition of brown fat features in WAT. Interestingly, MR antagonists markedly reduced the autophagic rate both in murine preadipocytes in vitro (10(-5) M) and in WAT depots in vivo, with a concomitant increase in UCP1 protein expression. Moreover, the autophagy repressor bafilomycin A1 (10(-8) M) mimicked the effect of MR antagonists, increasing UCP1 protein expression in primary preadipocytes. Hence, we showed that adipocyte MR regulates brown remodeling of WAT through a modulation of autophagy. These results provide a rationale for the use of MR antagonists to prevent the adverse metabolic consequences of adipocyte dysfunction.
Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Androstenos/farmacologia , Autofagia/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Intolerância à Glucose/prevenção & controle , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Receptores de Mineralocorticoides/fisiologia , Espironolactona/farmacologia , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Adipogenia/fisiologia , Aldosterona/farmacologia , Androstenos/uso terapêutico , Animais , Composição Corporal/efeitos dos fármacos , Células Cultivadas , Feminino , Perfilação da Expressão Gênica , Intolerância à Glucose/etiologia , Canal Inguinal , Gordura Intra-Abdominal/efeitos dos fármacos , Canais Iônicos/biossíntese , Canais Iônicos/genética , Macrolídeos/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Proteínas Mitocondriais/biossíntese , Proteínas Mitocondriais/genética , Obesidade/tratamento farmacológico , Obesidade/fisiopatologia , Obesidade/prevenção & controle , Receptores de Mineralocorticoides/efeitos dos fármacos , Espironolactona/uso terapêutico , Proteína Desacopladora 1 , Regulação para Cima/efeitos dos fármacos , Aumento de Peso/efeitos dos fármacosRESUMO
Brown adipose tissue (BAT) and brown-like cells in white adipose tissue (WAT) can dissipate energy through thermogenesis, a process mediated by uncoupling protein 1 (UCP1). We investigated whether stress hormones ACTH and corticosterone contribute to BAT activation and browning of WAT. ACTH and corticosterone were studied in male mice exposed to 4 or 23°C for 24 h. Direct effects were studied in T37i mouse brown adipocytes and primary cultured murine BAT and inguinal WAT (iWAT) cells. In vivo effects were studied using (18)F-deoxyglucose positron emission tomography. Cold exposure doubled serum ACTH concentrations (P=0.03) and fecal corticosterone excretion (P=0.008). In T37i cells, ACTH dose-dependently increased Ucp1 mRNA (EC50=1.8 nM) but also induced Ucp1 protein content 88% (P=0.02), glycerol release 32% (P=0.03) and uncoupled respiration 40% (P=0.003). In cultured BAT and iWAT, ACTH elevated Ucp1 mRNA by 3-fold (P=0.03) and 3.7-fold (P=0.01), respectively. In T37i cells, corticosterone prevented induction of Ucp1 mRNA and Ucp1 protein by both ACTH and norepinephrine in a glucocorticoid receptor (GR)-dependent fashion. ACTH and GR antagonist RU486 independently doubled BAT (18)F-deoxyglucose uptake (P=0.0003 and P=0.004, respectively) in vivo. Our results show that ACTH activates BAT and browning of WAT while corticosterone counteracts this.
Assuntos
Tecido Adiposo Marrom/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Corticosterona/metabolismo , Adipócitos/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Canais Iônicos/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Mitocondriais/metabolismo , Receptores de Glucocorticoides/metabolismo , Termogênese/fisiologia , Proteína Desacopladora 1RESUMO
The use of glucagon-like peptide-1 (GLP-1) receptor-based multi-agonists in the treatment of type 2 diabetes and obesity holds great promise for improving glycaemic control and weight management. Unimolecular dual and triple agonists targeting multiple gut hormone-related pathways are currently in clinical trials, with recent evidence supporting their efficacy. However, significant knowledge gaps remain regarding the biological mechanisms and potential adverse effects associated with these multi-target agents. The mechanisms underlying the therapeutic efficacy of GLP-1 receptor-based multi-agonists remain somewhat mysterious, and hidden threats may be associated with the use of gut hormone-based polyagonists. In this review, we provide a critical analysis of the benefits and risks associated with the use of these new drugs in the management of obesity and diabetes, while also exploring new potential applications of GLP-1-based pharmacology beyond the field of metabolic disease.
