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2.
Cell Rep ; 42(12): 113536, 2023 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-38060447

RESUMO

Fibroblast growth factor 21 (FGF21), an endocrine signal robustly increased by protein restriction independently of an animal's energy status, exerts profound effects on feeding behavior and metabolism. Here, we demonstrate that considering the nutritional contexts within which FGF21 is elevated can help reconcile current controversies over its roles in mediating macronutrient preference, food intake, and energy expenditure. We show that FGF21 is primarily a driver of increased protein intake in mice and that the effect of FGF21 on sweet preference depends on the carbohydrate balance of the animal. Under no-choice feeding, FGF21 infusion either increased or decreased energy expenditure depending on whether the animal was fed a high- or low-energy diet, respectively. We show that while the role of FGF21 in mediating feeding behavior is complex, its role in promoting protein appetite is robust and that the effects on sweet preference and energy expenditure are macronutrient-state-dependent effects of FGF21.


Assuntos
Apetite , Fatores de Crescimento de Fibroblastos , Camundongos , Animais , Fatores de Crescimento de Fibroblastos/metabolismo , Comportamento Alimentar , Metabolismo Energético , Fígado/metabolismo
3.
J Physiol ; 601(17): 3813-3824, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37535037

RESUMO

It is known that dietary factors within the gestational and nursing period affect early life and stably affect later life traits in animals. However, there is very little understanding of whether dietary factors within the early life period from post-nursing to adulthood affect traits in adulthood. To address this, we conducted studies on male C57Bl/6J mice fed from 3 weeks (immediately post-nursing) until 12 weeks (full maturity) using nine different diets varying in all three major macronutrients to parse out the effects of individual macronutrients. Early life macronutrient balance affected body composition and glucose homeostasis in early adulthood, with dietary protein and fat showing major effects. Despite this, mice showed rapid reversal of the effects on body composition and glucose homeostasis of early life diet feeding, upon standard diet feeding in adulthood. However, some traits were persistent, with early life low dietary protein levels stably affecting lean and muscle mass, and early life dietary fat levels stably affecting serum and liver triglyceride levels. In summary, macronutrient balance in the post-nursing early life period does not stably affect adiposity or glucose homeostasis but does impact muscle mass and lipid homeostasis in adulthood, with prominent effects of both protein and fat levels. KEY POINTS: Early life dietary low protein and high fat levels lowered and heightened body mass, respectively. These effects did not substantially persist into adulthood with rapid catch-up growth on a normal diet. Early life protein (negative) and fat (positive) levels affected fat mass. Early life low protein levels negatively affected lean mass. Low protein effects on lower lean and muscle mass persisted into adulthood. Early life macronutrient balance effects did not affect later life glucose homeostasis but early life high fat level affected later life dyslipidaemia. Effects of dietary carbohydrate levels in early and later life were minor.


Assuntos
Gorduras na Dieta , Nutrientes , Camundongos , Masculino , Animais , Gorduras na Dieta/metabolismo , Gorduras na Dieta/farmacologia , Dieta com Restrição de Proteínas , Proteínas Alimentares , Glucose/metabolismo , Biometria
4.
Nutrients ; 13(5)2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33926065

RESUMO

Prior studies have reported that dietary protein dilution (DPD) or amino acid dilution promotes heightened water intake (i.e., hyperdipsia) however, the exact dietary requirements and the mechanism responsible for this effect are still unknown. Here, we show that dietary amino acid (AA) restriction is sufficient and required to drive hyperdipsia during DPD. Our studies demonstrate that particularly dietary essential AA (EAA) restriction, but not non-EAA, is responsible for the hyperdipsic effect of total dietary AA restriction (DAR). Additionally, by using diets with varying amounts of individual EAA under constant total AA supply, we demonstrate that restriction of threonine (Thr) or tryptophan (Trp) is mandatory and sufficient for the effects of DAR on hyperdipsia and that liver-derived fibroblast growth factor 21 (FGF21) is required for this hyperdipsic effect. Strikingly, artificially introducing Thr de novo biosynthesis in hepatocytes reversed hyperdipsia during DAR. In summary, our results show that the DPD effects on hyperdipsia are induced by the deprivation of Thr and Trp, and in turn, via liver/hepatocyte-derived FGF21.


