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1.
PLoS One ; 15(8): e0237708, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32817646

RESUMO

Parental high-fat diet (HFD) programs for obesity and hypertension in female offspring in rats, but it is unknown how the pregnancies of these offspring are impacted. Therefore, the hypothesis was tested that parental HFD exaggerates obesity and hypertension during pregnancy of the offspring. Wistar Hannover rat dams (the parental, P generation) were maintained on normal-fat diet (NFD) or HFD from weaning and were kept on respective diets through pregnancy and lactation. Their offspring (the first filial, F1 generation) were weaned onto the same diet as the P generation, or they were changed to the other diet to determine if combined HFD in the P and F1 generations exaggerates body weight and blood pressure levels during pregnancy in these offspring. This diet paradigm resulted in the following groups of pregnant F1 offspring: P-NFD/F1-NFD, P-HFD/F1-NFD, P-NFD/F1-HFD, and P-HFD/F1-HFD. Maternal body and adipose tissue weights were greatest in the P-HFD/F1-HFD group compared to the other 3 groups by the end of pregnancy. Plasma leptin and conscious mean arterial blood pressure were not significantly different between any group, although there was a main effect for increased blood pressure in the F1-HFD groups. Circulating levels of the antihypertensive pregnancy factor, placental growth factor (PlGF), were assessed. Although average PlGF levels were similar among all groups, correlative studies revealed that lower levels of PlGF were associated with higher blood pressure only in the P-HFD/F1-HFD group. In summary, HFD feeding from the P generation exaggerated HFD-induced body and adipose tissue weights in the pregnant offspring.


Assuntos
Hipertensão/sangue , Leptina/sangue , Obesidade/sangue , Fator de Crescimento Placentário/sangue , Efeitos Tardios da Exposição Pré-Natal/sangue , Adiposidade/genética , Animais , Pressão Sanguínea/genética , Peso Corporal/genética , Dieta Hiperlipídica , Modelos Animais de Doenças , Feminino , Humanos , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Herança Materna/genética , Obesidade/genética , Obesidade/fisiopatologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Desmame
2.
Nat Commun ; 11(1): 4150, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32811819

RESUMO

The systemic decline in autophagic activity with age impairs homeostasis in several tissues, leading to age-related diseases. A mechanistic understanding of adipocyte dysfunction with age could help to prevent age-related metabolic disorders, but the role of autophagy in aged adipocytes remains unclear. Here we show that, in contrast to other tissues, aged adipocytes upregulate autophagy due to a decline in the levels of Rubicon, a negative regulator of autophagy. Rubicon knockout in adipocytes causes fat atrophy and hepatic lipid accumulation due to reductions in the expression of adipogenic genes, which can be recovered by activation of PPARγ. SRC-1 and TIF2, coactivators of PPARγ, are degraded by autophagy in a manner that depends on their binding to GABARAP family proteins, and are significantly downregulated in Rubicon-ablated or aged adipocytes. Hence, we propose that age-dependent decline in adipose Rubicon exacerbates metabolic disorders by promoting excess autophagic degradation of SRC-1 and TIF2.


Assuntos
Adipócitos/metabolismo , Envelhecimento/fisiologia , Autofagia/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Doenças Metabólicas/metabolismo , Adipócitos/patologia , Adipogenia/genética , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Adiposidade/genética , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Autofagia/fisiologia , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Técnicas de Inativação de Genes , Glucose/genética , Glucose/metabolismo , Células HEK293 , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Metabolismo dos Lipídeos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/metabolismo , Coativador 1 de Receptor Nuclear/metabolismo , Coativador 2 de Receptor Nuclear/metabolismo , PPAR gama/metabolismo
3.
Gene ; 758: 144957, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32683081

RESUMO

Leptin receptor (LEPR) gene play a pivotal role in the regulation of fat deposition and energy homeostasis. This study investigated the presence and frequency of polymorphisms of bovine LEPR gene and determine whether the polymorphisms are associated with the fat deposition in two Chinese beef cattle breeds. Quantitative real-time polymerase chain reactions identified that the expression of LEPR gene was highest in the liver and subcutaneous fat. Four single nucleotide polymorphisms (SNPs) were identified including g.24169C > T, g.24256T > A, g.24267 G > C and g.24413T > A. A greater backfat thickness was associated with the AA genotype of g.24256T > A compared to the TT genotype. A greater intramuscular fat content was associated with the GG genotype of g.24267 G > C compared to the CC genotype. Both g.24169C > T and g.24413T > A were not correlated with fat deposition. These results indicated that the SNP g.24256T > A and g.24267 G > C of LEPR gene may be useful markers for genetic improvement of fat deposition in Chinese beef cattle breeds.


