RESUMO
G-protein-coupled receptors (GPCRs) mediate neuromodulation through the activation of heterotrimeric G proteins (Gαßγ). Classical models depict that G protein activation leads to a one-to-one formation of Gα-GTP and Gßγ species. Each of these species propagates signaling by independently acting on effectors, but the mechanisms by which response fidelity is ensured by coordinating Gα and Gßγ responses remain unknown. Here, we reveal a paradigm of G protein regulation whereby the neuronal protein GINIP (Gα inhibitory interacting protein) biases inhibitory GPCR responses to favor Gßγ over Gα signaling. Tight binding of GINIP to Gαi-GTP precludes its association with effectors (adenylyl cyclase) and, simultaneously, with regulator-of-G-protein-signaling (RGS) proteins that accelerate deactivation. As a consequence, Gαi-GTP signaling is dampened, whereas Gßγ signaling is enhanced. We show that this mechanism is essential to prevent the imbalances of neurotransmission that underlie increased seizure susceptibility in mice. Our findings reveal an additional layer of regulation within a quintessential mechanism of signal transduction that sets the tone of neurotransmission.
Assuntos
Subunidades beta da Proteína de Ligação ao GTP , Proteínas Heterotriméricas de Ligação ao GTP , Camundongos , Animais , Subunidades Proteicas/metabolismo , Transdução de Sinais/fisiologia , Proteínas Heterotriméricas de Ligação ao GTP/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Guanosina Trifosfato , Subunidades beta da Proteína de Ligação ao GTP/genéticaRESUMO
GNAO1 encephalopathy is a neurodevelopmental disorder with a spectrum of symptoms that include dystonic movements, seizures and developmental delay. While numerous GNAO1 mutations are associated with this disorder, the functional consequences of pathological variants are not completely understood. Here, we deployed the invertebrate C. elegans as a whole-animal behavioral model to study the functional effects of GNAO1 disorder-associated mutations. We tested several pathological GNAO1 mutations for effects on locomotor behaviors using a combination of CRISPR/Cas9 gene editing and transgenic overexpression in vivo. We report that all three mutations tested (G42R, G203R and R209C) result in strong loss of function defects when evaluated as homozygous CRISPR alleles. In addition, mutations produced dominant negative effects assessed using both heterozygous CRISPR alleles and transgenic overexpression. Experiments in mice confirmed dominant negative effects of GNAO1 G42R, which impaired numerous motor behaviors. Thus, GNAO1 pathological mutations result in conserved functional outcomes across animal models. Our study further establishes the molecular genetic basis of GNAO1 encephalopathy, and develops a CRISPR-based pipeline for functionally evaluating mutations associated with neurodevelopmental disorders.
Assuntos
Encefalopatias , Transtornos do Neurodesenvolvimento , Animais , Encefalopatias/genética , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Proteínas de Ligação ao GTP/genética , Camundongos , Mutação , Transtornos do Neurodesenvolvimento/genéticaRESUMO
The habenula, an ancient small brain area in the epithalamus, densely expresses nicotinic acetylcholine receptors and is critical for nicotine intake and aversion. As such, identification of strategies to manipulate habenular activity may yield approaches to treat nicotine addiction. Here we show that GPR151, an orphan G-protein-coupled receptor (GPCR) highly enriched in the habenula of humans and rodents, is expressed at presynaptic membranes and synaptic vesicles and associates with synaptic components controlling vesicle release and ion transport. Deletion of Gpr151 inhibits evoked neurotransmission but enhances spontaneous miniature synaptic currents and eliminates short-term plasticity induced by nicotine. We find that GPR151 couples to the G-alpha inhibitory protein Gαo1 to reduce cyclic adenosine monophosphate (cAMP) levels in mice and in GPR151-expressing cell lines that are amenable to ligand screens. Gpr151- knockout (KO) mice show diminished behavioral responses to nicotine and self-administer greater quantities of the drug, phenotypes rescued by viral reexpression of Gpr151 in the habenula. These data identify GPR151 as a critical modulator of habenular function that controls nicotine addiction vulnerability.