Assuntos
Aminoácidos Essenciais/administração & dosagem , Proteínas Alimentares/administração & dosagem , Fatores de Crescimento de Fibroblastos/metabolismo , Polidipsia , Animais , Ingestão de Líquidos , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Necessidades Nutricionais , Água
5.
Nat Metab ; 3(3): 394-409, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33758419

RESUMO

Both obesity and sarcopenia are frequently associated in ageing, and together may promote the progression of related conditions such as diabetes and frailty. However, little is known about the pathophysiological mechanisms underpinning this association. Here we show that systemic alanine metabolism is linked to glycaemic control. We find that expression of alanine aminotransferases is increased in the liver in mice with obesity and diabetes, as well as in humans with type 2 diabetes. Hepatocyte-selective silencing of both alanine aminotransferase enzymes in mice with obesity and diabetes retards hyperglycaemia and reverses skeletal muscle atrophy through restoration of skeletal muscle protein synthesis. Mechanistically, liver alanine catabolism driven by chronic glucocorticoid and glucagon signalling promotes hyperglycaemia and skeletal muscle wasting. We further provide evidence for amino acid-induced metabolic cross-talk between the liver and skeletal muscle in ex vivo experiments. Taken together, we reveal a metabolic inter-tissue cross-talk that links skeletal muscle atrophy and hyperglycaemia in type 2 diabetes.


Assuntos
Alanina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Hiperglicemia/metabolismo , Fígado/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/metabolismo , Alanina/sangue , Alanina Transaminase/sangue , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Homeostase , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo
6.
Nat Commun ; 11(1): 2894, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32518324

RESUMO

Dietary protein dilution (DPD) promotes metabolic-remodelling and -health but the precise nutritional components driving this response remain elusive. Here, by mimicking amino acid (AA) supply from a casein-based diet, we demonstrate that restriction of dietary essential AA (EAA), but not non-EAA, drives the systemic metabolic response to total AA deprivation; independent from dietary carbohydrate supply. Furthermore, systemic deprivation of threonine and tryptophan, independent of total AA supply, are both adequate and necessary to confer the systemic metabolic response to both diet, and genetic AA-transport loss, driven AA restriction. Dietary threonine restriction (DTR) retards the development of obesity-associated metabolic dysfunction. Liver-derived fibroblast growth factor 21 is required for the metabolic remodelling with DTR. Strikingly, hepatocyte-selective establishment of threonine biosynthetic capacity reverses the systemic metabolic response to DTR. Taken together, our studies of mice demonstrate that the restriction of EAA are sufficient and necessary to confer the systemic metabolic effects of DPD.


Assuntos
Aminoácidos Essenciais/deficiência , Ração Animal , Proteinúria/metabolismo , Animais , Proteínas Alimentares/metabolismo , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Hormônios Gastrointestinais/metabolismo , Hepatócitos/metabolismo , Homeostase , Fígado/metabolismo , Masculino , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Fenótipo , Treonina/deficiência , Triptofano/deficiência
7.
Cell Stem Cell ; 25(2): 241-257.e8, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31303549

RESUMO

Brain tumor stem cells (BTSCs) are a chemoresistant population that can drive tumor growth and relapse, but the lack of BTSC-specific markers prevents selective targeting that spares resident stem cells. Through a ribosome-profiling analysis of mouse neural stem cells (NSCs) and BTSCs, we find glycerol-3-phosphate dehydrogenase 1 (GPD1) expression specifically in BTSCs and not in NSCs. GPD1 expression is present in the dormant BTSC population, which is enriched at tumor borders and drives tumor relapse after chemotherapy. GPD1 inhibition prolongs survival in mouse models of glioblastoma in part through altering cellular metabolism and protein translation, compromising BTSC maintenance. Metabolomic and lipidomic analyses confirm that GPD1+ BTSCs have a profile distinct from that of NSCs, which is dependent on GPD1 expression. Similar GPD1 expression patterns and prognostic associations are observed in human gliomas. This study provides an attractive therapeutic target for treating brain tumors and new insights into mechanisms regulating BTSC dormancy.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Glioma/metabolismo , Glicerolfosfato Desidrogenase/metabolismo , Células-Tronco Neoplásicas/fisiologia , Células-Tronco Neurais/fisiologia , Neurônios/fisiologia , Animais , Biomarcadores Tumorais/metabolismo , Encéfalo/patologia , Neoplasias Encefálicas/patologia , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Regulação Neoplásica da Expressão Gênica , Glioblastoma/patologia , Glioma/patologia , Glicerolfosfato Desidrogenase/genética , Humanos , Metaboloma , Camundongos , Recidiva , Células Tumorais Cultivadas
8.
J Neurosci ; 29(43): 13640-8, 2009 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-19864576

RESUMO

Growth/differentiation factor-15 (GDF-15) is a widely expressed distant member of the TGF-beta superfamily with prominent neurotrophic effects on midbrain dopaminergic neurons. We show here that GDF-15-deficient mice exhibit progressive postnatal losses of spinal, facial, and trigeminal motoneurons. This deficit reaches a approximately 20% maximum at 6 months and is accompanied by losses of motor axons and significant impairment of rotarod skills. Similarly, sensory neurons in dorsal root ganglia (L4, L5) are reduced by 20%, whereas sympathetic neurons are not affected. GDF-15 is expressed and secreted by Schwann cells, retrogradely transported along adult sciatic nerve axons, and promotes survival of axotomized facial neurons as well as cultured motor, sensory, and sympathetic neurons. Despite striking similarities in the GDF-15 and CNTF knock-out phenotypes, expression levels of CNTF and other neurotrophic factors in the sciatic nerve were unaltered suggesting that GDF-15 is a genuine novel trophic factor for motor and sensory neurons.


