RESUMO
The relationship between lipid metabolism and longevity remains unclear. Although fat oxidation is essential for weight loss, whether it remains beneficial when sustained for long periods, and the extent to which it may attenuate or augment lifespan remain important unanswered questions. Here, we develop an experimental handle in the Caenorhabditis elegans model system, in which we uncover the mechanisms that connect long-term fat oxidation with longevity. We find that sustained ß-oxidation via activation of the conserved triglyceride lipase ATGL-1, triggers a feedback transcriptional loop that involves the mito-nuclear transcription factor ATFS-1, and a previously unknown and highly conserved repressor of ATGL-1 called HLH-11/AP4. This feedback loop orchestrates the dual control of fat oxidation and lifespan, and shields the organism from life-shortening mitochondrial stress in the face of continuous fat oxidation. Thus, we uncover one mechanism by which fat oxidation can be sustained for long periods without deleterious effects on longevity.
Assuntos
Caenorhabditis elegans/fisiologia , Retroalimentação Fisiológica , Metabolismo dos Lipídeos/fisiologia , Longevidade/fisiologia , Animais , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Lipase/genética , Lipase/metabolismo , Oxirredução , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
OBJECTIVES: Extracts of the hops plant have been shown to reduce weight and insulin resistance in rodents and humans, but elucidation of the mechanisms responsible for these benefits has been hindered by the use of heterogeneous hops-derived mixtures. Because hop extracts are used as flavoring agents for their bitter properties, we hypothesized that bitter taste receptors (Tas2rs) could be mediating their beneficial effects in metabolic disease. Studies have shown that exposure of cultured enteroendocrine cells to bitter tastants can stimulate release of hormones, including glucagon-like peptide 1 (GLP-1). These findings have led to the suggestion that activation of Tas2rs may be of benefit in diabetes, but this tenet has not been tested. Here, we have assessed the ability of a pure derivative of a hops isohumulone with anti-diabetic properties, KDT501, to signal through Tas2rs. We have further used this compound as a tool to systematically assess the impact of bitter taste receptor activation in obesity-diabetes. METHODS: KDT501 was tested in a panel of bitter taste receptor signaling assays. Diet-induced obese mice (DIO) were dosed orally with KDT501 and acute effects on glucose homeostasis determined. A wide range of metabolic parameters were evaluated in DIO mice chronically treated with KDT501 to establish the full impact of activating gut bitter taste signaling. RESULTS: We show that KDT501 signals through Tas2r108, one of 35 mouse Tas2rs. In DIO mice, acute treatment stimulated GLP-1 secretion and enhanced glucose tolerance. Chronic treatment caused weight and fat mass loss, increased energy expenditure, enhanced glucose tolerance and insulin sensitivity, normalized plasma lipids, and induced broad suppression of inflammatory markers. Chronic KDT501 treatment altered enteroendocrine hormone levels and bile acid homeostasis and stimulated sustained GLP-1 release. Combined treatment with a dipeptidyl peptidase IV inhibitor amplified the incretin-based benefits of this pure isohumulone. CONCLUSIONS: Activation of Tas2r108 in the gut results in a remodeling of enteroendocrine hormone release and bile acid metabolism that ameliorates multiple features of metabolic syndrome. Targeting extraoral bitter taste receptors may be useful in metabolic disease.
Assuntos
Ciclopentanos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/fisiologia , Animais , Peso Corporal/efeitos dos fármacos , Ciclopentanos/farmacologia , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Células Enteroendócrinas/metabolismo , Peptídeo 1 Semelhante ao Glucagon/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Humulus/metabolismo , Hipoglicemiantes/farmacologia , Resistência à Insulina/fisiologia , Mucosa Intestinal/metabolismo , Intestinos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
The mechanisms by which the sensory environment influences metabolic homeostasis remains poorly understood. In this report, we show that oxygen, a potent environmental signal, is an important regulator of whole body lipid metabolism. C. elegans oxygen-sensing neurons reciprocally regulate peripheral lipid metabolism under normoxia in the following way: under high oxygen and food absence, URX sensory neurons are activated, and stimulate fat loss in the intestine, the major metabolic organ for C. elegans. Under lower oxygen conditions or when food is present, the BAG sensory neurons respond by repressing the resting properties of the URX neurons. A genetic screen to identify modulators of this effect led to the identification of a BAG-neuron-specific neuropeptide called FLP-17, whose cognate receptor EGL-6 functions in URX neurons. Thus, BAG sensory neurons counterbalance the metabolic effect of tonically active URX neurons via neuropeptide communication. The combined regulatory actions of these neurons serve to precisely tune the rate and extent of fat loss to the availability of food and oxygen, and provides an interesting example of the myriad mechanisms underlying homeostatic control.
