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1.
Nat Commun ; 11(1): 1729, 2020 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-32265438

RESUMO

The TrkB receptor is critical for the control of energy balance, as mutations in its gene (NTRK2) lead to hyperphagia and severe obesity. The main neural substrate mediating the appetite-suppressing activity of TrkB, however, remains unknown. Here, we demonstrate that selective Ntrk2 deletion within paraventricular hypothalamus (PVH) leads to severe hyperphagic obesity. Furthermore, chemogenetic activation or inhibition of TrkB-expressing PVH (PVHTrkB) neurons suppresses or increases food intake, respectively. PVHTrkB neurons project to multiple brain regions, including ventromedial hypothalamus (VMH) and lateral parabrachial nucleus (LPBN). We find that PVHTrkB neurons projecting to LPBN are distinct from those to VMH, yet Ntrk2 deletion in PVH neurons projecting to either VMH or LPBN results in hyperphagia and obesity. Additionally, TrkB activation with BDNF increases firing of these PVH neurons. Therefore, TrkB signaling is a key regulator of a previously uncharacterized neuronal population within the PVH that impinges upon multiple circuits to govern appetite.


Assuntos
Hiperfagia/metabolismo , Glicoproteínas de Membrana/metabolismo , Neurônios/metabolismo , Obesidade/metabolismo , Núcleo Hipotalâmico Paraventricular/citologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Proteínas Tirosina Quinases/metabolismo , Animais , Apetite/genética , Comportamento Alimentar/fisiologia , Feminino , Hiperfagia/genética , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/genética , Núcleos Parabraquiais/citologia , Núcleos Parabraquiais/metabolismo , Núcleos Parabraquiais/fisiopatologia , Proteínas Tirosina Quinases/genética , Núcleo Hipotalâmico Ventromedial/citologia , Núcleo Hipotalâmico Ventromedial/metabolismo
2.
Int J Behav Med ; 27(2): 247-254, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32124245

RESUMO

BACKGROUND: Distress intolerance, one's inability to withstand distressing emotional or physical states, is a transdiagnostic vulnerability implicated in affect-based health behaviors, including cigarette smoking and poor weight control. The current study evaluated associations between distress intolerance and the reliance on cigarettes for management of weight, appetite, or body dissatisfaction, which may pose a burden for cessation and increase risk of weight-related health problems. METHOD: Daily smokers (n = 577) completed an online survey assessing distress tolerance and reliance on cigarettes for weight and shape control with the four subscales of the Smoking and Weight Eating Episodes Test (SWEET). Four hierarchical regression models were constructed to test the association between distress intolerance and SWEET scores, accounting for the effect of relevant covarying factors. RESULTS: After adjusting for model covariates, distress intolerance was significantly incrementally associated with greater tendency to rely on cigarettes to suppress appetite (adjR2 = .040), prevent overeating (adjR2 = .034), cope with body dissatisfaction (adjR2 = .046), and cope with nicotine withdrawal-related appetite increases (adjR2 = .030). CONCLUSION: Distress intolerance may play an etiological role in maladaptive use of cigarettes to control appetite, weight, and body dissatisfaction among daily smokers, particularly those with weight- or shape-related concerns. Interventions aimed at increasing perceived ability to withstand distress could potentially reduce reliance on cigarettes for the aforementioned purposes.


Assuntos
Adaptação Psicológica , Apetite/fisiologia , Fumantes/psicologia , Fumar/psicologia , Adulto , Peso Corporal , Feminino , Humanos , Hiperfagia/psicologia , Masculino , Pessoa de Meia-Idade , Abandono do Hábito de Fumar/psicologia , Inquéritos e Questionários
3.
PLoS Biol ; 18(2): e3000629, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32097406

RESUMO

Human biology has evolved to keep body fat within a range that supports survival. During the last 25 years, obesity biologists have uncovered key aspects of physiology that prevent fat mass from becoming too low. In contrast, the mechanisms that counteract excessive adipose expansion are largely unknown. Evidence dating back to the 1950s suggests the existence of a blood-borne molecule that defends against weight gain. In this article, we discuss the research supporting an "unidentified factor of overfeeding" and models that explain its role in body weight control. If it exists, revealing the identity of this factor could end a long-lasting enigma of energy balance regulation and facilitate a much-needed breakthrough in the pharmacological treatment of obesity.


