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PURPOSE: 3D visualization is an important part of learning anatomy with cadavers generally used to effectuate this. However, high cost, ethical considerations, and limited accessibility can often limit the suitability of cadavers as teaching tools. Anatomical 3D printed models offer an alternative tool for teaching gross anatomy due to their low cost and accessibility. This study aims to investigate if combing gamification with 3D printed models can enhance the learning experience and be effective for teaching anatomy. METHODS: 3D printed models of the bones of the foot and ankle were generated, and 267 first-year medical students from 2 consecutive cohorts worked in groups to put it together as a puzzle. Participants completed a questionnaire regarding perceptions of 3D models and their knowledge of foot anatomy, before and after the session and were asked to provide comments. RESULTS: Analysis of the responses showed a significant increase in the confidence of the learners in their anatomy knowledge and an increased appreciation of the role that 3D models have in enhancing the learning experience. After the session, there were many comments saying how enjoyable and engaging 3D models were. CONCLUSION: Through the puzzle element of the session, the students were challenged mentally to work out the anatomical features of the foot and ankle. The combined elements of the puzzle and the features of the 3D model assembly made the activity fun and conducive to active learning. The possibility of having fun was not something the students had considered before the session.
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Anatomia , Tornozelo , Educação de Graduação em Medicina , Pé , Modelos Anatômicos , Impressão Tridimensional , Estudantes de Medicina , Humanos , Estudantes de Medicina/psicologia , Estudantes de Medicina/estatística & dados numéricos , Educação de Graduação em Medicina/métodos , Pé/anatomia & histologia , Tornozelo/anatomia & histologia , Anatomia/educação , Inquéritos e Questionários , Imageamento Tridimensional , Masculino , Feminino , CadáverRESUMO
BACKGROUND: Though it is well established that neonatal nutrition plays a major role in lifelong offspring health, the mechanisms underpinning this have not been well defined. Early postnatal accelerated growth resulting from maternal nutritional status is associated with increased appetite and body weight. Likewise, slow growth correlates with decreased appetite and body weight. Food consumption and food-seeking behaviour are directly modulated by central serotonergic (5-hydroxytryptamine, 5-HT) pathways. This study examined the effect of a rat maternal postnatal low protein (PLP) diet on 5-HT receptor mediated food intake in offspring. METHODS: Microarray analyses, in situ hybridization or laser capture microdissection of the ARC followed by RT-PCR were used to identify genes up- or down-regulated in the arcuate nucleus of the hypothalamus (ARC) of 3-month-old male PLP rats. Third ventricle cannulation was used to identify altered sensitivity to serotonin receptor agonists and antagonists with respect to food intake. RESULTS: Male PLP offspring consumed less food and had lower growth rates up to 3 months of age compared with Control offspring from dams fed a normal diet. In total, 97 genes were upregulated including the 5-HT5A receptor (5-HT5AR) and 149 downregulated genes in PLP rats compared with Controls. The former obesity medication fenfluramine and the 5-HT receptor agonist 5-Carboxamidotryptamine (5-CT) significantly suppressed food intake in both groups, but the PLP offspring were more sensitive to d-fenfluramine and 5-CT compared with Controls. The effect of 5-CT was antagonized by the 5-HT5AR antagonist SB699551. 5-CT also reduced NPY-induced hyperphagia in both Control and PLP rats but was more effective in PLP offspring. CONCLUSIONS: Postnatal low protein programming of growth in rats enhances the central effects of serotonin on appetite by increasing hypothalamic 5-HT5AR expression and sensitivity. These findings provide insight into the possible mechanisms through which a maternal low protein diet during lactation programs reduced growth and appetite in offspring.