Assuntos
Diabetes Mellitus Tipo 2 , Doenças Metabólicas , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Doenças Metabólicas/tratamento farmacológico , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêuticoRESUMO
The hypothalamic arcuate nucleus (ARH) contains neurons vital for maintaining energy homeostasis that sense and respond to changes in blood-borne metabolic hormones. Despite its juxtaposition to the median eminence (ME), a circumventricular organ lacking a blood-brain barrier and thus exposed to circulating molecules, only a few ventral ARH neurons perceive these extravasating metabolic signals due to a poorly understood ME/ARH diffusion barrier. Here, we show in male mice that aggrecan, a perineural-net proteoglycan deposited by orexigenic ARH neurons, creates a peculiar ventrodorsal diffusion gradient. Fasting enhances aggrecan deposition more dorsally, reinforcing the diffusion barrier, particularly around neurons adjacent to fenestrated capillary loops that enter the ARH. The disruption of aggrecan deposits results in unregulated diffusion of blood-borne molecules into the ARH and impairs food intake. Our findings reveal the molecular nature and plasticity of the ME/ARH diffusion barrier, and indicate its physiological role in hypothalamic metabolic hormone sensing.
Assuntos
Agrecanas , Núcleo Arqueado do Hipotálamo , Metabolismo Energético , Neurônios , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Masculino , Neurônios/metabolismo , Agrecanas/metabolismo , Camundongos , Eminência Mediana/metabolismo , Camundongos Endogâmicos C57BL , Ingestão de Alimentos/fisiologia , Jejum/metabolismo , Barreira Hematoencefálica/metabolismo , Transdução de SinaisRESUMO
The hypothalamus contains a remarkable diversity of neurons that orchestrate behavioural and metabolic outputs in a highly plastic manner. Neuronal diversity is key to enabling hypothalamic functions and, according to the neuroscience dogma, it is predetermined during embryonic life. Here, by combining lineage tracing of hypothalamic pro-opiomelanocortin (Pomc) neurons with single-cell profiling approaches in adult male mice, we uncovered subpopulations of 'Ghost' neurons endowed with atypical molecular and functional identity. Compared to 'classical' Pomc neurons, Ghost neurons exhibit negligible Pomc expression and are 'invisible' to available neuroanatomical approaches and promoter-based reporter mice for studying Pomc biology. Ghost neuron numbers augment in diet-induced obese mice, independent of neurogenesis or cell death, but weight loss can reverse this shift. Our work challenges the notion of fixed, developmentally programmed neuronal identities in the mature hypothalamus and highlight the ability of specialised neurons to reversibly adapt their functional identity to adult-onset obesogenic stimuli.
Assuntos
Hipotálamo , Neurônios , Obesidade , Pró-Opiomelanocortina , Análise de Célula Única , Animais , Pró-Opiomelanocortina/metabolismo , Pró-Opiomelanocortina/genética , Neurônios/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Masculino , Camundongos , Hipotálamo/metabolismo , Hipotálamo/citologia , Modelos Animais de Doenças , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese , Camundongos ObesosRESUMO
Obesity is a chronic and debilitating disorder that originates from alterations in energy-sensing brain circuits controlling body weight gain and food intake. The dysregulated syntheses and actions of lipid mediators in the hypothalamus induce weight gain and overfeeding, but the molecular and cellular underpinnings of these alterations remain elusive. In response to changes in the nutritional status, different lipid sensing pathways in the hypothalamus direct body energy needs in a Yin-Yang model. Endocannabinoids orchestrate the crosstalk between hypothalamic circuits and the sympathetic nervous system to promote food intake and energy accumulation during fasting, whereas bile acids act on the same top-down axis to reduce energy intake and possibly storage after the meal. In obesity, the bioavailability and downstream cellular actions of endocannabinoids and bile acids are altered in hypothalamic neurons involved in body weight and metabolic control. Thus, the onset and progression of this disease might result from an imbalance in hypothalamic sensing of multiple lipid signals, which are possibly integrated by common molecular nodes. In this viewpoint, we discuss a possible model that explains how bile acids and endocannabinoids may exert their effects on energy balance regulation via interconnected mechanisms at the level of the hypothalamic neuronal circuits. Therefore, we propose a new conceptual framework for understanding and treating central mechanisms of maladaptive lipid action in obesity.