Assuntos
Depressores do Apetite/metabolismo , Peso Corporal/fisiologia , Hormônios/metabolismo , Tecido Adiposo/metabolismo , Animais , Depressores do Apetite/sangue , Hormônios/sangue , Humanos , Hiperfagia/genética , Hiperfagia/metabolismo , Obesidade/genética , Obesidade/metabolismo , Parabiose , Ganho de Peso/fisiologia
4.
Ann R Coll Surg Engl ; 102(5): e97-e99, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32081032

RESUMO

Laparoscopic Heller myotomy is the mainstay surgical treatment of oesophageal achalasia and has proven to be safe and effective over the course of time. Oesophageal perforation after myotomy can be a serious complication with devastating outcomes. Most commonly, mucosal perforation are detected intraoperatively or early postoperatively. We present an extremely rare case of late oesophageal perforation in a 28-year-old man treated with laparoscopic Heller myotomy for type II oesophageal achalasia, and its successful minimally invasive repair with laparoscopic primary suturing.


Assuntos
Acalasia Esofágica/cirurgia , Perfuração Esofágica/cirurgia , Miotomia de Heller/efeitos adversos , Hiperfagia/complicações , Complicações Pós-Operatórias/cirurgia , Adulto , Perfuração Esofágica/diagnóstico por imagem , Perfuração Esofágica/etiologia , Humanos , Laparoscopia , Masculino , Pneumoperitônio/diagnóstico por imagem , Pneumoperitônio/etiologia , Pneumoperitônio/cirurgia , Complicações Pós-Operatórias/diagnóstico por imagem , Complicações Pós-Operatórias/etiologia , Técnicas de Sutura , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento
5.
FASEB J ; 34(1): 148-160, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914634

RESUMO

Deletion of murine Thm1, an intraflagellar transport A (IFT-A) component that mediates ciliary protein trafficking, causes hyperphagia, obesity, and metabolic syndrome. The role of Thm1 or IFT-A in adipogenesis and insulin sensitivity is unknown. Here, we report that Thm1 knockdown in 3T3-L1 pre-adipocytes promotes adipogenesis and enhances insulin sensitivity in vitro. Yet, pre-obese Thm1 conditional knockout mice show systemic insulin resistance. While insulin-induced AKT activation in Thm1 mutant adipose depots and skeletal muscle are similar to those of control littermates, an attenuated insulin response arises in the mutant liver. Insulin treatment of control and Thm1 mutant primary hepatocytes results in similar AKT activation. Moreover, pair-feeding Thm1 conditional knockout mice produces a normal insulin response, both in the liver and systemically. Thus, hyperphagia caused by a cilia defect, induces hepatic insulin resistance via a non-cell autonomous mechanism. In turn, hepatic insulin resistance drives systemic insulin resistance prior to an obese phenotype. These data demonstrate that insulin signaling across cell types is regulated differentially, and that the liver is particularly susceptible to hyperphagia-induced insulin resistance and a critical determinant of systemic insulin resistance.


Assuntos
Proteínas do Citoesqueleto/metabolismo , Hiperfagia/metabolismo , Resistência à Insulina/fisiologia , Células 3T3-L1 , Adipócitos , Adipogenia , Animais , Proteínas do Citoesqueleto/genética , Predisposição Genética para Doença , Hepatócitos/metabolismo , Insulina/metabolismo , Insulina/farmacologia , Camundongos , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo
6.
Am J Physiol Endocrinol Metab ; 318(2): E286-E296, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31891539