Assuntos
Caenorhabditis elegans/metabolismo , Metabolismo dos Lipídeos , Neuropeptídeos/metabolismo , Oxigênio/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Comunicação Celular , Guanilato Ciclase/metabolismo , Mucosa Intestinal/metabolismo , Transdução de SinaisRESUMO
The brain-specific isoform of renin (Ren-b) has been proposed as a negative regulator of the brain renin-angiotensin system (RAS). We analyzed mice with a selective deletion of Ren-b which preserved expression of the classical renin (Ren-a) isoform. We reported that Ren-bNull mice exhibited central RAS activation and hypertension through increased expression of Ren-a, but the dipsogenic and metabolic effects in Ren-bNull mice are unknown. Fluid intake was similar in control and Ren-bNull mice at baseline and both exhibited an equivalent dipsogenic response to deoxycorticosterone acetate-salt. Dehydration promoted increased water intake in Ren-bNull mice, particularly after deoxycorticosterone acetate-salt. Ren-bNull and control mice exhibited similar body weight when fed a chow diet. However, when fed a high-fat diet, male Ren-bNull mice gained significantly less weight than control mice, an effect blunted in females. This difference was not because of changes in food intake, energy absorption, or physical activity. Ren-bNull mice exhibited increased resting metabolic rate concomitant with increased uncoupled protein 1 expression and sympathetic nerve activity to the interscapular brown adipose tissue, suggesting increased thermogenesis. Ren-bNull mice were modestly intolerant to glucose and had normal insulin sensitivity. Another mouse model with markedly enhanced brain RAS activity (sRA mice) exhibited pronounced insulin sensitivity concomitant with increased brown adipose tissue glucose uptake. Altogether, these data support the hypothesis that the brain RAS regulates energy homeostasis by controlling resting metabolic rate, and that Ren-b deficiency increases brain RAS activity. Thus, the relative level of expression of Ren-b and Ren-a may control activity of the brain RAS.
Assuntos
Metabolismo Basal/fisiologia , Encéfalo/metabolismo , Hipertensão/metabolismo , Sistema Renina-Angiotensina/fisiologia , Renina/metabolismo , Animais , Ingestão de Líquidos/fisiologia , Metabolismo Energético/fisiologia , Camundongos , Isoformas de Proteínas , Sistema Nervoso Simpático/metabolismoRESUMO
Leptin contributes to the control of resting metabolic rate (RMR) and blood pressure (BP) through its actions in the arcuate nucleus (ARC). The renin-angiotensin system (RAS) and angiotensin AT1 receptors within the brain are also involved in the control of RMR and BP, but whether this regulation overlaps with leptin's actions is unclear. Here, we have demonstrated the selective requirement of the AT1A receptor in leptin-mediated control of RMR. We observed that AT1A receptors colocalized with leptin receptors (LEPRs) in the ARC. Cellular coexpression of AT1A and LEPR was almost exclusive to the ARC and occurred primarily within neurons expressing agouti-related peptide (AgRP). Mice lacking the AT1A receptor specifically in LEPR-expressing cells failed to show an increase in RMR in response to a high-fat diet and deoxycorticosterone acetate-salt (DOCA-salt) treatments, but BP control remained intact. Accordingly, loss of RMR control was recapitulated in mice lacking AT1A in AgRP-expressing cells. We conclude that angiotensin activates divergent mechanisms to control BP and RMR and that the brain RAS functions as a major integrator for RMR control through its actions at leptin-sensitive AgRP cells of the ARC.
Assuntos
Angiotensina II/fisiologia , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores para Leptina/metabolismo , Proteína Relacionada com Agouti/fisiologia , Animais , Núcleo Arqueado do Hipotálamo/metabolismo , Metabolismo Basal , Pressão Sanguínea , Dieta Hiperlipídica , Feminino , Neurônios GABAérgicos/metabolismo , Leptina/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pró-Opiomelanocortina/fisiologia , Transporte Proteico , alfa-MSH/fisiologiaRESUMO
Activation of the brain renin-angiotensin system (RAS) stimulates energy expenditure through increasing of the resting metabolic rate (RMR), and this effect requires simultaneous suppression of the circulating and/or adipose RAS. To identify the mechanism by which the peripheral RAS opposes RMR control by the brain RAS, we examined mice with transgenic activation of the brain RAS (sRA mice). sRA mice exhibit increased RMR through increased energy flux in the inguinal adipose tissue, and this effect is attenuated by angiotensin II type 2 receptor (AT2) activation. AT2 activation in inguinal adipocytes opposes norepinephrine-induced uncoupling protein-1 (UCP1) production and aspects of cellular respiration, but not lipolysis. AT2 activation also opposes inguinal adipocyte function and differentiation responses to epidermal growth factor (EGF). These results highlight a major, multifaceted role for AT2 within inguinal adipocytes in the control of RMR. The AT2 receptor may therefore contribute to body fat distribution and adipose depot-specific effects upon cardio-metabolic health.