Assuntos
Habenula/fisiologia , Plasticidade Neuronal/fisiologia , Nicotina/metabolismo , Agonistas Nicotínicos/metabolismo , Receptores Acoplados a Proteínas G/fisiologia , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Animais , Células CHO , Cricetulus , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Habenula/metabolismo , Humanos , Camundongos Knockout , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/genética , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Receptores Acoplados a Proteínas G/genética , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologiaRESUMO
OBJECTIVES: Gut microbiota is a key component in obesity and type 2 diabetes, yet mechanisms and metabolites central to this interaction remain unclear. We examined the human gut microbiome's functional composition in healthy metabolic state and the most severe states of obesity and type 2 diabetes within the MetaCardis cohort. We focused on the role of B vitamins and B7/B8 biotin for regulation of host metabolic state, as these vitamins influence both microbial function and host metabolism and inflammation. DESIGN: We performed metagenomic analyses in 1545 subjects from the MetaCardis cohorts and different murine experiments, including germ-free and antibiotic treated animals, faecal microbiota transfer, bariatric surgery and supplementation with biotin and prebiotics in mice. RESULTS: Severe obesity is associated with an absolute deficiency in bacterial biotin producers and transporters, whose abundances correlate with host metabolic and inflammatory phenotypes. We found suboptimal circulating biotin levels in severe obesity and altered expression of biotin-associated genes in human adipose tissue. In mice, the absence or depletion of gut microbiota by antibiotics confirmed the microbial contribution to host biotin levels. Bariatric surgery, which improves metabolism and inflammation, associates with increased bacterial biotin producers and improved host systemic biotin in humans and mice. Finally, supplementing high-fat diet-fed mice with fructo-oligosaccharides and biotin improves not only the microbiome diversity, but also the potential of bacterial production of biotin and B vitamins, while limiting weight gain and glycaemic deterioration. CONCLUSION: Strategies combining biotin and prebiotic supplementation could help prevent the deterioration of metabolic states in severe obesity. TRIAL REGISTRATION NUMBER: NCT02059538.
Assuntos
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Obesidade Mórbida , Complexo Vitamínico B , Humanos , Camundongos , Animais , Prebióticos , Obesidade Mórbida/cirurgia , Biotina/farmacologia , Complexo Vitamínico B/farmacologia , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , InflamaçãoRESUMO
BACKGROUND: Personalizing approaches to prevention and treatment of obesity will be a crucial aspect of precision health initiatives. However, in considering individual susceptibility to obesity, much remains to be learned about how to support healthy weight management in different population subgroups, environments and geographical locations. SUBJECTS/METHODS: The International Weight Control Registry (IWCR) has been launched to facilitate a deeper and broader understanding of the spectrum of factors contributing to success and challenges in weight loss and weight loss maintenance in individuals and across population groups. The IWCR registry aims to recruit, enroll and follow a diverse cohort of adults with varying rates of success in weight management. Data collection methods include questionnaires of demographic variables, weight history, and behavioral, cultural, economic, psychological, and environmental domains. A subset of participants will provide objective measures of physical activity, weight, and body composition along with detailed reports of dietary intake. Lastly, participants will be able to provide qualitative information in an unstructured format on additional topics they feel are relevant, and environmental data will be obtained from public sources based on participant zip code. CONCLUSIONS: The IWCR will be a resource for researchers to inform improvements in interventions for weight loss and weight loss maintenance in different countries, and to examine environmental and policy-level factors that affect weight management in different population groups. This large scale, multi-level approach aims to inform efforts to reduce the prevalence of obesity worldwide and its associated comorbidities and economic impacts. TRIAL REGISTRATION: NCT04907396 (clinicaltrials.gov) sponsor SB Roberts; Tufts University IRB #13075.