RESUMO

Increased myocardial partitioning of dietary fatty acids (DFA) and decreased left ventricular (LV) function is associated with insulin resistance in prediabetes. We hypothesized that enhanced myocardial DFA partitioning and reduced LV function might be induced concomitantly with reduced insulin sensitivity upon a 7-day hypercaloric (+50% in caloric intake), high-saturated fat (~11%energy), and simple carbohydrates (~54%energy) diet (HIGHCAL) versus an isocaloric diet (ISOCAL) with a moderate amount of saturated fat (~8%energy) and carbohydrates (~50%energy). Thirteen healthy subjects (7 men/6 women) underwent HIGHCAL versus ISOCAL in a randomized crossover design, with organ-specific DFA partitioning and LV function measured using the oral 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid and [11C]acetate positron emission tomography methods at the end of both interventions. HIGHCAL induced a decrease in insulin sensitivity indexes with no significant change in body composition. HIGHCAL led to increased subcutaneous abdominal (+4.2 ± 1.6%, P < 0.04) and thigh (+2.4 ± 1.2%, P < 0.08) adipose tissue storage and reduced cardiac (-0.31 ± 0.11 mean standard uptake value [(SUV), P < 0.03] and skeletal muscle (-0.17 ± 0.08 SUV, P < 0.05) DFA partitioning without change in LV function. We conclude that early increase in adipose tissue DFA storage protects the heart and skeletal muscles from potential deleterious effects of DFA.


Assuntos
Tecido Adiposo/metabolismo , Gorduras na Dieta/farmacologia , Ácidos Graxos/metabolismo , Hiperfagia/metabolismo , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Adulto , Composição Corporal , Estudos Cross-Over , Carboidratos da Dieta/farmacologia , Feminino , Voluntários Saudáveis , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Função Ventricular Esquerda/efeitos dos fármacos
7.
Sleep Health ; 6(1): 88-91, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31680050

RESUMO

OBJECTIVE: Our modern society has created two tightly linked epidemics: insufficient sleep and obesity. Although laboratory studies have established that sleep loss is associated with increased caloric intake, the critical question of how habitual at-home sleep duration influences total caloric and macronutrient intake during subsequent total sleep deprivation remains largely unexplored. METHODS: At-home sleep patterns were monitored via wrist actigraphy for at least one week before a 29-h in-laboratory total sleep deprivation (TSD) session (N = 45). Participants had ad-libitum access to food, which was measured at 6-h intervals throughout the in-laboratory session. RESULTS: Short habitual sleep duration was significantly associated with increased caloric and macronutrient intake during the last 6 h of TSD (06:00-12:00). CONCLUSIONS: Short habitual sleep increases the risk for morning overeating after acute sleep deprivation. Early identification and behavioral intervention of those at risk of overeating may help reduce the likelihood of long-term health consequences.


Assuntos
Ingestão de Energia , Nutrientes/administração & dosagem , Privação do Sono , Sono , Adulto , Feminino , Humanos , Hiperfagia/epidemiologia , Masculino , Fatores de Risco , Fatores de Tempo , Adulto Jovem
8.
Nat Hum Behav ; 4(1): 27-35, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31659319

RESUMO

Obesity is a widespread health condition1, likely to be driven by the increased availability of inexpensive high-calorie food2. People vary greatly in their behavioural response to food. Such variation is likely to be driven by behavioural styles3,4, as behaviour accounts for overall food intake5. A prominent hypothesis is that people with obesity respond to rewards similarly to people with addictions such as alcohol abuse or smoking6,7. For instance, perceived overeating or 'uncontrolled eating' (UE) is the most common obesity-associated personality trait8 and resembles the perceived loss of control seen in drug addiction. Likewise, both obesity and addictive behaviours have similar correlations with broad personality domains3. Here we seek to empirically test whether obesity and UE overlap behaviourally with addiction and psychiatric disorders, collectively referred to as phenotypes. We test for behavioural similarity by linking the personality profiles of each phenotype. NEO Personality Inventory profiles of 28 phenotypes were extracted from 22 studies, encompassing summary statistics from 18,611 unique participants. Obesity had moderate and UE high behavioural similarity with addictions. UE also overlapped behaviourally with most psychiatric phenotypes, whereas obesity was behaviourally similar with mood disorders and certain personality disorders. Facet-based phenotype profiles provided more information than domain-based profiles.