Assuntos
Fator 15 de Diferenciação de Crescimento/fisiologia , Neurônios Motores/fisiologia , Neurônios/fisiologia , Animais , Morte Celular/fisiologia , Sobrevivência Celular/fisiologia , Células Cultivadas , Fator Neurotrófico Ciliar/metabolismo , Nervo Facial/crescimento & desenvolvimento , Nervo Facial/fisiopatologia , Gânglios Espinais/fisiopatologia , Fator 15 de Diferenciação de Crescimento/deficiência , Fator 15 de Diferenciação de Crescimento/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Destreza Motora/fisiologia , Músculo Esquelético/fisiopatologia , Células de Schwann/fisiologia , Nervo Isquiático/fisiopatologia , Células Receptoras Sensoriais/fisiologia , Medula Espinal/crescimento & desenvolvimento , Medula Espinal/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Nervo Trigêmeo/crescimento & desenvolvimento , Nervo Trigêmeo/fisiopatologia
9.
Proc Natl Acad Sci U S A ; 106(6): 2001-6, 2009 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-19179400

RESUMO

Regulated exocytosis requires tight coupling of the membrane fusion machinery to a triggering signal and a fast response time. Complexins are part of this regulation and, together with synaptotagmins, control calcium-dependent exocytosis. Stimulatory and inhibitory functions have been reported for complexins. To test if complexins directly affect membrane fusion, we analyzed the 4 known mammalian complexin isoforms in a reconstituted fusion assay. In contrast to complexin III (CpxIII) and CpxIV, CpxI and CpxII stimulated soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-pin assembly and membrane fusion. This stimulatory effect required a preincubation at low temperature and was specific for neuronal t-SNAREs. Stimulation of membrane fusion was lost when the carboxy-terminal domain of CpxI was deleted or serine 115, a putative phosphorylation site, was mutated. Transfer of the carboxy-terminal domain of CpxI to CpxIII resulted in a stimulatory CpxIII-I chimera. Thus, the carboxy-terminal domains of CpxI and CpxII promote the fusion of high-curvature liposomes.


Assuntos
Lipossomos , Fusão de Membrana , Proteínas do Tecido Nervoso/farmacologia , Proteínas Adaptadoras de Transporte Vesicular , Sequência de Aminoácidos , Lipossomos/química , Estrutura Terciária de Proteína , Proteínas SNARE/farmacologia , Proteína 2 Associada à Membrana da Vesícula/farmacologia
10.
Eur J Neurosci ; 25(4): 1079-86, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17331204

RESUMO

Alzheimer's disease (AD) is characterized by neurofibrillary tangles and extracellular plaques, which consist mainly of beta-amyloid derived from the beta-amyloid precursor protein (APP). An additional feature of AD is axonopathy, which might contribute to impairment of cognitive functions. Specifically, axonal transport defects have been reported in AD animal models, including mice and flies that overexpress APP and tau. Here we demonstrate that the APP-induced traffic jam of vesicles in peripheral nerves of Drosophila melanogaster larvae depends on the four residues NPTY motif in the APP intracellular domain. Furthermore, heterologous expression of Fe65 and JIP1b, scaffolding proteins interacting with the NPTY motif, also perturb axonal transport. Together, these data indicate that JIP1b or Fe65 may be involved in the APP-induced axonal transport defect. Moreover, we have characterized neurotransmission at the neuromuscular junction in transgenic larvae that express human APP. Consistent with the observation that these larvae do not show any obvious movement deficits, we found no changes in basal synaptic transmission. However, short-term synaptic plasticity was affected by overexpression of APP. Together, our results show that overexpression of APP induces partial stalling of axonal transport vesicles, paralleled by abnormalities in synaptic plasticity, which may provide a functional link to the deterioration of cognitive functions observed in AD.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Axônios/metabolismo , Junção Neuromuscular/fisiologia , Sinaptotagminas/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Motivos de Aminoácidos/fisiologia , Análise de Variância , Animais , Animais Geneticamente Modificados , Drosophila melanogaster , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Larva , Camundongos , Mutagênese/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo
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