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Apetite/fisiologia , Peso Corporal/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/genética , Hipotálamo/metabolismo , Receptores de Serotonina , Animais , Dieta , Feminino , Masculino , Obesidade/metabolismo , Ratos , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Transcriptoma/genéticaRESUMO
Studies in sarcolipin knockout mice have led to the suggestion that skeletal muscle sarcolipin plays a role in thermogenesis. The mechanism proposed is uncoupling of the sarcoplasmic reticulum calcium pump. However, in other work sarcolipin was not detected in mouse skeletal tissue. We have therefore measured sarcolipin levels in mouse skeletal muscle using semi-quantitative western blotting and synthetic mouse sarcolipin. Sarcolipin levels were so low that it is unlikely that knocking out sarcolipin would have a measurable effect on thermogenesis by SERCA. In addition, overexpression of neither wild type nor FLAG-tagged variants of mouse sarcolipin in transgenic mice had any major significant effects on body mass, energy expenditure, even when mice were fed on a high fat diet.
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Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Proteolipídeos/genética , Proteolipídeos/metabolismo , Animais , Peso Corporal/genética , Peso Corporal/fisiologia , Dieta Hiperlipídica , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Oligopeptídeos/genética , Oligopeptídeos/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Termogênese/genética , Termogênese/fisiologia , Regulação para CimaRESUMO
Various foods are associated with effects against metabolic diseases such as insulin resistance and type 2 diabetes; however, their mechanisms of action are mostly unclear. Fatty acids may contribute by acting as precursors of signalling molecules or by direct activity on receptors. The medium- and long-chain NEFA receptor FFA1 (free fatty acid receptor 1, previously known as GPR40) has been linked to enhancement of glucose-stimulated insulin secretion, whereas FFA4 (free fatty acid receptor 4, previously known as GPR120) has been associated with insulin-sensitising and anti-inflammatory effects, and both receptors are reported to protect pancreatic islets and promote secretion of appetite and glucose-regulating hormones. Hypothesising that FFA1 and FFA4 mediate therapeutic effects of dietary components, we screened a broad selection of NEFA on FFA1 and FFA4 and characterised active compounds in concentration-response curves. Of the screened compounds, pinolenic acid, a constituent of pine nut oil, was identified as a relatively potent and efficacious dual FFA1/FFA4 agonist, and its suitability for further studies was confirmed by additional in vitro characterisation. Pine nut oil and free and esterified pure pinolenic acid were tested in an acute glucose tolerance test in mice. Pine nut oil showed a moderately but significantly improved glucose tolerance compared with maize oil. Pure pinolenic acid or ethyl ester gave robust and highly significant improvements of glucose tolerance. In conclusion, the present results indicate that pinolenic acid is a comparatively potent and efficacious dual FFA1/FFA4 agonist that exerts antidiabetic effects in an acute mouse model. The compound thus deserves attention as a potential active dietary ingredient to prevent or counteract metabolic diseases.
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Gorduras na Dieta/farmacologia , Ácidos Linolênicos/farmacologia , Síndrome Metabólica/prevenção & controle , Receptores Acoplados a Proteínas G/genética , Animais , Diabetes Mellitus Tipo 2/prevenção & controle , Modelos Animais de Doenças , Teste de Tolerância a Glucose , Células HEK293 , Humanos , Insulina/sangue , Insulina/metabolismo , Resistência à Insulina , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nozes/química , Pinus , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismoRESUMO
BACKGROUND: Texture within biological specimens may reveal critical insights, while being very difficult to quantify. This is a particular problem in histological analysis. For example, cross-polar images of picrosirius stained skin reveal exquisite structure, allowing changes in the basketweave conformation of healthy collagen to be assessed. Existing techniques measure gross pathological changes, such as fibrosis, but are not sufficiently sensitive to detect more subtle and progressive pathological changes in the dermis, such as those seen in ageing. Moreover, screening methods for cutaneous therapeutics require accurate, unsupervised and high-throughput image analysis techniques. RESULTS: By analyzing spectra of images post Gabor filtering and Fast Fourier Transform, we were able to measure subtle changes in collagen fibre orientation intractable to existing techniques. We detected the progressive loss of collagen basketweave structure in a series of chronologically aged skin samples, as well as in skin derived from a model of type 2 diabetes mellitus. CONCLUSIONS: We describe a novel bioimaging approach with implications for the evaluation of pathology in a broader range of biological situations.