Assuntos
Comportamento Aditivo/fisiopatologia , Comportamento Alimentar/fisiologia , Hiperfagia/fisiopatologia , Transtornos Mentais/fisiopatologia , Obesidade/fisiopatologia , Personalidade/fisiologia , Recompensa , Autocontrole , Humanos , Fenótipo
9.
Am J Clin Nutr ; 111(1): 17-20, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31637411

RESUMO

The Vermont overfeeding studies were published 50 y ago and began a change in the acceptance of obesity as a bona fide area of academic interest. This article chronicles the experience of the author with acute weight gain while overfeeding, in the context of current obesity research, and presents a glimpse of things to come. The pain associated with acute overeating is illustrated by the firsthand experience of the author. The rapid return to normal weight contrasts with the difficulty that almost all people with obesity experience when they attempt to lose and maintain weight loss. Contrasting the response to overfeeding of individuals who are "resistant" to obesity with those who are obesity prone provides an avenue for unraveling the difficulties people with obesity face when they try to lose weight.


Assuntos
Hiperfagia/fisiopatologia , Obesidade/fisiopatologia , Autoexperimentação , Humanos , Hiperfagia/metabolismo , Hiperfagia/psicologia , Obesidade/metabolismo , Obesidade/psicologia , Ganho de Peso , Perda de Peso
10.
J Altern Complement Med ; 26(2): 98-106, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31765223

RESUMO

Background: Growing obesity rates are a problem worldwide. Several studies of emotional freedom techniques (EFT), a brief psychophysiologic technique, have indicated that it may be a promising addition to traditional weight loss interventions. Objective: The current study evaluated food cravings, dietary restraint, subjective power of food, weight changes, and self-reported symptoms (e.g., somatic, anxious, and depressive) 2 years after an 8-week online self-directed EFT intervention with additional online support. Design: Participants were initially randomly allocated to a treatment or waitlist group. The treatment group was instructed to self-pace through an online EFT treatment program made up of seven modules throughout the 8-week intervention period, and the waitlist was also completed at the end of this period. Results: Analyses of the online EFT intervention program indicated significantly reduced scores for food cravings (-28.2%), power of food (-26.7%), depression (-12.3%), anxiety (-23.3%), and somatic symptoms (-10.6%) from pre to postintervention and from pre (baseline) until the 2-year follow-up and significantly improved scores for restraint (+13.4%). Further improvements were experienced for carbohydrates and fast food cravings between 6 months and 2 years. Body Mass Index and weight significantly decreased from pre- to 12 months follow-up although there were no differences at the 2-year point. Conclusions: As an online intervention program, EFT was very effective in reducing food cravings, perceived power of food, psychologic symptomatology, and improving dietary restraint and maintaining those improvements over a 2-year period. The addition of EFT to traditional weight loss interventions is timely and supported by this research.


Assuntos
Terapias Complementares/métodos , Hiperfagia/terapia , Internet , Psicofísica/métodos , Adulto , Fissura , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/terapia , Perda de Peso
11.
Nutrients ; 11(11)2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31717368

RESUMO

(1) High-fat (HF) diet leads to gut microbiota dysbiosis which is associated with systemic inflammation. Bacterial-driven inflammation is sufficient to alter vagally mediated satiety and induce hyperphagia. Promoting bacterial fermentation improves gastrointestinal (GI) epithelial barrier function and reduces inflammation. Resistant starch escape digestion and can be fermented by bacteria in the distal gut. Therefore, we hypothesized that potato RS supplementation in HF-fed rats would lead to compositional changes in microbiota composition associated with improved inflammatory status and vagal signaling. (2) Male Wistar rats (n = 8/group) were fed a low-fat chow (LF, 13% fat), HF (45% fat), or an isocaloric HF supplemented with 12% potato RS (HFRS) diet. (3) The HFRS-fed rats consumed significantly less energy than HF animals throughout the experiment. Systemic inflammation and glucose homeostasis were improved in the HFRS compared to HF rats. Cholecystokinin-induced satiety was abolished in HF-fed rats and restored in HFRS rats. HF feeding led to a significant decrease in positive c fiber staining in the brainstem which was averted by RS supplementation. (4) The RS supplementation prevented dysbiosis and systemic inflammation. Additionally, microbiota manipulation via dietary potato RS prevented HF-diet-induced reorganization of vagal afferent fibers, loss in CCK-induced satiety, and hyperphagia.