Assuntos
Adiposidade/genética , Distribuição da Gordura Corporal , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Animais , Bovinos , Frequência do Gene/genética , Estudos de Associação Genética , Genótipo , Leptina/metabolismo , Polimorfismo de Nucleotídeo Único/genética
4.
Nat Commun ; 11(1): 2797, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493999

RESUMO

Fat distribution is an independent cardiometabolic risk factor. However, its molecular and cellular underpinnings remain obscure. Here we demonstrate that two independent GWAS signals at RSPO3, which are associated with increased body mass index-adjusted waist-to-hip ratio, act to specifically increase RSPO3 expression in subcutaneous adipocytes. These variants are also associated with reduced lower-body fat, enlarged gluteal adipocytes and insulin resistance. Based on human cellular studies RSPO3 may limit gluteofemoral adipose tissue (AT) expansion by suppressing adipogenesis and increasing gluteal adipocyte susceptibility to apoptosis. RSPO3 may also promote upper-body fat distribution by stimulating abdominal adipose progenitor (AP) proliferation. The distinct biological responses elicited by RSPO3 in abdominal versus gluteal APs in vitro are associated with differential changes in WNT signalling. Zebrafish carrying a nonsense rspo3 mutation display altered fat distribution. Our study identifies RSPO3 as an important determinant of peripheral AT storage capacity.


Assuntos
Adipócitos/citologia , Adipócitos/metabolismo , Distribuição da Gordura Corporal , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Trombospondinas/metabolismo , Proteínas de Peixe-Zebra/metabolismo , Adipócitos/efeitos dos fármacos , Tecido Adiposo/metabolismo , Adiposidade/genética , Adulto , Alelos , Animais , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Tamanho Celular/efeitos dos fármacos , Doxiciclina/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Mutação/genética , Polimorfismo de Nucleotídeo Único/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Caracteres Sexuais , Células-Tronco/metabolismo , Trombospondinas/genética , Relação Cintura-Quadril , Via de Sinalização Wnt/efeitos dos fármacos , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
5.
PLoS Genet ; 16(6): e1008790, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32525877

RESUMO

Recent discoveries from large-scale genome-wide association studies (GWASs) explain a larger proportion of the genetic variability to BMI and obesity. The genetic risk associated with BMI and obesity can be assessed by an obesity-specific genetic risk score (GRS) constructed from genome-wide significant genetic variants. The aim of our study is to examine whether the duration and exclusivity of breastfeeding can attenuate BMI increase during childhood and adolescence due to genetic risks. A total sample of 5,266 children (2,690 boys and 2,576 girls) from the Avon Longitudinal Study of Parents and Children (ALSPAC) was used for the analysis. We evaluated the role of breastfeeding (exclusivity and duration) in modulating BMI increase attributed to the GRS from birth to 18 years of age. The GRS was composed of 69 variants associated with adult BMI and 25 non-overlapping SNPs associated with pediatric BMI. In the high genetic susceptible group (upper GRS quartile), exclusive breastfeeding (EBF) to 5 months reduces BMI by 1.14 kg/m2 (95% CI, 0.37 to 1.91, p = 0.0037) in 18-year-old boys, which compensates a 3.9-decile GRS increase. In 18-year-old girls, EBF to 5 months decreases BMI by 1.53 kg/m2 (95% CI, 0.76 to 2.29, p<0.0001), which compensates a 7.0-decile GRS increase. EBF acts early in life by delaying the age at adiposity peak and at adiposity rebound. EBF to 3 months or non-exclusive breastfeeding was associated with a significantly diminished impact on reducing BMI growth during childhood. EBF influences early life growth and development and thus may play a critical role in preventing overweight and obesity among children at high-risk due to genetic factors.


Assuntos
Índice de Massa Corporal , Aleitamento Materno/estatística & dados numéricos , Obesidade/genética , Adiposidade/genética , Adolescente , Aleitamento Materno/métodos , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Obesidade/epidemiologia , Obesidade/prevenção & controle , Polimorfismo de Nucleotídeo Único , Adulto Jovem
6.
Nat Commun ; 11(1): 2922, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32523103

RESUMO

The conversion of white adipocytes to thermogenic beige adipocytes represents a potential mechanism to treat obesity and related metabolic disorders. However, the mechanisms involved in converting white to beige adipose tissue remain incompletely understood. Here we show profound beiging in a genetic mouse model lacking the transcriptional repressor Krüppel-like factor 3 (KLF3). Bone marrow transplants from these animals confer the beige phenotype on wild type recipients. Analysis of the cellular and molecular changes reveal an accumulation of eosinophils in adipose tissue. We examine the transcriptomic profile of adipose-resident eosinophils and posit that KLF3 regulates adipose tissue function via transcriptional control of secreted molecules linked to beiging. Furthermore, we provide evidence that eosinophils may directly act on adipocytes to drive beiging and highlight the critical role of these little-understood immune cells in thermogenesis.