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Colágeno/química , Diabetes Mellitus Experimental/patologia , Animais , Colágeno/genética , Derme/química , Derme/patologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Análise de Fourier , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Microscopia de Polarização , Pele/química , Pele/patologia , Envelhecimento da Pele/genética , Envelhecimento da Pele/patologiaRESUMO
SCFA are produced in the gut by bacterial fermentation of undigested carbohydrates. Activation of the Gαi-protein-coupled receptor GPR41 by SCFA in ß-cells and sympathetic ganglia inhibits insulin secretion and increases sympathetic outflow, respectively. A possible role in stimulating leptin secretion by adipocytes is disputed. In the present study, we investigated energy balance and glucose homoeostasis in GPR41 knockout mice fed on a standard low-fat or a high-fat diet. When fed on the low-fat diet, body fat mass was raised and glucose tolerance was impaired in male but not female knockout mice compared to wild-type mice. Soleus muscle and heart weights were reduced in the male mice, but total body lean mass was unchanged. When fed on the high-fat diet, body fat mass was raised in male but not female GPR41 knockout mice, but by no more in the males than when they were fed on the low-fat diet. Body lean mass and energy expenditure were reduced in male mice but not in female knockout mice. These results suggest that the absence of GPR41 increases body fat content in male mice. Gut-derived SCFA may raise energy expenditure and help to protect against obesity by activating GPR41.
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Tecido Adiposo/metabolismo , Composição Corporal/genética , Gorduras na Dieta/farmacologia , Metabolismo Energético/genética , Ácidos Graxos Voláteis/metabolismo , Obesidade/genética , Receptores Acoplados a Proteínas G/genética , Tecido Adiposo/efeitos dos fármacos , Animais , Bactérias/metabolismo , Compartimentos de Líquidos Corporais/efeitos dos fármacos , Compartimentos de Líquidos Corporais/metabolismo , Dieta com Restrição de Gorduras , Dieta Hiperlipídica , Gorduras na Dieta/metabolismo , Feminino , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Intolerância à Glucose/genética , Coração/efeitos dos fármacos , Insulina/metabolismo , Secreção de Insulina , Leptina/metabolismo , Masculino , Camundongos , Camundongos Knockout , Músculo Esquelético/efeitos dos fármacos , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/prevenção & controle , Tamanho do Órgão , Receptores Acoplados a Proteínas G/metabolismo , Fatores SexuaisRESUMO
BACKGROUND: Medical students demonstrate higher levels of psychological distress compared with the general population and other student groups, especially at exam times. Mindfulness interventions show promise in stress reduction for this group, and in the reduction of cortisol, an established clinical marker of the body's stress response. This study investigated the relationship of mindfulness to exam-induced stress, salivary cortisol and exam performance in undergraduate medical students. METHODS: A controlled pre-post analysis design with within-groups comparisons. 67 medical students completed the five facet mindfulness questionnaire (FFMQ) and provided saliva samples, from which cortisol was extracted, during group work (control/baseline) and immediately prior to end of year 2 examinations (experimental). Academic performance data was extracted for comparison with measures. RESULTS: Exam-induced salivary cortisol concentration showed a significant negative relation with exam performance. Total FFMQ score showed a significant positive relation with exam performance and a significant negative relation with exam-induced salivary cortisol. The specific mindfulness facets of acting with awareness, non-judging and non-reacting also showed a positive correlation with exam performance. CONCLUSIONS: This study suggests that there exists an important relationship between mindfulness and the physiological biomarker of stress, cortisol, and this manifests into improved assessment outcomes potentially through healthier, more adaptive coping and stress management strategies. In particular, this study identifies the acting with awareness, non-judging and non-reacting facets of mindfulness to be significantly associated with exam performance suggesting that these may be important facets for clinical educators to target when helping students with mindfulness practice.