Assuntos
Obesidade , Redução de Peso , Adulto , Exercício Físico , Nível de Saúde , Humanos , Obesidade/epidemiologia , Obesidade/prevenção & controle , Sistema de RegistrosRESUMO
The striatum plays a fundamental role in motor learning and reward-related behaviors that are synergistically shaped by populations of D1 dopamine receptor (D1R)- and D2 dopamine receptor (D2R)-expressing medium spiny neurons (MSNs). How various neurotransmitter inputs converging on common intracellular pathways are parsed out to regulate distinct behavioral outcomes in a neuron-specific manner is poorly understood. Here, we reveal that distinct contributions of D1R-MSNs and D2R-MSNs towards reward and motor behaviors are delineated by the multifaceted signaling protein neurofibromin 1 (NF1). Using genetic mouse models, we show that NF1 in D1R-MSN modulates opioid reward, whereas loss of NF1 in D2R-MSNs delays motor learning by impeding the formation and consolidation of repetitive motor sequences. We found that motor learning deficits upon NF1 loss were associated with the disruption in dopamine signaling to cAMP in D2R-MSN. Restoration of cAMP levels pharmacologically or chemogenetically rescued the motor learning deficits seen upon NF1 loss in D2R-MSN. Our findings illustrate that multiplex signaling capabilities of MSNs are deployed at the level of intracellular pathways to achieve cell-specific control over behavioral outcomes.
Assuntos
Corpo Estriado/fisiologia , Neurofibromina 1/metabolismo , Neurônios/fisiologia , Animais , AMP Cíclico/metabolismo , Dopamina/metabolismo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Atividade Motora/fisiologia , Neurônios/metabolismo , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Recompensa , Transdução de SinaisRESUMO
Lifestyle interventions for weight loss combine support for changing diet and physical activity with weight management education and are considered the first line treatment for obesity. A variety of diet-focused interventions including time-restricted eating are also increasingly being promoted for weight management. This chapter reviews different types of interventions for weight management, their underlying health behavior change models, and effectiveness to date in randomized trials. The results justify increasing efforts to improve program effectiveness generally, and to personalize interventions to support long-term adherence. The high prevalence of obesity worldwide, combined with the known increase in risk of non-communicable diseases with duration of excess weight, provides a compelling justification for routine delivery of effective weight management interventions in the community and in clinical care.
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Obesidade , Redução de Peso , Exercício Físico , Humanos , Estilo de Vida , Obesidade/epidemiologia , Obesidade/terapiaRESUMO
Abstract: Recent investigations highlight the importance of the gut microbiota and bacteria-derived metabolites as key components in obesity and metabolic health. The microbiota-gut-brain axis presents promising targets for future obesity treatments and prevention. However, the current state of evidence and existing clinical applications of the microbiota-gut-brain axis have yet to be summarized in a thorough review. Therefore, we sought to examine current evidence on the effect of lifestyle, dietary, pharmacological, and surgical interventions on the microbiota-gut-brain axis. In addition, this review highlights potential next steps in research toward characterizing the role of the microbiota-gut-brain axis in metabolic health, along with possible interventions to address obesity.
Assuntos
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Humanos , Diabetes Mellitus Tipo 2/terapia , Eixo Encéfalo-Intestino , Obesidade/terapia , Dieta , Encéfalo/metabolismoRESUMO
BACKGROUND: Epidemiological studies suggest that higher fruits and vegetables (F&V) consumption correlates with reduced risk of hepatic steatosis, yet evidence for causality and the underlying mechanisms is lacking. OBJECTIVES: We aimed to determine the causal relation between F&V consumption and improved metabolic disorders in mice fed high-fat (HF) (Experiment-1) or normal-fat (Experiment-2) diets and its underlying mechanisms. METHODS: Six-week-old male C57BL/6J mice were randomly grouped and fed diets supplemented at 0%-15% (wt:wt) with a freeze-dried powder composed of 24 commonly consumed F&V (human equivalent of 0-9 servings/d) for 20 wk. In Experiment-1, mice were fed an HF (45% kcal fat) diet with 0% (HF0), 5%, 10%, or 15% (HF15) F&V or a matched low-fat control diet (10% kcal fat). In Experiment-2, mice were fed an AIN-93 diet (basal) (B, 16% kcal fat) with 0% (B0), 