IF1 is a cold-regulated switch of ATP synthase hydrolytic activity to support thermogenesis in brown fat.

While mechanisms controlling uncoupling protein-1 (UCP1) in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis, it remains unclear whether F1Fo-ATP synthase function is also regulated in brown adipose tissue (BAT). Here, we show that inhibitory factor 1 (IF1, encoded by Atp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In vivo, IF1 levels are diminished in BAT of cold-adapted mice compared to controls. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential (MMP) through ATP hydrolysis (the so-called "reverse mode" of ATP synthase) is increased in brown fat. In cultured brown adipocytes, IF1 overexpression results in an inability of mitochondria to sustain the MMP upon adrenergic stimulation, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus-mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in BAT. Taken together, our work identifies downregulation of IF1 upon cold as a critical event for the facilitation of the reverse mode of ATP synthase as well as to enable energetic adaptation of BAT to effectively support non-shivering thermogenesis.

Inhibition of Crif1 protects fatty acid-induced POMC neuron-like cell-line damage by increasing CPT-1 function.

Hypothalamic proopiomelanocortin (POMC) neurons are sensors of signals that reflect the energy stored in the body. Inducing mild stress in proopiomelanocortin neurons protects them from the damage promoted by the consumption of a high-fat diet, mitigating the development of obesity; however, the cellular mechanisms behind these effects are unknown. Here, we induced mild stress in a proopiomelanocortin neuron cell line by inhibiting Crif1. In proopiomelanocortin neurons exposed to high levels of palmitate, the partial inhibition of Crif1 reverted the defects in mitochondrial respiration and ATP production; this was accompanied by improved mitochondrial fusion/fission cycling. Furthermore, the partial inhibition of Crif1 resulted in increased reactive oxygen species production, increased fatty acid oxidation, and reduced dependency on glucose for mitochondrial respiration. These changes were dependent on the activity of CPT-1. Thus, we identified a CPT-1-dependent metabolic shift toward greater utilization of fatty acids as substrates for respiration as the mechanism behind the protective effect of mild stress against palmitate-induced damage of proopiomelanocortin neurons.NEW & NOTEWORTHY Saturated fats can damage hypothalamic neurons resulting in positive energy balance, and this is mitigated by mild cellular stress; however, the mechanisms behind this protective effect are unknown. Using a proopiomelanocortin cell line, we show that under exposure to a high concentration of palmitate, the partial inhibition of the mitochondrial protein Crif1 results in protection due to a metabolic shift warranted by the increased expression and activity of the mitochondrial fatty acid transporter CPT-1.

Investigation of Beige Fat Biology and Metabolism Using the CRISPR SunTag-p65-HSF1 Activation System.

Clustered regularly interspaced short palindromic repeats (CRISPR) technology has prompted a revolution in biology, and recent tools have been applied far beyond the originally described gene editing. The CRISPR activation (CRISPRa) system combines the catalytically inactive Cas9 (dCas9) protein with distinct transcription modules to induce endogenous gene expression. SunTag-p65-HSF1 (SPH) is a recently developed CRISPRa technology that combines components of synergistic activation mediators (SAMs) with the SunTag activators. This system allows the overexpression of single or multiple genes by designing a customized single-guide RNA (sgRNA). In this study, a previously developed SPH mouse was used to generate a conditional mouse expressing SPH in adipocytes (adiponectin Cre lineage), named AdipoSPH. To induce a white-to-beige fat (browning) phenotype, an adeno-associated virus (AAV) carrying sgRNA targeting the endogenous Prdm16 gene (a well-established transcription factor related to brown and beige fat development) was injected into the inguinal white adipose tissue (iWAT). This mouse model induced the expression of endogenous Prdm16 and activated the thermogenic gene program. Moreover, in vitro SPH-induced Prdm16 overexpression enhanced the oxygen consumption of beige adipocytes, phenocopying the results of a previous Prdm16 transgenic mouse model. Thus, this protocol describes a versatile, cost-effective, and time-effective mouse model for investigating adipose tissue biology.

Dietary Intervention Associated With Moderate-Intensity Continuous Training Leads to Changes in the Inflammatory Profile in Visceral Adipose Tissue but Not in Skeletal Muscle in Diet-Induced Obese Rats.