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Atenção Plena , Estudantes de Medicina , Atenção , Humanos , Hidrocortisona , Estudantes de Medicina/psicologia , Inquéritos e QuestionáriosRESUMO
Previous studies have shown that agonists of GPR17 stimulate, while antagonists inhibit feeding. However, whole body knockout of GPR17 in mice of the C57Bl/6 strain did not affect energy balance, whereas selective knockout in oligodendrocytes or pro-opiomelanocortin neurons provided protection from high fat diet-induced obesity and impaired glucose homeostasis. We reasoned that whole body knockout of GPR17 in mice of the 129 strain might elicit more marked effects because the 129 strain is more susceptible than the C57Bl/6 strain to increased sympathetic activity and less susceptible to high fat diet-induced obesity. Consistent with this hypothesis, compared to wild-type mice, and when fed on either a chow or a high fat diet, GPR17 -/- mice of the 129 strain displayed increased expression of uncoupling protein-1 in white adipose tissue, lower body weight and fat content, reduced plasma leptin, non-esterified fatty acids and triglycerides, and resistance to high fat diet-induced glucose intolerance. Not only energy expenditure, but also energy intake was raised. Administration of leptin did not suppress the increased food intake in GPR17 -/- mice of the 129 strain, whereas it did suppress food intake in GPR17 +/+ mice. The only difference between GPR17 +/- and GPR17 +/+ mice of the C57Bl/6 strain was that the body weight of the GPR17 -/- mice was lower than that of the GPR17 +/+ mice when the mice were fed on a standard chow diet. We propose that the absence of GPR17 raises sympathetic activity in mice of the 129 strain in response to a low plasma fuel supply, and that the consequent loss of body fat is partly mitigated by increased energy intake.
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Ingestão de Energia , Leptina/sangue , Leptina/farmacologia , Proteínas do Tecido Nervoso/genética , Receptores Acoplados a Proteínas G/genética , Magreza/genética , Tecido Adiposo/metabolismo , Animais , Composição Corporal/genética , Ingestão de Energia/efeitos dos fármacos , Ingestão de Energia/fisiologia , Feminino , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Especificidade da Espécie , Magreza/sangueRESUMO
This chapter describes the detailed protocol for the isolation and purification of islets of Langerhans from rodent pancreas using collagenase digestion. The first step of the process is to separate and isolate the insulin-producing islets of Langerhans from the rest of the pancreas. The pancreas is excised from the animal, trimmed of nonpancreatic tissues before being inflated and chopped into small pieces. The connective tissue is then broken down with a collagenase enzyme solution to selectively digest the bulk of the exocrine tissue while leaving the endocrine islets intact and separated from their surrounding non-islet tissue. Once this process is completed, the islets of Langerhans are separated from the remaining mixture by centrifugation and purified by the means of hand picking. Once isolated, the subsequent islets can be used for several varied experimental processes, including transplantation, the study of pathophysiological mechanisms in diabetic conditions, and in the screening of novel therapeutic approaches in pharmacological research.
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Separação Celular/métodos , Ilhotas Pancreáticas , Roedores , Animais , Técnicas de Cultura de Células , Colagenases , Ilhotas Pancreáticas/citologia , Transplante das Ilhotas Pancreáticas , Técnicas de Cultura de TecidosRESUMO
BACKGROUND: The importance of teaching the skills and practice of evidence-based medicine (EBM) for medical professionals has steadily grown in recent years. Alongside this growth is a need to evaluate the effectiveness of EBM curriculum as assessed by competency in the five 'A's': asking, acquiring, appraising, applying and assessing (impact and performance). EBM educators in medical education will benefit from a compendium of existing assessment tools for assessing EBM competencies in their settings. The purpose of this review is to provide a systematic review and taxonomy of validated tools that evaluate EBM teaching in medical education. METHODS: We searched MEDLINE, EMBASE, Cochrane library, Educational Resources Information Centre (ERIC), Best Evidence Medical Education (BEME) databases and references of retrieved articles published between January 2005 and March 2019. We have presented the identified tools along with their psychometric properties including validity, reliability and relevance to the five domains of EBM practice and dimensions of EBM learning. We also assessed the quality of the tools to identify high quality tools as those supported by established interrater reliability (if applicable), objective (non-self-reported) outcome measures and achieved ≥ 3 types of established validity evidence. We have reported our study in accordance with the PRISMA guidelines. RESULTS: We identified 1719 potentially relevant articles of which 63 full text articles were assessed for eligibility against inclusion and exclusion criteria. Twelve articles each with a unique and newly identified tool were included in the final analysis. Of the twelve tools, all of them assessed the third step of EBM practice (appraise) and four assessed just that one step. None of the twelve tools assessed the last step of EBM practice (assess). Of the seven domains of EBM learning, ten tools assessed knowledge gain, nine assessed skills and-one assessed attitude. None addressed reaction to EBM teaching, self-efficacy, behaviours or patient benefit. Of the twelve tools identified, six were high quality. We have also provided a taxonomy of tools using the CREATE framework, for EBM teachers in medical education. CONCLUSIONS: Six tools of reasonable validity are available for evaluating most steps of EBM and some domains of EBM learning. Further development and validation of tools that evaluate all the steps in EBM and all educational outcome domains are needed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018116203.