RESUMO
Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARÉ/É£) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARÉ/É£ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/tesaglitazar does not differ from the pharmacokinetically matched GLP-1RA in GLP-1R signalling, but shows GLP-1R-dependent PPARÉ£-retinoic acid receptor heterodimerization and enhanced improvements of body weight, food intake and glucose metabolism relative to the GLP-1RA or tesaglitazar alone in obese male mice. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout mice and shows preserved effects in obese mice at subthreshold doses for the GLP-1RA and tesaglitazar. Liquid chromatography-mass spectrometry-based proteomics identified PPAR regulated proteins in the hypothalamus that are acutely upregulated by GLP-1RA/tesaglitazar. Our data show that GLP-1RA/tesaglitazar improves glucose control with superior efficacy to the GLP-1RA or tesaglitazar alone and suggest that this conjugate might hold therapeutic value to acutely treat hyperglycaemia and insulin resistance.
Assuntos
Diabetes Mellitus Tipo 2 , PPAR alfa , Alcanossulfonatos , Animais , Peso Corporal , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1 , Glucose , Masculino , Camundongos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , PPAR alfa/agonistas , PPAR alfa/uso terapêutico , FenilpropionatosRESUMO
Hypothalamic AgRP and POMC neurons are conventionally viewed as the yin and yang of the body's energy status, since they act in an opposite manner to modulate appetite and systemic energy metabolism. However, although AgRP neurons' functions are comparatively well understood, a unifying theory of how POMC neuronal cells operate has remained elusive, probably due to their high level of heterogeneity, which suggests that their physiological roles might be more complex than initially thought. In this Perspective, we propose a conceptual framework that integrates POMC neuronal heterogeneity with appetite regulation, whole-body metabolic physiology and the development of obesity. We highlight emerging evidence indicating that POMC neurons respond to distinct combinations of interoceptive signals and food-related cues to fine-tune divergent metabolic pathways and behaviours necessary for survival. The new framework we propose reflects the high degree of developmental plasticity of this neuronal population and may enable progress towards understanding of both the aetiology and treatment of metabolic disorders.
Assuntos
Metabolismo Energético/fisiologia , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismo , Proteína Relacionada com Agouti/metabolismo , Animais , Humanos , Camundongos , Pró-Opiomelanocortina/genética , RNA Mensageiro/metabolismo , Receptor Tipo 4 de Melanocortina/metabolismoRESUMO
Glucagon-like peptide 1 receptor (GLP-1R) agonists effectively improve glycemia and body weight in patients with type 2 diabetes and obesity but have limited weight-lowering efficacy and minimal insulin sensitizing action. In preclinical models, peripherally restricted cannabinoid receptor type 1 (CB1R) inhibitors, which are devoid of the neuropsychiatric adverse effects observed with brain-penetrant CB1R blockers, ameliorate obesity and its multiple metabolic complications. Using mouse models with genetic loss of CB1R or GLP-1R, we demonstrate that these two metabolic receptors modulate food intake and body weight via reciprocal functional interactions. In diet-induced obese mice, the coadministration of a peripheral CB1R inhibitor with long-acting GLP-1R agonists achieves greater reduction in body weight and fat mass than monotherapies by promoting negative energy balance. This cotreatment also results in larger improvements in systemic and hepatic insulin action, systemic dyslipidemia, and reduction of hepatic steatosis. Thus, peripheral CB1R blockade may allow safely potentiating the antiobesity and antidiabetic effects of currently available GLP-1R agonists.