This study aimed to determine the concentrations of inflammatory markers in visceral adipose tissue (VAT) and skeletal muscle, and changes in body mass and adipocyte size in diet-induced obese rats after moderate-intensity continuous training (MICT) and/or dietary intervention. After 8 weeks of obesity induction through a high-fat diet (HFD) consumption, twenty diet-induced obese male Wistar rats were divided into four groups as follows: (i) control rats fed with HFD (HFD-SED), (ii) obese rats fed with HFD and submitted to MICT (HFD-MICT), (iii) obese rats that were submitted to a nutritional intervention by switching HFD to chow diet (CD-SED), and (iv) obese rats that were submitted to MICT and nutritional intervention (CD-MICT). All the animals in the training groups were submitted to MICT, with an intensity of 50-85% of V max , 60 min/day, 3 days/week for 8 weeks. Gastrocnemius muscle (GAST) and mesenteric adipose tissue (mWAT) were collected to quantify tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and IL-10 using ELISA. The body mass was recorded before and after the experimental protocols, and the adipocyte morphology was assessed using histological analysis. The results showed that HFD-SED had higher body mass, higher concentrations of inflammatory markers in mWAT, and higher increase in adipocyte size. The CD-SED and CD-MICT groups presented with reduced body mass, relative weight of mWAT, and adipocyte size. Moreover, the inflammatory markers in mWAT were reduced after dietary intervention (TNF-α), MICT (IL-10 and TNF-α), or both interventions combined (IL-6 and TNF-α). In contrast, there was no reduction in GAST-relative weight or concentrations of inflammatory markers for any treatment. Finally, we concluded that 8 weeks of dietary intervention alone and combined with MICT were effective in reducing some of the deleterious effects caused by obesity.

Dietary Intervention, When Not Associated With Exercise, Upregulates Irisin/FNDC5 While Reducing Visceral Adiposity Markers in Obese Rats.

Obesity is an epidemic disease and the expansion of adipose tissue, especially visceral fat, promotes the secretion of factors that lead to comorbidities such as diabetes and cardiovascular diseases. Thus, diet and exercise have been proposed as an intervention to reverse these complications. An adipocytokine, known as irisin, mediates the beneficial effects of exercise. It has been proposed as a therapeutic potential in controlling obesity. In view of the above, this paper attempts to determine the modulation of irisin, visceral adiposity and biochemical markers in response to dietary intervention and aerobic exercise. To do this, 52 diet-induced obese male Wistar rats were divided into the following four groups: high-fat diet and exercise (HFD-Ex); HFD-Sedentary (HFD-Sed); chow-diet and exercise (CD-Exercise); and CD-Sed. The exercise-trained group performed a treadmill protocol for 60 min/day, 3 days/week for 8 weeks. Body mass (BM), body fat (BF), fat mass (FM), and fat-free mass (FFM) were analyzed. Mesenteric (MES), epididymal (EPI), and retroperitoneal (RET) adipose tissue was collected and histological analysis was performed. Biochemical irisin, triglycerides, glucose, insulin and inflammatory markers were determined and, FNDC5 protein expression was analyzed. In this study, the diet was the most important factor in reducing visceral adiposity in the short and long term. Exercise was an important factor in preserving muscle mass and reducing visceral depots after a long term. Moreover, the combination of diet and exercise can enhance these effects. Diet and exercise exclusively were the factors capable of increasing the values of irisin/FNDC5, however it did not bring cumulative effects of both interventions. Prescriptions to enhance the obesity treatments should involve reducing visceral adiposity by reducing the fat content in the diet associated with aerobic exercise.

High-Intensity Interval Training Does Not Change Vaspin and Omentin and Does Not Reduce Visceral Adipose Tissue in Obese Rats.