5%, 10%, or 15% (B15) F&V supplementation. Body weight and composition, food intake, hepatic steatosis, inflammation, ceramide levels, sphingomyelinase activity, and gut microbiota were assessed. RESULTS: In Experiment-1, mice fed the HF15 diet had lower weight gain (17.9%), hepatic steatosis (48.4%), adipose tissue inflammation, blood (24.6%) and liver (33.9%) ceramide concentrations, and sphingomyelinase activity (38.8%) than HF0 mice (P < 0.05 for all). In Experiment-2, mice fed the B15 diet had no significant changes in weight gain but showed less hepatic steatosis (28.5%), blood and adipose tissue inflammation, and lower blood (30.0%) ceramide concentrations than B0 mice (P < 0.05 for all). These F&V effects were associated with favorable microbiota changes. CONCLUSIONS: These findings represent the first evidence for a causal role of high F&V intake in mitigating hepatic steatosis in mice. These beneficial effects may be mediated through changes in ceramide and/or gut microbiota, and suggest that higher than currently recommended servings of F&V may be needed to achieve maximum health benefits.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/prevenção & controle , Frutas , Doenças Metabólicas/etiologia , Verduras , Ração Animal , Animais , Ceramidas/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Aumento de PesoRESUMO
Lipidomic techniques can improve our understanding of complex lipid interactions that regulate metabolic diseases. Here, a serum phospholipidomics analysis identified associations between phosphatidylglycerols (PGs) and gut microbiota dysbiosis. Compared with the other phospholipids, serum PGs were the most elevated in patients with low microbiota gene richness, which were normalized after a dietary intervention that restored gut microbial diversity. Serum PG levels were positively correlated with metagenomic functional capacities for bacterial LPS synthesis and host markers of low-grade inflammation; transcriptome databases identified PG synthase, the first committed enzyme in PG synthesis, as a potential mediator. Experiments in mice and cultured human-derived macrophages demonstrated that LPS induces PG release. Acute PG treatment in mice altered adipose tissue gene expression toward remodeling and inhibited ex vivo lipolysis in adipose tissue, suggesting that PGs favor lipid storage. Indeed, several PG species were associated with the severity of obesity in mice and humans. Finally, despite enrichment in PGs in bacterial membranes, experiments employing gnotobiotic mice colonized with recombinant PG overproducing Lactococcus lactis showed limited direct contribution of microbial PGs to the host. In summary, PGs are inflammation-responsive lipids indirectly regulated by the gut microbiota via endotoxins and regulate adipose tissue homeostasis in obesity.-Kayser, B. D., Lhomme, M., Prifti, E., Da Cunha, C., Marquet, F., Chain, F., Naas, I., Pelloux, V., Dao, M.-C., Kontush, A., Rizkalla, S. W., Aron-Wisnewsky, J., Bermúdez-Humarán, L. G., Oakley, F., Langella, P., Clément, K., Dugail, I. Phosphatidylglycerols are induced by gut dysbiosis and inflammation, and favorably modulate adipose tissue remodeling in obesity.
Assuntos
Tecido Adiposo/metabolismo , Disbiose/metabolismo , Inflamação/metabolismo , Obesidade/metabolismo , Fosfatidilgliceróis/metabolismo , Animais , Feminino , Humanos , Lipidômica/métodos , Lipólise/fisiologia , Masculino , Metagenômica/métodos , CamundongosRESUMO
The functional characterization of the GPCR interactome has predominantly focused on intracellular binding partners; however, the recent emergence of transsynaptic GPCR complexes represents an additional dimension to GPCR function that has previously been unaccounted for in drug discovery. Here, we characterize ELFN2 as a novel postsynaptic adhesion molecule with a distinct expression pattern throughout the brain and a selective binding with group III metabotropic glutamate receptors (mGluRs) in trans. Using a transcellular GPCR signaling platform, we report that ELFN2 critically alters group III mGluR secondary messenger signaling by directly altering G protein coupling kinetics and efficacy. Loss of ELFN2 in mice results in the selective downregulation of group III mGluRs and dysregulated glutamatergic synaptic transmission. Elfn2 knockout (Elfn2 KO) mice also feature a range of neuropsychiatric manifestations including seizure susceptibility, hyperactivity, and anxiety/compulsivity, which can be rescued by pharmacological augmentation of group III mGluRs. Thus, we conclude that extracellular transsynaptic scaffolding by ELFN2 in the brain is a cardinal organizational feature of group III mGluRs essential for their signaling properties and brain function.