Assuntos
Adipócitos/metabolismo , Encéfalo/metabolismo , Metabolismo Energético/fisiologia , Receptor Tipo 2 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/fisiologia , Tecido Adiposo Branco/metabolismo , Angiotensina II/metabolismo , Animais , Camundongos Endogâmicos C57BL , Obesidade/metabolismoRESUMO
Metabolic disease, specifically obesity, has now become the greatest challenge to improving cardiovascular health. The renin-angiotensin system (RAS) exists as both a circulating hormone system and as a local paracrine signaling mechanism within various tissues including the brain, kidney, and adipose, and this system is strongly implicated in cardiovascular health and disease. Growing evidence also implicates the RAS in the control of energy balance, supporting the concept that the RAS may be mechanistically involved in the pathogenesis of obesity and obesity hypertension. Here, we review the involvement of the RAS in the entire spectrum of whole organism energy balance mechanisms, including behaviors (food ingestion and spontaneous physical activity) and biological processes (digestive efficiency and both aerobic and nonaerobic resting metabolic rates). We hypothesize that opposing, tissue-specific effects of the RAS to modulate these various components of energy balance can explain the apparently paradoxical results reported by energy-balance studies that involve stimulating, versus disrupting, the RAS. We propose a model in which such opposing and tissue-specific effects of the RAS can explain the failure of simple, global RAS blockade to result in weight loss in humans, and hypothesize that obesity-mediated uncoupling of endogenous metabolic rate control mechanisms can explain the phenomenon of obesity-related hypertension.
Assuntos
Tecido Adiposo/metabolismo , Angiotensinas/metabolismo , Metabolismo Energético , Hipertensão/etiologia , Obesidade/etiologia , Sistema Renina-Angiotensina , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/fisiopatologia , Animais , Fármacos Antiobesidade/uso terapêutico , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiopatologia , Ingestão de Alimentos , Ingestão de Energia , Metabolismo Energético/efeitos dos fármacos , Comportamento Alimentar , Comportamentos Relacionados com a Saúde , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Transdução de SinaisRESUMO
Dietary fats and sodium are both palatable and are hypothesized to synergistically contribute to ingestive behavior and thereby obesity. Contrary to this hypothesis, C57BL/6J mice fed a 45% high fat diet exhibited weight gain that was inhibited by increased dietary sodium content. This suppressive effect of dietary sodium upon weight gain was mediated specifically through a reduction in digestive efficiency, with no effects on food intake behavior, physical activity, or resting metabolism. Replacement of circulating angiotensin II levels reversed the effects of high dietary sodium to suppress digestive efficiency. While the AT1 receptor antagonist losartan had no effect in mice fed low sodium, the AT2 receptor antagonist PD-123,319 suppressed digestive efficiency. Correspondingly, genetic deletion of the AT2 receptor in FVB/NCrl mice resulted in suppressed digestive efficiency even on a standard chow diet. Together these data underscore the importance of digestive efficiency in the pathogenesis of obesity, and implicate dietary sodium, the renin-angiotensin system, and the AT2 receptor in the control of digestive efficiency regardless of mouse strain or macronutrient composition of the diet. These findings highlight the need for greater understanding of nutrient absorption control physiology, and prompt more uniform assessment of digestive efficiency in animal studies of energy balance.
Assuntos
Gorduras na Dieta/farmacologia , Digestão/efeitos dos fármacos , Sistema Renina-Angiotensina/efeitos dos fármacos , Cloreto de Sódio na Dieta/farmacologia , Animais , Gorduras na Dieta/metabolismo , Digestão/genética , Deleção de Genes , Imidazóis/farmacologia , Absorção Intestinal/efeitos dos fármacos , Absorção Intestinal/genética , Losartan/farmacologia , Masculino , Camundongos , Piridinas/farmacologia , Receptor Tipo 2 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/metabolismo , Sistema Renina-Angiotensina/genéticaRESUMO
An indispensable role for the brain renin-angiotensin system (RAS) has been documented in most experimental animal models of hypertension. To identify the specific efferent pathway activated by the brain RAS that mediates hypertension, we examined the hypothesis that elevated arginine vasopressin (AVP) release is necessary for hypertension in a double-transgenic model of brain-specific RAS hyperactivity (the "sRA" mouse model). sRA mice experience elevated brain RAS activity due to human angiotensinogen expression plus neuron-specific human renin expression. Total daily loss of the 4-kDa AVP prosegment (copeptin) into urine was grossly elevated (≥8-fold). Immunohistochemical staining for AVP was increased in the supraoptic nucleus of sRA mice (~2-fold), but no quantitative difference in the paraventricular nucleus was observed. Chronic subcutaneous infusion of a nonselective AVP receptor antagonist conivaptan (YM-087, Vaprisol, 22 ng/h) or the V(2)-selective antagonist tolvaptan (OPC-41061, 22 ng/h) resulted in normalization of the baseline (~15 mmHg) hypertension in sRA mice. Abdominal aortas and second-order mesenteric arteries displayed AVP-specific desensitization, with minor or no changes in responses to phenylephrine and endothelin-1. Mesenteric arteries exhibited substantial reductions in V(1A) receptor mRNA, but no significant changes in V(2) receptor expression in kidney were observed. Chronic tolvaptan infusion also normalized the (5 mmol/l) hyponatremia of sRA mice. Together, these data support a major role for vasopressin in the hypertension of mice with brain-specific hyperactivity of the RAS and suggest a primary role of V(2) receptors.