This study aimed to determine the expression of omentin and vaspin, inflammatory markers, body composition, and lipid profile in diet-induced obese rats and high-intensity interval training (HIIT). Forty Wistar rats were divided into four groups: untrained normal diet, trained normal diet (T-ND), untrained high-fat diet (Unt-HFD), and trained high-fat diet (T-HFD). For the animals of the Unt-HFD and T-HFD groups, a high-fat diet was offered for 4 weeks. After that, all the animals in the T-ND and T-HFD groups were submitted to HITT, three times per week, for 10 weeks (2 weeks of adaptation and 8 weeks of HIIT). Muscle (gastrocnemius), liver, epididymal adipose tissue, retroperitoneal adipose tissue, visceral adipose tissue (VAT), and serum were collected to analyze TNF-α, IL-6, PCR, IL-8, IL-10, IL-4, vaspin, and omentin. A body composition analysis was performed before adaptation to HIIT protocol and after the last exercise session using dual-energy X-ray absorptiometry. Omentin and vaspin in the VAT were quantified using Western blotting. The results showed that, when fed a high-fat diet, the animals obtained significant gains in body fat and elevated serum concentrations of vaspin and blood triglycerides. The HIIT was able to minimize body fat gain but did not reduce visceral fat despite the increase in maximum exercise capacity. Moreover, there was a reduction in the serum levels of adiponectin, IL-6, and IL-10. Finally, we concluded that, although the training protocol was able to slow down the weight gain of the animals, there was no reduction in visceral fat or an improvement in the inflammatory profile, including no changes in omentin and vaspin.

Avaliação da qualidade de vida de indivíduos com carcinoma bem diferenciado de tireoide pelo whoqol-100* / Quality of life assessment of individuals with well-differentiated thyroid carcinoma using whoqol-100 / Evaluación de la calidad de vida de individuos con carcinoma bien diferenciado de tiroides mediante el whoqol-100

Este estudo objetivou avaliar a qualidade de vida de pacientes em acompanhamento clínico por carcinoma bem diferenciado de tireoide, por meio do questionário WHOQOL-100. Trata-se de estudo quantitativo realizado entre março de 2015 e março de 2017 em São Carlos, SP, Brasil, descritivo e transversal, que avaliou 280 indivíduos, sendo 70 com carcinoma de tireoide e 210 controles, divididos em ≤45 e >45 anos. Os resultados mostraram que o grupo carcinoma de tireoide ≤ 45 anos apresentou prejuízo nos domínios físico (p=0,0032) e nível de independência (p<0,0001), e melhora no domínio meio ambiente (0,0138). O grupo com carcinoma de tireoide > 45 anos apresentou melhora no domínio meio ambiente (0,0002) e qualidade de vida global (p=0,00146) em relação aos controles. Esses achados, frutos de uma análise abrangente da qualidade de vida de pacientes com carcinoma diferenciado de tireoide, podem contribuir para o entendimento das repercussões da doença e seu tratamento (AU).

This study aimed to assess the quality of life of patients under clinical monitoring due to well-differentiated thyroidcarcinoma using the WHOQOL-100 questionnaire. A quantitative, descriptive and cross-sectional study was undertaken betweenMarch 2015 and March 2017 in São Carlos, SP, Brazil, evaluating 280 individuals, being 70 suffering from thyroid carcinoma and 210controls, divided in≤45 and >45 years. The results showed that the group with thyroid carcinoma≤45 years presented impairments inthe physical domain (p=0.0032) and in the level of independence (p<0.0001), and improvements in the environment domain (0.0138).The group with thyroid carcinoma > 45 years presented improvements in the environment domain (0.0002) and in the global qualityof life (p=0.00146) in relation to the controls. These findings, resulting from a comprehensive analysis of the quality of life of patientswith differentiated thyroid carcinoma, can contribute to the understanding of the repercussions the disease and its treatment entail (AU).

Este estudio objetivó evaluar la cualidad de vida de pacientes en seguimiento clínico por carcinoma bien diferenciadode tiroides, mediante el cuestionario WHOQOL-100. Se trata de estudio cuantitativo desarrollado entre marzo del 2015 y marzodel 2017 en São Carlos, SP, Brasil, descriptivo y trasversal, que evaluó 280 individuos, siendo 70 con carcinoma de tiroides y 210controles, divididos en≤45 y >45 años. Los resultados mostraron que el grupo carcinoma de tiroides≤45 años presentó perjuicio enlos dominios físico (p=0,0032) y nivel de independencia (p<0,0001), y mejora en el dominio medio ambiente (0,0138). El grupo concarcinoma de tiroides > 45 años presentó mejora en el dominio medio ambiente (0,0002) y calidad de vida global (p=0,00146) conrelación a los controles. Eses hallazgos, frutos de un análisis amplio de la calidad de vida de pacientes con carcinoma diferenciadode tiroides, pueden contribuir a la comprensión de las repercusiones de la enfermedad y su tratamiento (AU).