Assuntos
Bactérias/crescimento & desenvolvimento , Encéfalo/fisiopatologia , Suplementos Nutricionais , Disbiose , Microbioma Gastrointestinal , Inflamação/prevenção & controle , Intestinos/inervação , Intestinos/microbiologia , Obesidade/prevenção & controle , Solanum tuberosum , Amido/administração & dosagem , Nervo Vago/fisiopatologia , Ração Animal , Animais , Bactérias/metabolismo , Encéfalo/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Comportamento Alimentar , Fermentação , Hiperfagia/metabolismo , Hiperfagia/microbiologia , Hiperfagia/fisiopatologia , Hiperfagia/prevenção & controle , Inflamação/metabolismo , Inflamação/microbiologia , Inflamação/fisiopatologia , Masculino , Obesidade/metabolismo , Obesidade/microbiologia , Obesidade/fisiopatologia , Raízes de Plantas , Ratos Wistar , Resposta de Saciedade , Amido/metabolismo , Nervo Vago/metabolismo , Ganho de Peso
12.
Nat Med ; 25(11): 1733-1738, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31700171

RESUMO

The G-protein-coupled receptor accessory protein MRAP2 is implicated in energy control in rodents, notably via the melanocortin-4 receptor1. Although some MRAP2 mutations have been described in people with obesity1-3, their functional consequences on adiposity remain elusive. Using large-scale sequencing of MRAP2 in 9,418 people, we identified 23 rare heterozygous variants associated with increased obesity risk in both adults and children. Functional assessment of each variant shows that loss-of-function MRAP2 variants are pathogenic for monogenic hyperphagic obesity, hyperglycemia and hypertension. This contrasts with other monogenic forms of obesity characterized by excessive hunger, including melanocortin-4 receptor deficiency, that present with low blood pressure and normal glucose tolerance4. The pleiotropic metabolic effect of loss-of-function mutations in MRAP2 might be due to the failure of different MRAP2-regulated G-protein-coupled receptors in various tissues including pancreatic islets.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Predisposição Genética para Doença , Hiperfagia/genética , Obesidade/genética , Adolescente , Adulto , Criança , Metabolismo Energético/genética , Feminino , Humanos , Hiperglicemia/complicações , Hiperglicemia/genética , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperfagia/complicações , Hiperfagia/metabolismo , Hiperfagia/patologia , Hipertensão/complicações , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/patologia , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Mutação com Perda de Função/genética , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Obesidade/patologia , Receptor Tipo 4 de Melanocortina/genética , Fatores de Risco , Adulto Jovem
13.
Exp Suppl ; 111: 419-441, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31588542

RESUMO

Obesity is caused by an imbalance between energy intake and output, influenced by numerous environmental, biological, and genetic factors. Only a minority of people with obesity have a genetic defect that is the main cause of their obesity. A key symptom for most of these disorders is early-onset obesity and hyperphagia. For some genetic obesity disorders, the hyperphagia is the main characteristic, often caused by disruptions of the leptin-melanocortin pathway, the central pathway that regulates the body's satiety and energy balance. For other disorders, obesity is part of a distinct combination of other clinical features such as intellectual disability, dysmorphic facial features, or organ abnormalities. This chapter focuses on genetic obesity disorders and also summarizes the present knowledge on the genetics of the more common polygenic/multifactorial obesity.