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Educação Médica , Competência Clínica , Currículo , Medicina Baseada em Evidências , Humanos , Aprendizagem , Reprodutibilidade dos Testes , EnsinoRESUMO
BACKGROUND: The insulin-sensitizing phytocannabinoid, Δ(9)-tetrahydrocannabivarin (THCV) can signal partly via G-protein coupled receptor-55 (GPR55 behaving as either an agonist or an antagonist depending on the assay). The cannabinoid receptor type 1 (CB1R) inverse agonist rimonabant is also a GPR55 agonist under some conditions. Previous studies have shown varied effects of deletion of GPR55 on energy balance and glucose homeostasis in mice. The contribution of signalling via GPR55 to the metabolic effects of THCV and rimonabant has been little studied. METHODS: In a preliminary experiment, energy balance and glucose homeostasis were studied in GPR55 knockout and wild-type mice fed on both standard chow (to 20 weeks of age) and high fat diets (from 6 to 15 weeks of age). In the main experiment, all mice were fed on the high fat diet (from 6 to 14 weeks of age). In addition to replicating the preliminary experiment, the effects of once daily administration of THCV (15 mg kg-1 po) and rimonabant (10 mg kg-1 po) were compared in the two genotypes. RESULTS: There was no effect of genotype on absolute body weight or weight gain, body composition measured by either dual-energy X-ray absorptiometry or Nuclear Magnetic Resonance (NMR), fat pad weights, food intake, energy expenditure, locomotor activity, glucose tolerance or insulin tolerance in mice fed on chow. When the mice were fed a high fat diet, there was again no effect of genotype on these various aspects of energy balance. However, in both experiments, glucose tolerance was worse in the knockout than the wild-type mice. Genotype did not affect insulin tolerance in either experiment. Weight loss in rimonabant- and THCV-treated mice was lower in knockout than in wild-type mice, but surprisingly there was no detectable effect of genotype on the effects of the drugs on any aspect of glucose homeostasis after taking into account the effect of genotype in vehicle-treated mice. CONCLUSIONS: Our two experiments differ from those reported by others in finding impaired glucose tolerance in GPR55 knockout mice in the absence of any effect on body weight, body composition, locomotor activity or energy expenditure. Nor could we detect any effect of genotype on insulin tolerance, so the possibility that GPR55 regulates glucose-stimulated insulin secretion merits further investigation. By contrast with the genotype effect in untreated mice, we found that THCV and rimonabant reduced weight gain, and this effect was in part mediated by GPR55.
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AIM: This review provides a comprehensive overview of more than 100 of the most cited studies in general medical journals and evaluates whether citations predict the quality of a scientific article. BACKGROUND: The number of citations is commonly used as a measure of the quality and impact of a scientific article. However, it is often criticised that the number of citations is in fact a poor indicator of the true quality, as it can be influenced by different factors such as current trends. METHODS: This review was conducted in line with the PRISMA guidelines. The Journal Citation Report (JCR) within Incites allowed the evaluation and comparison of articles, published in general medical journals, using far-reaching citation data drawn from scholarly and technical journals and conference proceedings. All steps of the review were performed in duplicate and conflicts were resolved through consensus. RESULTS: The 100 most cited articles published from 1963 until the end of 2018 were identified. The number of citations ranged from 4012 to 31853. Most of the articles were published in the 2000's, followed by the 1990's, 1980's, 1970's and 1960's, respectively. All of the articles were published in five journals. There were 50 studies at level II, 28 at level V, 10 at level IV, 7 at level III, and 5 at Level I. CONCLUSION: This systematic review provides an overview of the most cited articles, published in general medical journals. The number of citations provides an indication of the quality of evidence. However, researchers and clinicians should use standardized assessment tools rather than solely rely on the number of citations in order to judge the quality of published articles.