Assuntos
Proteínas do Tecido Nervoso/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Encéfalo/metabolismo , Feminino , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Moléculas de Adesão de Célula Nervosa/metabolismo , Transmissão Sináptica/fisiologiaRESUMO
OBJECTIVES: Decreased gut microbial gene richness (MGR) and compositional changes are associated with adverse metabolism in overweight or moderate obesity, but lack characterisation in severe obesity. Bariatric surgery (BS) improves metabolism and inflammation in severe obesity and is associated with gut microbiota modifications. Here, we characterised severe obesity-associated dysbiosis (ie, MGR, microbiota composition and functional characteristics) and assessed whether BS would rescue these changes. DESIGN: Sixty-one severely obese subjects, candidates for adjustable gastric banding (AGB, n=20) or Roux-en-Y-gastric bypass (RYGB, n=41), were enrolled. Twenty-four subjects were followed at 1, 3 and 12 months post-BS. Gut microbiota and serum metabolome were analysed using shotgun metagenomics and liquid chromatography mass spectrometry (LC-MS). Confirmation groups were included. RESULTS: Low gene richness (LGC) was present in 75% of patients and correlated with increased trunk-fat mass and comorbidities (type 2 diabetes, hypertension and severity). Seventy-eight metagenomic species were altered with LGC, among which 50% were associated with adverse body composition and metabolic phenotypes. Nine serum metabolites (including glutarate, 3-methoxyphenylacetic acid and L-histidine) and functional modules containing protein families involved in their metabolism were strongly associated with low MGR. BS increased MGR 1 year postsurgery, but most RYGB patients remained with low MGR 1 year post-BS, despite greater metabolic improvement than AGB patients. CONCLUSIONS: We identified major gut microbiota alterations in severe obesity, which include decreased MGR and related functional pathways linked with metabolic deteriorations. The lack of full rescue post-BS calls for additional strategies to improve the gut microbiota ecosystem and microbiome-host interactions in severe obesity. TRIAL REGISTRATION NUMBER: NCT01454232.
Assuntos
Cirurgia Bariátrica , Disbiose/etiologia , Microbioma Gastrointestinal , Obesidade Mórbida/microbiologia , Obesidade Mórbida/cirurgia , Adulto , Biomarcadores/sangue , Cromatografia Líquida , Comorbidade , Feminino , Humanos , Masculino , Espectrometria de Massas , Metagenômica , Fenótipo , Estudos Prospectivos , Fatores de RiscoRESUMO
In the striatum, medium spiny neurons (MSNs) are heavily involved in controlling movement and reward. MSNs form two distinct populations expressing either dopamine receptor 1 (D1-MSN) or dopamine receptor 2 (D2-MSN), which differ in their projection targets and neurochemical composition. The activity of both types of MSNs is shaped by multiple neuromodulatory inputs processed by GPCRs that fundamentally impact their synaptic properties biasing behavioral outcomes. How these GPCR signaling cascades are regulated and what downstream targets they recruit in D1-MSN and D2-MSN populations are incompletely understood. In this study, we examined the cellular and molecular mechanisms underlying the action of RGS9-2, a key GPCR regulator in MSNs implicated in both movement control and actions of addictive drugs. Imaging cultured striatal neurons, we found that ablation of RGS9-2 significantly reduced calcium influx through NMDARs. Electrophysiological recordings in slices confirmed inhibition of NMDAR function in MSNs, resulting in enhanced AMPAR/NMDAR ratio. Accordingly, male mice lacking RGS9-2 displayed behavioral hypersensitivity to NMDAR blockade by MK-801 or ketamine. Recordings from genetically identified populations of striatal neurons revealed that these changes were selective to D2-MSNs. Surprisingly, we found that these postsynaptic effects resulted in remodeling of presynaptic inputs to D2-MSNs increasing the frequency of mEPSC and inhibiting paired-pulse ratio. Pharmacological dissection revealed that these adaptations were mediated by the NMDAR-dependent inhibition of retrograde endocannabinoid signaling from D2-MSNs to CB1 receptor on presynaptic terminals. Together, these data demonstrate a novel mechanism for pathway selective regulation of synaptic plasticity in MSNs controlled by GPCR signaling.SIGNIFICANCE STATEMENT This study identifies a role for a major G-protein regulator in controlling synaptic properties of striatal neurons in a pathway selective fashion.