Relações familiares, álcool e outras drogas: uma revisão integrativa / Family relationships, alcohol and other drugs: integrative review

Trata-se de uma revisão integrativa objetivando responder a seguinte pergunta: "Qual o conhecimento científico produzido sobre as relações familiares e problemática do uso, abuso e dependência de álcool e outras drogas, principalmente quanto ao relacionado a fatores de risco e proteção?" Objetivo da pesquisa: analisar a produção científica sobre as relações familiares e uso, abuso e dependência de álcool e outras drogas. Método: revisão de literatura nas bases de dados BIREME (SciELO, LILACS, PubMed (MEDLINE) e Psycinfo. Resultados: Foram encontrados 2.625 artigos, sendo selecionados 15 artigos, (10) PubMed (MEDLINE) e (5) Scielo. Houve predomínio de 12 publicações a partir de 2009. Conclusão: a comunicação familiar pode ser considerada tanto situação de risco como de proteção, requerendo dos profissionais de saúde uma escuta qualificada e habilidades para intervenção terapêutica junto à família nesse tema.

This is an integrative review aimed to answer the following question: "What is the scientific knowledge produced on family relationships and problematic use, abuse and dependence on alcohol and other drugs, especially in their risk and protective factors?" The purpose of the research was to analyze the scientific literature on family relationships and use, abuse and dependence on alcohol and other drugs. Method: literature review in BIREME databases (SciELO, LILACS, PubMed (MEDLINE) and PsycINFO. Results: There were 2,625 articles found, and 15 articleswere selected: (10) PubMed (MEDLINE ) and (5) Scielo. There were 12 publications predominating from 2009. Conclusion: family communication can be considered both risk and protection by requiring health professionals qualified listening and skills for therapeutic intervention with the family in this area.

A implementação da intervenção breve na atenção primária à saúde: revisão integrativa / The implementation of the brief intervention in primary health care: integrative review

Este estudo objetivou caracterizar a produção do conhecimento científico sobre a implementação de intervenção breve (IB) na atenção primária à saúde e identificar as dificuldades da equipe de saúde sobre o tema. Realizou-se uma revisão integrativa em base de dados Medline/PubMed, LILACS e SciELO, de 1999 a 2014. Os resultados apontaram a necessidade de capacitação de profissionais de saúde no rastreamento do uso de álcool e realização da IB. As dificuldades da equipe envolveram problemas no planejamento e organização do sistema de saúde e crenças desta em relação ao usuário de álcool e à IB. Concluiu-se a necessidade de divulgação desses estudos aos profissionais de saúde, possibilitando políticas públicas de incentivo à introdução dessa estratégia em serviços de saúde.

This study aimed to analyze the production of scientific knowledge about the implementation of brief intervention (BI) in primary health care and identify difficulties for the health care team regarding this theme. The literature review included articles from national and international scientific journals dating from 1999 to 2014, from Medline/PubMed, LILACS, and SciELO electronic library bases. The results indicate the need for training of health professionals in screening for alcohol use and conducting the BI. Team difficulties involved problems in the planning and organization of the health system and team beliefs in relation to the alcohol user and the BI. It was concluded these studies need to be disseminated to healthcare professionals, by enabling public policies to encourage the introduction of this strategy in the health services.