Assuntos
Tecido Adiposo/metabolismo , Eosinófilos/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Transdução de Sinais/fisiologia , Adiposidade/genética , Adiposidade/fisiologia , Animais , Células COS , Chlorocebus aethiops , Imunoprecipitação da Cromatina , Citometria de Fluxo , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Obesidade/metabolismo , Transdução de Sinais/genética , Software
7.
Am J Physiol Endocrinol Metab ; 319(1): E146-E162, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32421370

RESUMO

Secreted hormones facilitate tissue cross talk to maintain energy balance. We previously described C1q/TNF-related protein 12 (CTRP12) as a novel metabolic hormone. Gain-of-function and partial-deficiency mouse models have highlighted important roles for this fat-derived adipokine in modulating systemic metabolism. Whether CTRP12 is essential and required for metabolic homeostasis is unknown. We show here that homozygous deletion of Ctrp12 gene results in sexually dimorphic phenotypes. Under basal conditions, complete loss of CTRP12 had little impact on male mice, whereas it decreased body weight (driven by reduced lean mass and liver weight) and improved insulin sensitivity in female mice. When challenged with a high-fat diet, Ctrp12 knockout (KO) male mice had decreased energy expenditure, increased weight gain and adiposity, elevated serum TNFα level, and reduced insulin sensitivity. In contrast, female KO mice had reduced weight gain and liver weight. The expression of lipid synthesis and catabolism genes, as well as profibrotic, endoplasmic reticulum stress, and oxidative stress genes were largely unaffected in the adipose tissue of Ctrp12 KO male mice. Despite greater adiposity and insulin resistance, Ctrp12 KO male mice fed an obesogenic diet had lower circulating triglyceride and free fatty acid levels. In contrast, lipid profiles of the leaner female KO mice were not different from those of WT controls. These data suggest that CTRP12 contributes to whole body energy metabolism in genotype-, diet-, and sex-dependent manners, underscoring complex gene-environment interactions influencing metabolic outcomes.


Assuntos
Adipocinas/genética , Peso Corporal/genética , Dieta Hiperlipídica , Metabolismo Energético/genética , Resistência à Insulina/genética , Tecido Adiposo/metabolismo , Adiposidade/genética , Animais , Estresse do Retículo Endoplasmático/genética , Ácidos Graxos não Esterificados/metabolismo , Feminino , Fibrose/genética , Expressão Gênica , Interação Gene-Ambiente , Metabolismo dos Lipídeos/genética , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Tamanho do Órgão , Estresse Oxidativo/genética , Fatores Sexuais , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Ganho de Peso/genética
8.
PLoS One ; 15(5): e0227720, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407314

RESUMO

Numerous mutational studies have demonstrated that circadian clock proteins regulate behavior and metabolism. Nr1d1(Rev-erbα) is a key regulator of circadian gene expression and a pleiotropic regulator of skeletal muscle homeostasis and lipid metabolism. Loss of Rev-erbα expression induces muscular atrophy, high adiposity, and metabolic syndrome in mice. Here we show that, unlike knockout mice, Nr1d1 heterozygous mice are not susceptible to muscular atrophy and in fact paradoxically possess larger myofiber diameters and improved neuromuscular function, compared to wildtype mice. Heterozygous mice lacked dyslipidemia, a characteristic of Nr1d1 knockout mice and displayed increased whole-body fatty-acid oxidation during periods of inactivity (light cycle). Heterozygous mice also exhibited higher rates of glucose uptake when fasted, and had elevated basal rates of gluconeogenesis compared to wildtype and knockout littermates. Rev-erbα ablation suppressed glycolysis and fatty acid-oxidation in white-adipose tissue (WAT), whereas partial Rev-erbα loss, curiously stimulated these processes. Our investigations revealed that Rev-erbα dose-dependently regulates glucose metabolism and fatty acid oxidation in WAT and muscle.


