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1.
Cell ; 187(15): 3877-3879, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39059363

RESUMO

In this interview with Cell, Dr. Giles Yeo shares his journey into metabolism research, his strategies for engaging audiences, and the challenges of simplifying complex concepts. He also discusses the impact of social media, the advantages of podcasting, and the question he's most afraid of.


Assuntos
Mídias Sociais , Humanos , Comunicação , Metabolismo , História do Século XXI
2.
PLoS Med ; 21(7): e1004437, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-39052689

RESUMO

In the Editorial, Giles Yeo discusses if it is possible that the UPF concept could be doing more harm than good.

3.
Diabetes Metab Res Rev ; 40(5): e3829, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38850100

RESUMO

AIMS: Pancreatic polypeptide (PP) is elevated in people with vascular risk factors such as type 2 diabetes or increased visceral fat. We investigated potential relationships between PP and microvascular and macrovascular complications of diabetes. MATERIALS AND METHODS: Animal study: Subcutaneous PP infusion for 4 weeks in high fat diet mouse model. Retinal mRNA submitted for Ingenuity Pathway Analysis. Human study: fasting PP measured in 1478 participants and vascular complications recorded over median 5.5 (IQR 4.9-5.8) years follow-up. RESULTS: Animal study: The retinal transcriptional response to PP was indicative of cellular stress and damage, and this footprint matched responses described in previously published studies of retinal disease. Of mechanistic importance the transcriptional landscape was consistent with upregulation of folliculin, a recently identified susceptibility gene for diabetic retinopathy. Human study: Adjusting for established risk factors, PP was associated with prevalent and incident clinically significant retinopathy (odds ratio (OR) 1.289 (1.107-1.501) p = 0.001; hazard ratio (HR) 1.259 (1.035-1.531) p = 0.0213), albuminuria (OR 1.277 (1.124-1.454), p = 0.0002; HR 1.608 (1.208-2.141) p = 0.0011), and macrovascular disease (OR 1.021 (1.006-1.037) p = 0.0068; HR 1.324 (1.089-1.61), p = 0.0049), in individuals with type 2 diabetes, and progression to diabetes in non-diabetic individuals (HR 1.402 (1.081-1.818), p = 0.0109). CONCLUSIONS: Elevated fasting PP is independently associated with vascular complications of diabetes and affects retinal pathways potentially influencing retinal neuronal survival. Our results suggest possible new roles for PP-fold peptides in the pathophysiology of diabetes complications and vascular risk stratification.


Assuntos
Diabetes Mellitus Tipo 2 , Angiopatias Diabéticas , Retinopatia Diabética , Jejum , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/epidemiologia , Animais , Camundongos , Seguimentos , Retinopatia Diabética/etiologia , Retinopatia Diabética/epidemiologia , Retinopatia Diabética/patologia , Prognóstico , Incidência , Biomarcadores/análise , Fatores de Risco , Idoso
4.
Curr Biol ; 34(8): 1646-1656.e4, 2024 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-38518777

RESUMO

The obesity epidemic is principally driven by the consumption of more calories than the body requires. It is therefore essential that the mechanisms underpinning feeding behavior are defined. Neurons within the brainstem dorsal vagal complex (DVC) receive direct information from the digestive system and project to second-order regions in the brain to regulate food intake. Although γ-aminobutyric acid is expressed in the DVC (GABADVC), its function in this region has not been defined. In order to discover the unique gene expression signature of GABADVC cells, we used single-nucleus RNA sequencing (Nuc-seq), and this revealed 19 separate clusters. We next probed the function of GABADVC cells and discovered that the selective activation of GABADVC neurons significantly controls food intake and body weight. Optogenetic interrogation of GABADVC circuitry identified GABADVC → hypothalamic arcuate nucleus (ARC) projections as appetite suppressive without creating aversion. Electrophysiological analysis revealed that GABADVC → ARC stimulation inhibits hunger-promoting neuropeptide Y (NPY) neurons via GABA release. Adopting an intersectional genetics strategy, we clarify that the GABADVC → ARC circuit curbs food intake. These data identify GABADVC as a new modulator of feeding behavior and body weight and a controller of orexigenic NPY neuron activity, thereby providing insight into the neural underpinnings of obesity.


Assuntos
Núcleo Arqueado do Hipotálamo , Tronco Encefálico , Comportamento Alimentar , Núcleo Arqueado do Hipotálamo/metabolismo , Núcleo Arqueado do Hipotálamo/fisiologia , Animais , Tronco Encefálico/fisiologia , Tronco Encefálico/metabolismo , Camundongos , Masculino , Comportamento Alimentar/fisiologia , Neurônios GABAérgicos/fisiologia , Neurônios GABAérgicos/metabolismo , Ácido gama-Aminobutírico/metabolismo , Ingestão de Alimentos/fisiologia , Camundongos Endogâmicos C57BL , Feminino
5.
Sci Adv ; 10(10): eadj3823, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38446876

RESUMO

Mutations that perturb leptin-melanocortin signaling are known to cause hyperphagia and obesity, but energy expenditure has not been well studied outside rodents. We report on a common canine mutation in pro-opiomelanocortin (POMC), which prevents production of ß-melanocyte-stimulating hormone (ß-MSH) and ß-endorphin but not α-MSH; humans, similar to dogs, produce α-MSH and ß-MSH from the POMC propeptide, but rodents produce only α-MSH. We show that energy expenditure is markedly lower in affected dogs, which also have increased motivational salience in response to a food cue, indicating increased wanting or hunger. There was no difference in satiety at a modified ad libitum meal or in their hedonic response to food, nor disruption of adrenocorticotropic hormone (ACTH) or thyroid axes. In vitro, we show that ß-MSH signals comparably to α-MSH at melanocortin receptors. These data implicate ß-MSH and ß-endorphin as important in determining hunger and moderating energy expenditure and suggest that this role is independent of the presence of α-MSH.