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Epidemiological evidence together with experimental models shows a direct relationship between fetal and early postnatal growth patterns and an increased risk of adult metabolic disease. Maternal health and nutrition are key determinants in influencing infant growth but the precise molecular mechanisms underlying this relationship are unclear, although it is evident that there are critical time windows when these effects are important. Animal models show mechanistic parallels with human populations and highlight that the early environment represents a therapeutic window for protection from obesity and metabolic disease. The observation that developmental programming can be reversed has been demonstrated in studies in which both maternal and neonatal leptin treatment prevents the induction of the adverse metabolic phenotype. Given that orally administered peptides are absorbed intact by the new born, the prospect of providing supplemental leptin either as drops or in milk deserves serious consideration as a means of reducing or reversing the obesity and type 2 diabetes epidemic.
Assuntos
Comportamento Alimentar/fisiologia , Leptina/metabolismo , Obesidade/fisiopatologia , Adulto , Animais , Modelos Animais de Doenças , Feminino , Humanos , Lactente , Recém-Nascido , Leptina/uso terapêutico , Síndrome Metabólica/fisiopatologia , Obesidade/prevenção & controle , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/prevenção & controleRESUMO
INTRODUCTION: Obesity is considered a major risk factor for gallstone formation and is important due to its increasing prevalence worldwide. Many studies have reported an increased incidence of gallstone formation following bariatric surgery. This report documents a rare case of a complicated cholecystitis following sleeve gastrectomy and describes our management of the case and the management options for gallbladder disease in bariatric patients. PRESENTATION OF CASE: A 60-year-old male was diagnosed with asymptomatic cholelithiasis at the time of sleeve gastrectomy for obesity treatment. Two months after the procedure, he presented to the emergency department with symptoms of acute cholecystitis, which were initially managed conservatively. Six weeks later, he underwent a laparoscopic cholecystectomy. Intra-operative findings revealed a rare case of a complicated cholecystitis where the gallstone was half-eroded into the greater omentum. DISCUSSION: A notable proportion of bariatric patients develop symptomatic complicated cholecystitis following laparoscopic sleeve gastrectomy, compared to the normal population. Furthermore, complications develop quickly and technical difficulties are associated with subsequent surgeries. Thus, early cholecystectomy is justified. CONCLUSION: Patients with asymptomatic cholelithiasis, undergoing sleeve gastrectomy, may benefit from concomitant cholecystectomy. The question is yet controversial. This highlights the need for more clinical research in the field.
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The free fatty acid receptor 4 (FFA4 or GPR120) has appeared as an interesting potential target for the treatment of metabolic disorders. At present, most FFA4 ligands are carboxylic acids that are assumed to mimic the endogenous long-chain fatty acid agonists. Here, we report preliminary structure-activity relationship studies of a previously disclosed nonacidic sulfonamide FFA4 agonist. Mutagenesis studies indicate that the compounds are orthosteric agonists despite the absence of a carboxylate function. The preferred compounds showed full agonist activity on FFA4 and complete selectivity over FFA1, although a significant fraction of these noncarboxylic acids also showed partial antagonistic activity on FFA1. Studies in normal and diet-induced obese (DIO) mice with the preferred compound 34 showed improved glucose tolerance after oral dosing in an oral glucose tolerance test. Chronic dosing of 34 in DIO mice resulted in significantly increased insulin sensitivity and a moderate but significant reduction in bodyweight, effects that were also present in mice lacking FFA1 but absent in mice lacking FFA4.