Assuntos
Peso Corporal/fisiologia , Ingestão de Alimentos/fisiologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Obesidade/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Animais , Glicemia/metabolismo , Composição Corporal/fisiologia , Dieta Hiperlipídica , Metabolismo Energético , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Insulina/sangue , Leptina/sangue , Masculino , Camundongos , Camundongos Knockout , Obesidade/genética , Receptor CB1 de Canabinoide/genéticaRESUMO
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 SinaisRESUMO
Bile acids (BAs) improve metabolism and exert anti-obesity effects through the activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic BA signaling is implicated in body weight control and obesity pathophysiology remains unknown. Here we show that hypothalamic BA content is reduced in diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist in these animals decreases body weight and fat mass by activating the sympathetic nervous system, thereby promoting negative energy balance. Conversely, genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus favors the development of obesity and worsens established obesity by blunting sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the anti-obesity action of dietary BA supplementation. Together, these findings identify hypothalamic TGR5 signaling as a key mediator of a top-down neural mechanism that counteracts diet-induced obesity.
Assuntos
Ácidos e Sais Biliares/metabolismo , Obesidade/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Peso Corporal/genética , Metabolismo Energético/genética , Células HEK293 , Humanos , Hipotálamo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Camundongos Transgênicos , Obesidade/genética , Obesidade/prevenção & controle , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais/fisiologiaRESUMO
One important lesson from the last decade of studies in the field of systemic energy metabolism is that obesity is first and foremost a brain disease. Hypothalamic neurons dysfunction observed in response to chronic metabolic stress is a key pathogenic node linking consumption of hypercaloric diets with body weight gain and associated metabolic sequelae. A key hypothalamic neuronal population expressing the neuropeptide Pro-opio-melanocortin (POMC) displays altered electrical activity and dysregulated neuropeptides production capacity after long-term feeding with hypercaloric diets. However, whether such neuronal dysfunction represents a consequence or a mechanism of disease, remains a subject of debate. Here, we will review and highlight emerging pathogenic mechanisms that explain why POMC neurons undergo dysfunctional activity in response to caloric overload, and critically address whether these mechanisms may be causally implicated in the physiopathology of obesity and of its associated co-morbidities.
Assuntos
Doenças Metabólicas , Pró-Opiomelanocortina , Dieta , Humanos , Hipotálamo/metabolismo , Doenças Metabólicas/etiologia , Neurônios/metabolismo , Pró-Opiomelanocortina/metabolismoRESUMO
BACKGROUND/AIMS: The current approaches to study the molecular mechanisms involved in the pathophysiology of liver diseases often rely on the use of transgenic mice. However, experimental models of decompensated cirrhosis have not been clearly established in mice. Thus, we aimed to set an efficient and well-tolerated protocol to induce cirrhosis in mice able to progress up to the ascitic stage. METHODS: C57BL/6N mice received CCl(4) subcutaneously, intraperitoneally or by inhalation. In the latter group, gaseous CCl(4) was administered according to three different schedules: increasing exposure times, twice weekly (traditional protocol; TP), short inhalation cycles, twice or three times weekly. RESULTS: Portal hypertension, sodium retention, and ascites developed in all groups between 11 and 15 weeks. Mortality reached 70% in the TP group, but it was only 0-10% with all other protocols. All the inhalation groups had significantly more ascites at sacrifice than those receiving CCl(4) subcutaneously and intraperitoneally. Extensive abdominal adhesions and evidence of enhanced hepatic inflammation, as suggested by the increased gene expression of pro-inflammatory cytokines in liver tissue, were found in the intraperitoneal group, while large granulomas at the injection site and marked neutrophil infiltration of lungs developed in the subcutaneous group. No extra-hepatic damage could be detected in mice inhaling CCl(4). CONCLUSIONS: The use of short cycles of CCl(4) inhalation represents a novel, safe, and effective method to induce decompensated cirrhosis in mice. Intraperitoneal CCl(4) leads instead to abdominal adhesions precluding a correct evaluation of ascites, while subcutaneous CCl(4) causes an unwanted systemic inflammatory response.