Triagem de hipotireoidismo em crianças - Visão dos médicos da atenção primária à saúde de um município de médio porte / Hypothyroidism screening in children: Views of primary health care physicians from a medium-sized city / Detección de hipotiroidismo en niños - Visión de los médicos de atención primaria a la salud de un municipio de tamaño medio

Objetivo: Avaliar quais parâmetros os médicos da atenção primária à saúde do município de São Carlos, SP, Brasil, adotam para realizar triagem de função tireoidiana em crianças e adolescentes, quais exames complementares são solicitados e qual a conduta diante de resultados laboratoriais alterados. Métodos: Estudo transversal descritivo, no qual participaram 26 profissionais, correspondendo a 96,3% de todos os médicos da atenção primária da cidade que atuam no cuidado de crianças e adolescentes. Os participantes responderam por escrito quais as três situações mais frequentes na prática clínica em que indicavam triagem de hipotireoidismo na população pediátrica, quais os exames laboratoriais solicitados nesta avaliação e a qual conduta frente a exames com resultados alterados. Resultados: As situações clínicas mais frequentes apontadas pelos participantes como indicações de avaliação tireoidiana foram: obesidade, com 23 respostas (88,5%); baixa estatura, com 16 (61,5%); e síndrome de Down, com 8 (30,8%). Nove médicos (34,6%) responderam realizar o rastreio pela dosagem de TSH e T4l e outros 9 (34,6%), pela dosagem de TSH isolado. A conduta mais frequente diante de um resultado alterado foi o encaminhamento ao endocrinologista pediátrico, com 14 respostas (53,8%). Conclusão: O cenário encontrado neste estudo mostra que exames de função tireoidiana são solicitados rotineiramente por médicos da atenção primária no acompanhamento de crianças obesas. Como a obesidade infantil tem uma alta prevalência, isso pode determinar aumento importante dos custos do serviço de saúde e sobrecarga nos serviços de atenção especializada.

Objective: To determine which parameters are used by primary care physicians of São Carlos city, SP, Brazil, to screen thyroid function in children and adolescents, which tests are required for the assessment, and what options are provided to patients with abnormal results. Methods: This was a descriptive study in which 26 professionals participated, corresponding to 96.3% of all primary care physicians who provide medical care to children and adolescents. The participants provided written answers for questions regarding the 3 most common situations in clinical practice that warranted a hypothyroidism screening test in the pediatric population; the laboratory tests required for the assessment, and the options provided to patients with abnormal results. Results: The most common clinical situations identified by the physicians as indications for evaluation of thyroid function were obesity (23 answers; 88.5%), short stature (16 answers; 61.5%), and Down syndrome (8 answers; 30.8%). Nine physicians (34.6%) screened thyroid function by using the TSH and FT4 tests, whereas 9 other physicians (34.6%) used only the TSH test. In case of abnormal results, most physicians referred the patient to a pediatric endocrinologist (14 answers; 53.8%). Conclusion: Thus, the findings of this study indicate that thyroid function tests are routinely ordered by primary care physicians for the follow-up of obese children. As childhood obesity is highly prevalent, it may lead to a significant increase in health service costs and overload secondary care services.

Objetivo: Evaluar los parámetros que los médicos de atención primaria de salud en la ciudad de São Carlos, SP, Brasil, adoptan para realizar exámenes de función de la tiroides en niños y adolescentes, los exámenes complementarios necesarios y cual conducta ante los resultados anormales de laboratorio. Métodos: Estudio descriptivo, que asistieron 26 profesionales, representando 96,3% de todos los médicos de atención primaria de la ciudad que trabajan con niños y adolescentes. Ellos respondieron cuales son las tres situaciones más comunes en la práctica clínica que indican cribado de hipotiroidismo en la población pediátrica, que exámenes adicionales solicitados en esta evaluación y cual conducta delante los exámenes laboratoriales con resultados anormales. Resultados: Las situaciones clínicas más frecuentes identificadas por los participantes como indicadoras de evaluación de la tiroides son: la obesidad con 23 respuestas (88,5%), baja estatura, con 16 (61,5%) y el síndrome de Down con 8 (30,8%). 9 (34,6%) médicos dijeron realizar rastreo por medio de la TSH y T4 libre y otros 9 (34,6%), a través de la dosis de TSH aislado. La conducta más mencionada ante un resultado anormal fué un encaminamiento al endocrinologista pediatra, con 14 respuestas (53,8%). Conclusión: El escenario en este estudio muestra que los exámenes de función de la tiroide son solicitados rutinariamente por los médicos de atención primaria en el acompañamiento de niños obesos. Como la obesidad infantil tiene una alta prevalencia, esto puede causar incremento en los costos de los servicios de salud y en las despensas generales en los servicios de atención especializada.