Assuntos
Corpo Estriado/fisiologia , Neurônios Dopaminérgicos/fisiologia , Proteínas RGS/fisiologia , Transmissão Sináptica/fisiologia , Animais , Sinalização do Cálcio , Células Cultivadas , Corpo Estriado/citologia , Neurônios Dopaminérgicos/química , Neurônios Dopaminérgicos/classificação , Neurônios Dopaminérgicos/efeitos dos fármacos , Endocanabinoides/fisiologia , Comportamento Exploratório , Feminino , Genes Reporter , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Knockout , Técnicas de Patch-Clamp , Terminações Pré-Sinápticas/metabolismo , Proteínas RGS/deficiência , Proteínas RGS/genética , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/fisiologia , Receptores de Dopamina D2/análise , Receptores de Dopamina D2/genética , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Teste de Desempenho do Rota-Rod , Sinapses/fisiologiaRESUMO
The gut bacterial species Akkermansia muciniphila is associated with a healthier clinical profile. The purpose of this study was to determine the association between A. muciniphila and glucose homeostasis in patients undergoing bariatric surgery (BS): gastric banding (GB) or Roux-en-Y gastric bypass (RYGB). This nonrandomized prospective study included 65 women with severe obesity. Longitudinal analysis included subjects for whom A. muciniphila data were available at follow-up [1, 3, and 12 mo; GB (n = 10) or RYGB (n = 11)]. Glucose homeostasis markers were measured under fasting conditions (glucose, insulin, and HbA1c) or during an oral glucose tolerance test. Fecal microbiota was analyzed using shotgun metagenomics, and A. muciniphila relative abundance was assessed with 16S rRNA quantitative PCR. A. muciniphila relative abundance was significantly lower in severe obesity [mean body mass index, 45.7 kg/m2 (SD 5.4)] than in moderate obesity [33.2 kg/m2 (SD 3.8)] but not associated with glucose homeostasis markers. A significant increase in A. muciniphila relative abundance after RYGB was not correlated with metabolic improvement. Baseline A. muciniphila abundance was correlated with bacterial gene richness and was highest in the high-richness Ruminococcaceae enterotype. A. muciniphila increased in relative abundance after BS in patients with low baseline A. muciniphila abundance, especially those with a Bacteroides type 2 enterotype classification. Although decreased in severe obesity, relative abundance of A. muciniphila was not associated with glucose homeostasis before or after BS. A certain level of A. muciniphila abundance might be required to observe a beneficial link to health. The severity of obesity and gut dysbiosis may partly explain the discrepancy with previous findings in less obese populations.