Assuntos
Dislipidemias/genética , Músculo Esquelético/metabolismo , Atrofia Muscular/genética , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Tecido Adiposo Branco/metabolismo , Adiposidade/genética , Animais , Comportamento Animal/fisiologia , Relógios Circadianos/genética , Dislipidemias/metabolismo , Dislipidemias/patologia , Ácidos Graxos/metabolismo , Gluconeogênese/genética , Glucose/metabolismo , Heterozigoto , Humanos , Metabolismo dos Lipídeos/genética , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Camundongos , Camundongos Knockout , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Miofibrilas/genética , Miofibrilas/metabolismo , Miofibrilas/patologia , Fotoperíodo
9.
Chemosphere ; 255: 127000, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32417515

RESUMO

BACKGROUND: Bisphenol-A (BPA) exposure is widespread and early life exposure is associated with metabolic syndrome. While visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) are implicated in the development of metabolic syndrome, the adipose depot-specific effects of prenatal BPA treatment are poorly understood. OBJECTIVE: To determine the impact of prenatal BPA exposure on genome-wide gene expression of VAT and SAT depots. METHODS: RNA sequencing was performed on SAT and VAT from 21-month old control and prenatal BPA-treated female sheep. Gene expression and pathway differences between SAT and VAT depots with or without prenatal BPA-treatment and the effect of prenatal BPA treatment on each depot were tested. RESULTS: There were 179 differentially expressed genes (padjusted < 0.05, log2-fold change >2.5) between SAT and VAT. Development and immune response pathways were upregulated in SAT, while metabolic pathways were upregulated in VAT. These adipose depot-specific genes and pathways were consistent with prenatal BPA-treatment. In SAT, BPA-treatment resulted in differential expression of 108 genes (78% upregulated with BPA) and altered pathways (immune response downregulated, RNA processing upregulated). In contrast in VAT, BPA-treatment differentially expressed 4 genes and upregulated chromatin and RNA processing pathways. CONCLUSION: Prenatal BPA-treatment induces adult depot-specific alterations in RNA expression in inflammation, RNA processing, and chromatin pathways, reflecting the diverse roles of SAT and VAT in regulating lipid storage and insulin sensitivity. These adipose tissue transcriptional dysregulations may contribute to the metabolic disorders observed in prenatal BPA-treated female sheep.


Assuntos
Adiposidade/efeitos dos fármacos , Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Gordura Intra-Abdominal/efeitos dos fármacos , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Gordura Subcutânea/efeitos dos fármacos , Adiposidade/genética , Animais , Compostos Benzidrílicos/sangue , Regulação para Baixo , Disruptores Endócrinos/sangue , Feminino , Perfilação da Expressão Gênica , Inflamação , Gordura Intra-Abdominal/crescimento & desenvolvimento , Gordura Intra-Abdominal/metabolismo , Masculino , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , Fenóis/sangue , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , RNA/genética , RNA/metabolismo , Ovinos , Gordura Subcutânea/crescimento & desenvolvimento , Gordura Subcutânea/metabolismo
10.
BMJ ; 369: m1203, 2020 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-32376654

RESUMO

OBJECTIVE: To evaluate whether body size in early life has an independent effect on risk of disease in later life or whether its influence is mediated by body size in adulthood. DESIGN: Two sample univariable and multivariable mendelian randomisation. SETTING: The UK Biobank prospective cohort study and four large scale genome-wide association studies (GWAS) consortiums. PARTICIPANTS: 453 169 participants enrolled in UK Biobank and a combined total of more than 700 000 people from different GWAS consortiums. EXPOSURES: Measured body mass index during adulthood (mean age 56.5) and self-reported perceived body size at age 10. MAIN OUTCOME MEASURES: Coronary artery disease, type 2 diabetes, breast cancer, and prostate cancer. RESULTS: Having a larger genetically predicted body size in early life was associated with an increased odds of coronary artery disease (odds ratio 1.49 for each change in body size category unless stated otherwise, 95% confidence interval 1.33 to 1.68) and type 2 diabetes (2.32, 1.76 to 3.05) based on univariable mendelian randomisation analyses. However, little evidence was found of a direct effect (ie, not through adult body size) based on multivariable mendelian randomisation estimates (coronary artery disease: 1.02, 0.86 to 1.22; type 2 diabetes:1.16, 0.74 to 1.82). In the multivariable mendelian randomisation analysis of breast cancer risk, strong evidence was found of a protective direct effect for larger body size in early life (0.59, 0.50 to 0.71), with less evidence of a direct effect of adult body size on this outcome (1.08, 0.93 to 1.27). Including age at menarche as an additional exposure provided weak evidence of a total causal effect (univariable mendelian randomisation odds ratio 0.98, 95% confidence interval 0.91 to 1.06) but strong evidence of a direct causal effect, independent of early life and adult body size (multivariable mendelian randomisation odds ratio 0.90, 0.85 to 0.95). No strong evidence was found of a causal effect of either early or later life measures on prostate cancer (early life body size odds ratio 1.06, 95% confidence interval 0.81 to 1.40; adult body size 0.87, 0.70 to 1.08). CONCLUSIONS: The findings suggest that the positive association between body size in childhood and risk of coronary artery disease and type 2 diabetes in adulthood can be attributed to individuals remaining large into later life. However, having a smaller body size during childhood might increase the risk of breast cancer regardless of body size in adulthood, with timing of puberty also putatively playing a role.