Assuntos
beta-Endorfina , beta-MSH , Humanos , Cães , Animais , beta-Endorfina/genética , Metabolismo Basal , Pró-Opiomelanocortina/genética , Fome , alfa-MSH/genética
6.
Nat Metab ; 6(4): 764-777, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38429390

RESUMO

Surviving long periods without food has shaped human evolution. In ancient and modern societies, prolonged fasting was/is practiced by billions of people globally for religious purposes, used to treat diseases such as epilepsy, and recently gained popularity as weight loss intervention, but we still have a very limited understanding of the systemic adaptions in humans to extreme caloric restriction of different durations. Here we show that a 7-day water-only fast leads to an average weight loss of 5.7 kg (±0.8 kg) among 12 volunteers (5 women, 7 men). We demonstrate nine distinct proteomic response profiles, with systemic changes evident only after 3 days of complete calorie restriction based on in-depth characterization of the temporal trajectories of ~3,000 plasma proteins measured before, daily during, and after fasting. The multi-organ response to complete caloric restriction shows distinct effects of fasting duration and weight loss and is remarkably conserved across volunteers with >1,000 significantly responding proteins. The fasting signature is strongly enriched for extracellular matrix proteins from various body sites, demonstrating profound non-metabolic adaptions, including extreme changes in the brain-specific extracellular matrix protein tenascin-R. Using proteogenomic approaches, we estimate the health consequences for 212 proteins that change during fasting across ~500 outcomes and identified putative beneficial (SWAP70 and rheumatoid arthritis or HYOU1 and heart disease), as well as adverse effects. Our results advance our understanding of prolonged fasting in humans beyond a merely energy-centric adaptions towards a systemic response that can inform targeted therapeutic modulation.


Assuntos
Restrição Calórica , Jejum , Proteoma , Humanos , Proteoma/metabolismo , Feminino , Masculino , Adulto , Redução de Peso , Proteômica/métodos , Adaptação Fisiológica
7.
Clin Obes ; 14(3): e12659, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38602039

RESUMO

Nearly 90 clinicians and researchers from around the world attended the first IMPROVE 2022 International Meeting on Pathway-Related Obesity. Delegates attended in person or online from across Europe, Argentina and Israel to hear the latest scientific and clinical developments in hyperphagia and severe, early-onset obesity, and set out a vision of excellence for the future for improving the diagnosis, treatment, and care of patients with melanocortin-4 receptor (MC4R) pathway-related obesity. The meeting co-chair Peter Kühnen, Charité Universitätsmedizin Berlin, Germany, indicated that change was needed with the rapidly increasing prevalence of obesity and the associated complications to improve the understanding of the underlying mechanisms and acknowledge that monogenic forms of obesity can play an important role, providing insights that can be applied to a wider group of patients with obesity. World-leading experts presented the latest research and led discussions on the underlying science of obesity, diagnosis (including clinical and genetic approaches such as the role of defective MC4R signalling), and emerging clinical data and research with targeted pharmacological approaches. The aim of the meeting was to agree on the questions that needed to be addressed in future research and to ensure that optimised diagnostic work-up was used with new genetic testing tools becoming available. This should aid the planning of new evidence-based treatment strategies for the future, as explained by co-chair Martin Wabitsch, Ulm University Medical Center, Germany.


Assuntos
Obesidade , Receptor Tipo 4 de Melanocortina , Humanos , Hiperfagia , Obesidade/terapia , Receptor Tipo 4 de Melanocortina/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Transdução de Sinais
8.
Cell Metab ; 36(5): 1076-1087.e4, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38653246

RESUMO

Approximately 1 in 4 people worldwide have non-alcoholic fatty liver disease (NAFLD); however, there are currently no medications to treat this condition. This study investigated the role of adiposity-associated orphan G protein-coupled receptor 75 (GPR75) in liver lipid accumulation. We profiled Gpr75 expression and report that it is most abundant in the brain. Next, we generated the first single-cell-level analysis of Gpr75 and identified a subpopulation co-expressed with key appetite-regulating hypothalamic neurons. CRISPR-Cas9-deleted Gpr75 mice fed a palatable western diet high in fat adjusted caloric intake to remain in energy balance, thereby preventing NAFLD. Consistent with mouse results, analysis of whole-exome sequencing data from 428,719 individuals (UK Biobank) revealed that variants in GPR75 are associated with a reduced likelihood of hepatic steatosis. Here, we provide a significant advance in understanding of the expression and function of GPR75, demonstrating that it is a promising pharmaceutical target for NAFLD treatment.


Assuntos
Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica , Receptores Acoplados a Proteínas G , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Animais , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Camundongos , Humanos , Masculino , Tecido Adiposo/metabolismo , Camundongos Knockout , Fígado/metabolismo , Feminino , Adiposidade
9.
Nat Genet ; 56(4): 579-584, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38575728

RESUMO

Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.


Assuntos
Diabetes Mellitus Tipo 2 , Células-Tronco Pluripotentes Induzidas , Hepatopatias , Proteínas do Tecido Nervoso , Adulto , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Proteínas do Tecido Nervoso/genética , Obesidade/complicações , Obesidade/genética , Proteômica
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