Assuntos
Cirurgia Bariátrica , Microbioma Gastrointestinal , Obesidade Mórbida/microbiologia , Obesidade Mórbida/cirurgia , Verrucomicrobia , Adulto , Akkermansia , Disbiose , Fezes/microbiologia , Feminino , Glucose/metabolismo , Teste de Tolerância a Glucose , Nível de Saúde , Homeostase , Humanos , Resistência à Insulina , Estudos Longitudinais , Pessoa de Meia-Idade , Obesidade Mórbida/metabolismo , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Low gut microbiome richness is associated with dyslipidemia and insulin resistance, and ceramides and other sphingolipids are implicated in the development of diabetes. OBJECTIVES: Determine whether circulating sphingolipids, particularly ceramides, are associated with alterations in the gut microbiome among obese patients with increased diabetes risk. METHODS: This was a cross-sectional and longitudinal retrospective analysis of a dietary/weight loss intervention. Fasted serum was collected from 49 participants (41 women) and analyzed by HPLC-MS/MS to quantify 45 sphingolipids. Shotgun metagenomic sequencing of stool was performed to profile the gut microbiome. RESULTS: Confirming the link to deteriorated glucose homeostasis, serum ceramides were positively correlated with fasting glucose, but inversely correlated with fasting and OGTT-derived measures of insulin sensitivity and ß-cell function. Significant associations with gut dysbiosis were demonstrated, with SM and ceramides being inversely correlated with gene richness. Ceramides with fatty acid chain lengths of 20-24 carbons were the most associated with low richness. Diet-induced weight loss, which improved gene richness, decreased most sphingolipids. Thirty-one MGS, mostly corresponding to unidentified bacteria species, were inversely correlated with ceramides, including a number of Bifidobacterium and Methanobrevibacter smithii. Higher ceramide levels were also associated with increased metagenomic modules for lipopolysaccharide synthesis and flagellan synthesis, two pathogen-associated molecular patterns, and decreased enrichment of genes involved in methanogenesis and bile acid metabolism. CONCLUSION: This study identifies an association between gut microbiota richness, ceramides, and diabetes risk in overweight/obese humans, and suggests that the gut microbiota may contribute to dysregulation of lipid metabolism in metabolic disorders.
Assuntos
Ceramidas/sangue , Disbiose/sangue , Glucose/metabolismo , Metabolômica , Obesidade/sangue , Adulto , Ceramidas/metabolismo , Cromatografia Líquida de Alta Pressão , Estudos Transversais , Disbiose/metabolismo , Feminino , Microbioma Gastrointestinal , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Estudos Retrospectivos , Esfingolipídeos/sangue , Esfingolipídeos/metabolismo , Espectrometria de Massas em TandemRESUMO
OBJECTIVE: A wide variety of methods are available to assess dietary intake, each one with different strengths and weaknesses. Researchers face multiple challenges when diet and nutrition need to be accurately assessed, particularly in the selection of the most appropriate dietary assessment method for their study. The goal of the current collaborative work is to present a collection of available resources for dietary assessment implementation.Design/Setting/ParticipantsAs a follow-up to the 9th International Conference on Diet and Physical Activity Methods held in 2015, developers of dietary assessment toolkits agreed to collaborate in the preparation of the present paper, which provides an overview of each toolkit. The toolkits presented include: the Diet, Anthropometry and Physical Activity Measurement Toolkit (DAPA; UK); the National Cancer Institute's (NCI) Dietary Assessment Primer (USA); the Nutritools website (UK); the Australasian Child and Adolescent Obesity Research Network (ACAORN) method selector (Australia); and the Danone Dietary Assessment Toolkit (DanoneDAT; France). An at-a-glance summary of features and comparison of the toolkits is provided. RESULTS: The present review contains general background on dietary assessment, along with a summary of each of the included toolkits, a feature comparison table and direct links to each toolkit, all of which are freely available online. CONCLUSIONS: This overview of dietary assessment toolkits provides comprehensive information to aid users in the selection and implementation of the most appropriate dietary assessment method, or combination of methods, with the goal of collecting the highest-quality dietary data possible.
Assuntos
Inquéritos sobre Dietas , Internet , Avaliação Nutricional , Software , Antropometria , Ingestão de Alimentos , HumanosRESUMO
OBJECTIVE: Individuals with obesity and type 2 diabetes differ from lean and healthy individuals in their abundance of certain gut microbial species and microbial gene richness. Abundance of Akkermansia muciniphila, a mucin-degrading bacterium, has been inversely associated with body fat mass and glucose intolerance in mice, but more evidence is needed in humans. The impact of diet and weight loss on this bacterial species is unknown. Our objective was to evaluate the association between faecal A. muciniphila abundance, faecal microbiome gene richness, diet, host characteristics, and their changes after calorie restriction (CR). DESIGN: The intervention consisted of a 6-week CR period followed by a 6-week weight stabilisation diet in overweight and obese adults (N=49, including 41 women). Faecal A. muciniphila abundance, faecal microbial gene richness, diet and bioclinical parameters were measured at baseline and after CR and weight stabilisation. RESULTS: At baseline A. muciniphila was inversely related to fasting glucose, waist-to-hip ratio and subcutaneous adipocyte diameter. Subjects with higher gene richness and A. muciniphila abundance exhibited the healthiest metabolic status, particularly in fasting plasma glucose, plasma triglycerides and body fat distribution. Individuals with higher baseline A. muciniphila displayed greater improvement in insulin sensitivity markers and other clinical parameters after CR. These participants also experienced a reduction in A. muciniphila abundance, but it remained significantly higher than in individuals with lower baseline abundance. A. muciniphila was associated with microbial species known to be related to health. CONCLUSIONS: A. muciniphila is associated with a healthier metabolic status and better clinical outcomes after CR in overweight/obese adults. The interaction between gut microbiota ecology and A. muciniphila warrants further investigation. TRIAL REGISTRATION NUMBER: NCT01314690.