Assuntos
Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Sulfonamidas/química , Sulfonamidas/farmacologia , Animais , Linhagem Celular , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Modelos Moleculares , Simulação de Acoplamento Molecular , Receptores Acoplados a Proteínas G/metabolismo , Relação Estrutura-AtividadeRESUMO
Although obesity is a global epidemic, the physiological mechanisms involved are not well understood. Recent advances reveal that susceptibility to obesity can be programmed by maternal and neonatal nutrition. Specifically, a maternal low-protein diet during pregnancy causes decreased intrauterine growth, rapid postnatal catch-up growth and an increased risk for diet-induced obesity. Given that the synthesis of the neurotransmitter 5-hydroxytryptamine (5-HT) is nutritionally regulated and 5-HT is a trophic factor, we hypothesised that maternal diet influences fetal 5-HT exposure, which then influences development of the central appetite network and the subsequent efficacy of 5-HT to control energy balance in later life. Consistent with our hypothesis, pregnant rats fed a low-protein diet exhibited elevated serum levels of 5-HT, which was also evident in the placenta and fetal brains at embryonic day 16.5. This increase was associated with reduced levels of 5-HT2CR, the primary 5-HT receptor influencing appetite, in the fetal, neonatal and adult hypothalamus. As expected, a reduction of 5-HT2CR was associated with impaired sensitivity to 5-HT-mediated appetite suppression in adulthood. 5-HT primarily achieves effects on appetite by 5-HT2CR stimulation of pro-opiomelanocortin (POMC) peptides within the arcuate nucleus of the hypothalamus (ARC). We show that 5-HT2ARs are also anatomically positioned to influence the activity of ARC POMC neurons and that mRNA encoding 5-HT2AR is increased in the hypothalamus ofin uterogrowth-restricted offspring that underwent rapid postnatal catch-up growth. Furthermore, these animals at 3 months of age are more sensitive to appetite suppression induced by 5-HT2AR agonists. These findings not only reveal a 5-HT-mediated mechanism underlying the programming of susceptibility to obesity, but also provide a promising means to correct it, by treatment with a 5-HT2AR agonist.
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Crescimento e Desenvolvimento , Hipotálamo/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Animais , Animais Recém-Nascidos , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Peso Corporal/efeitos dos fármacos , Proteínas Alimentares/farmacologia , Comportamento Alimentar/efeitos dos fármacos , Feminino , Fenfluramina/administração & dosagem , Fenfluramina/farmacologia , Feto/efeitos dos fármacos , Feto/metabolismo , Crescimento e Desenvolvimento/efeitos dos fármacos , Hipotálamo/anatomia & histologia , Hipotálamo/efeitos dos fármacos , Hipotálamo/crescimento & desenvolvimento , Microdissecção e Captura a Laser , Masculino , Neurônios/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Ratos Wistar , Reprodutibilidade dos Testes , Serotonina/metabolismo , Fatores de Tempo , Triptofano/metabolismoRESUMO
The free fatty acid receptor 1 (FFA1 or GPR40) is established as an interesting potential target for treatment of type 2 diabetes. However, to obtain optimal ligands, it may be necessary to limit both lipophilicity and polar surface area, translating to a need for small compounds. We here describe the identification of 24, a potent FFA1 agonist with low lipophilicity and very high ligand efficiency that exhibit robust glucose lowering effect.
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Hipoglicemiantes/síntese química , Hipoglicemiantes/farmacologia , Fenilpropionatos/síntese química , Fenilpropionatos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Teste de Tolerância a Glucose , Ligantes , Lipídeos/química , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Relação Estrutura-AtividadeRESUMO
Despite significant advances in our understanding of the biology determining systemic energy homeostasis, the treatment of obesity remains a medical challenge. Activation of AMP-activated protein kinase (AMPK) has been proposed as an attractive strategy for the treatment of obesity and its complications. AMPK is a conserved, ubiquitously expressed, heterotrimeric serine/threonine kinase whose short-term activation has multiple beneficial metabolic effects. Whether these translate into long-term benefits for obesity and its complications is unknown. Here, we observe that mice with chronic AMPK activation, resulting from mutation of the AMPK γ2 subunit, exhibit ghrelin signaling-dependent hyperphagia, obesity, and impaired pancreatic islet insulin secretion. Humans bearing the homologous mutation manifest a congruent phenotype. Our studies highlight that long-term AMPK activation throughout all tissues can have adverse metabolic consequences, with implications for pharmacological strategies seeking to chronically activate AMPK systemically to treat metabolic disease.