Assuntos
Hiperfagia/genética , Obesidade/genética , Ingestão de Energia , Metabolismo Energético , Humanos , Leptina , Melanocortinas , Saciação
14.
Nutrients ; 11(9)2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31487791

RESUMO

With the obesity epidemic being largely attributed to overeating, much research has been aimed at understanding the psychological causes of overeating and using this knowledge to develop targeted interventions. Here, we review this literature under a model of food addiction and present evidence according to the fifth edition of the Diagnostic and Statistical Manual (DSM-5) criteria for substance use disorders. We review several innovative treatments related to a food addiction model ranging from cognitive intervention tasks to neuromodulation techniques. We conclude that there is evidence to suggest that, for some individuals, food can induce addictive-type behaviours similar to those seen with other addictive substances. However, with several DSM-5 criteria having limited application to overeating, the term 'food addiction' is likely to apply only in a minority of cases. Nevertheless, research investigating the underlying psychological causes of overeating within the context of food addiction has led to some novel and potentially effective interventions. Understanding the similarities and differences between the addictive characteristics of food and illicit substances should prove fruitful in further developing these interventions.


Assuntos
Dependência de Alimentos/diagnóstico , Dependência de Alimentos/terapia , Hiperfagia/diagnóstico , Hiperfagia/terapia , Humanos
15.
Diabetes ; 68(12): 2210-2222, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31530579

RESUMO

Melanin-concentrating hormone (MCH) is an important regulator of food intake, glucose metabolism, and adiposity. However, the mechanisms mediating these actions remain largely unknown. We used pharmacological and genetic approaches to show that the sirtuin 1 (SIRT1)/FoxO1 signaling pathway in the hypothalamic arcuate nucleus (ARC) mediates MCH-induced feeding, adiposity, and glucose intolerance. MCH reduces proopiomelanocortin (POMC) neuronal activity, and the SIRT1/FoxO1 pathway regulates the inhibitory effect of MCH on POMC expression. Remarkably, the metabolic actions of MCH are compromised in mice lacking SIRT1 specifically in POMC neurons. Of note, the actions of MCH are independent of agouti-related peptide (AgRP) neurons because inhibition of γ-aminobutyric acid receptor in the ARC did not prevent the orexigenic action of MCH, and the hypophagic effect of MCH silencing was maintained after chemogenetic stimulation of AgRP neurons. Central SIRT1 is required for MCH-induced weight gain through its actions on the sympathetic nervous system. The central MCH knockdown causes hypophagia and weight loss in diet-induced obese wild-type mice; however, these effects were abolished in mice overexpressing SIRT1 fed a high-fat diet. These data reveal the neuronal basis for the effects of MCH on food intake, body weight, and glucose metabolism and highlight the relevance of SIRT1/FoxO1 pathway in obesity.


Assuntos
Adiposidade/efeitos dos fármacos , Proteína Forkhead Box O1/metabolismo , Intolerância à Glucose/metabolismo , Hiperfagia/metabolismo , Hormônios Hipotalâmicos/farmacologia , Melaninas/farmacologia , Neurônios/efeitos dos fármacos , Hormônios Hipofisários/farmacologia , Pró-Opiomelanocortina/metabolismo , Sirtuína 1/metabolismo , Adiposidade/fisiologia , Animais , Proteína Forkhead Box O1/genética , Intolerância à Glucose/genética , Hiperfagia/genética , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Knockout , Neurônios/metabolismo , Técnicas de Patch-Clamp , Ratos Sprague-Dawley , Sirtuína 1/genética
16.
PLoS One ; 14(9): e0221615, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31545799