Assuntos
Dieta Redutora , Fezes/microbiologia , Microbioma Gastrointestinal , Obesidade/dietoterapia , Verrucomicrobia/isolamento & purificação , Adulto , Idoso , Biomarcadores/sangue , Glicemia/metabolismo , Feminino , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/microbiologia , Resultado do Tratamento , Triglicerídeos/sangueRESUMO
Lifestyle programs that reduce health risks and support weight loss (WL) in older adults face adherence and attendance challenges due to reduced energy requirements, impaired mobility, lack of transportation, and low social support. Tailored lifestyle and weight management programs are needed to better support healthy aging for older adults. Here, we developed and piloted an age-adapted, remotely delivered modification of the Diabetes Prevention Program (DPP). The modification includes age-appropriate goals, visuals, and examples; flexible dietary composition; remote classroom and fitness-monitoring technology; and standardized online classroom materials employing pedagogical and behavior change theory. The modifications were designed to safeguard fidelity and to boost adherence, engagement, and knowledge integration, with the convenience of a fully remote WL program for diverse older adults. Six-month pilot data are presented from older adults (55-85 years, body mass index (BMI) 27-39.9 kg/m2, N = 20) randomly allocated to an online DPP intervention with weight, diet, and activity monitored remotely, or into a waitlisted control. The intervention achieved 100% attendance and adherence to self-monitoring. The intervention group mean (±SD) body weight change was -9.5% (±4.1); 90% lost ≥ 5%. By contrast, the control group gained 2.4% (±1.8). Once thought incompatible with older adults, remote interventions are feasible for older adults and can support fidelity, adherence, engagement, and clinically significant WL. Standardized materials are provided for future implementation.
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Diabetes Mellitus Tipo 2 , Exercício Físico , Humanos , Idoso , Estudos de Viabilidade , Projetos Piloto , Índice de Massa CorporalRESUMO
[This corrects the article DOI: 10.3389/fnut.2023.1230061.].
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Background: The burden of obesity and chronic disease is increasing in the older US Hispanic/Latino adult population. There is limited evidence on successful weight management strategies as perceived by this population. Assessing barriers and opportunities for weight management using mixed methods is a robust approach to collect in-depth information that can be applied to the development of well-tailored weight management interventions for this population. Objective: The objective of this study was to assess perceived individual, interpersonal, and environmental factors that influence weight management in older Hispanic/Latino adults. Methods: This community-based cross-sectional study included 23 Hispanic/Latino older (>50y) adults with obesity (BMI >30 kg/m2). Perceived barriers and opportunities for weight management were assessed through validated questionnaires and focus groups. Prospectively registered on ClinicalTrials.gov (NCT03978416) on 7 June 2019. Results: In this demographically heterogeneous population, language acculturation was generally low, and the frequency of poor dietary behaviors was high. Participants linked financial strain to lower diet quality, as well as anxiety to uncontrolled eating and food cravings. Social support and trust in healthcare professionals were perceived as priorities for healthy eating. Structural and environmental barriers such as affordability and availability of culturally preferred foods were also identified as influences on food choices and eating behavior. Conclusions: This study revealed opportunities for culturally tailored weight management interventions in older Hispanic/Latino adults with obesity. Clinical Trial Registry Number: NCT03978416 (ClinicalTrials.gov).