RESUMO

INTRODUCTION: Prader-Willi syndrome (PWS) is a complex genetic condition characterized by hyperphagia, hypotonia, low muscle mass, excess body fat, developmental delays, intellectual disability, behavioral problems, and growth hormone deficiency. This study evaluated the safety and efficacy of orally administered Diazoxide Choline Controlled-Release Tablets (DCCR) in subjects with PWS. METHOD: This was a single-center, Phase II study and included a 10-week Open-Label Treatment Period during which subjects were dose escalated, followed by a 4-week Double-Blind, Placebo-Controlled Treatment Period. RESULTS: Five female and eight male overweight or obese, adolescent and adult subjects with genetically-confirmed PWS with an average age of 15.5±2.9 years were enrolled in the study. There was a statistically significant reduction in hyperphagia at the end of the Open-Label Treatment Period (-4.32, n = 11, p = 0.006). The onset of effect on hyperphagia was rapid and greater reductions in hyperphagia were seen in subjects with moderate to severe Baseline hyperphagia (-5.50, n = 6, p = 0.03), in subjects treated with the highest dose (-6.25, n = 4, p = 0.08), and in subjects with moderate to severe Baseline hyperphagia treated with the highest dose (-7.83, n = 3, p = 0.09). DCCR treatment resulted in a reduction in the number of subjects displaying aggressive behaviors (-57.1%, n = 10, p = 0.01), clinically-relevant reductions in fat mass (-1.58 kg, n = 11, p = 0.02) and increases in lean body mass (2.26 kg, n = 11, p = 0.003). There was a corresponding decrease in waist circumference, and trends for improvements in lipids and insulin resistance. The most common adverse events were peripheral edema and transient increases in glucose. Many of the adverse events were common medical complications of PWS and diazoxide. CONCLUSION: DCCR treatment appears to address various unmet needs associated with PWS, including hyperphagia and aggressive behaviors in this proof-of-concept study. If the results were replicated in a larger scale study, DCCR may be a preferred therapeutic option for patients with PWS.


Assuntos
Diazóxido/análogos & derivados , Síndrome de Prader-Willi/tratamento farmacológico , Adolescente , Metabolismo Basal/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Criança , Preparações de Ação Retardada , Diazóxido/administração & dosagem , Diazóxido/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Hiperinsulinismo/tratamento farmacológico , Hiperfagia/tratamento farmacológico , Masculino , Obesidade/tratamento farmacológico , Projetos Piloto , Síndrome de Prader-Willi/patologia , Síndrome de Prader-Willi/psicologia , Segurança , Circunferência da Cintura/efeitos dos fármacos , Adulto Jovem
17.
Transl Psychiatry ; 9(1): 193, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31431611

RESUMO

The pathophysiology of major depressive disorder (MDD) is highly heterogeneous. Previous evidence at the DNA level as well as on the serum protein level suggests that the role of inflammation in MDD pathology is stronger in patients with hyperphagia during an active episode. Which inflammatory pathways differ in MDD patients with hyperphagia inflammatory pathways in terms of gene expression is unknown. We analyzed whole-blood gene expression profiles of 881 current MDD cases and 331 controls from the Netherlands Study of Depression and Anxiety (NESDA). The MDD patients were stratified according to patients with hyperphagia (characterized by increased appetite and/or weight, N = 246) or hypophagia (characterized by decreased appetite and/or weight, N = 342). Using results of differential gene expression analysis between controls and the MDD subgroups, enrichment of curated inflammatory pathways was estimated. The majority of the pathways were significantly (FDR < 0.1) enriched in the expression profiles of MDD cases with hyperphagia, including top pathways related to factors responsible for the onset of inflammatory response ('caspase', 'GATA3', 'NFAT', and 'inflammasomes' pathways). Only two pathways ('adaptive immune system' and 'IL-8- and CXCR2-mediated signaling') were enriched in the MDD with hypophagia subgroup, these were also enriched in the total current MDD group and the group with hyperphagia. This confirms the importance of inflammation in MDD pathology of patients with hyperphagia, and suggests that distinguishing more uniform MDD phenotypes can help in finding their pathophysiological basis.


Assuntos
Transtorno Depressivo/genética , Expressão Gênica , Hiperfagia/genética , Inflamação/genética , Adulto , Transtorno Depressivo/complicações , Feminino , Humanos , Hiperfagia/complicações , Inflamação/complicações , Masculino , Pessoa de Meia-Idade , Transdução de Sinais
20.
Nat Rev Endocrinol ; 15(9): 500-501, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31273335
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