Assuntos
Adiposidade/genética , Neoplasias da Mama/epidemiologia , Doença da Artéria Coronariana/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Obesidade/genética , Neoplasias da Próstata/epidemiologia , Índice de Massa Corporal , Neoplasias da Mama/genética , Criança , Doença da Artéria Coronariana/genética , Diabetes Mellitus Tipo 2/genética , Feminino , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias da Próstata/genética , Medição de Risco , Fatores de Risco , Reino Unido/epidemiologia
11.
Nat Commun ; 11(1): 1841, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32296068

RESUMO

Brain insulin action regulates eating behavior and energy fluxes throughout the body. However, numerous people are brain insulin resistant. How brain insulin responsiveness affects long-term weight and body fat composition in humans is still unknown. Here we show that high brain insulin sensitivity before lifestyle intervention associates with a more pronounced reduction in total and visceral fat during the program. High brain insulin sensitivity is also associated with less regain of fat mass during a nine year follow-up. Cross-sectionally, strong insulin responsiveness of the hypothalamus associates with less visceral fat, while subcutaneous fat is unrelated. Our results demonstrate that high brain insulin sensitivity is linked to weight loss during lifestyle intervention and associates with a favorable body fat distribution. Since visceral fat is strongly linked to diabetes, cardiovascular risk and cancer, these findings have implications beyond metabolic diseases and indicate the necessity of strategies to resolve brain insulin resistance.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Adiposidade/genética , Adiposidade/fisiologia , Adulto , Composição Corporal/genética , Composição Corporal/fisiologia , Encéfalo/metabolismo , Estudos Transversais , Diabetes Mellitus Tipo 2/genética , Feminino , Humanos , Resistência à Insulina/genética , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade
12.
Clin Sci (Lond) ; 134(7): 921-939, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32239178

RESUMO

Maternal obesity determines obesity and metabolic diseases in the offspring. The white adipose tissue (WAT) orchestrates metabolic pathways, and its dysfunction contributes to metabolic disorders in a sex-dependent manner. Here, we tested if sex differences influence the molecular mechanisms of metabolic programming of WAT in offspring of obese dams. To this end, maternal obesity was induced with high-fat diet (HFD) and the offspring were studied at an early phase [postnatal day 21 (P21)], a late phase (P70) and finally P120. In the early phase we found a sex-independent increase in WAT in offspring of obese dams using magnetic resonance imaging (MRI), which was more pronounced in females than males. While the adipocyte size increased in both sexes, the distribution of WAT differed in males and females. As mechanistic hints, we identified an inflammatory response in females and a senescence-associated reduction in the preadipocyte factor DLK in males. In the late phase, the obese body composition persisted in both sexes, with a partial reversal in females. Moreover, female offspring recovered completely from both the adipocyte hypertrophy and the inflammatory response. These findings were linked to a dysregulation of lipolytic, adipogenic and stemness-related markers as well as AMPKα and Akt signaling. Finally, the sex-dependent metabolic programming persisted with sex-specific differences in adipocyte size until P120. In conclusion, we do not only provide new insights into the molecular mechanisms of sex-dependent metabolic programming of WAT dysfunction, but also highlight the sex-dependent development of low- and high-grade pathogenic obesity.


Assuntos
Adipócitos Brancos/metabolismo , Adipogenia , Tecido Adiposo Branco/metabolismo , Adiposidade , Dieta Hiperlipídica , Metabolismo Energético , Obesidade Materna/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Adipócitos Brancos/patologia , Adipogenia/genética , Tecido Adiposo Branco/patologia , Tecido Adiposo Branco/fisiopatologia , Adiposidade/genética , Fenômenos Fisiológicos da Nutrição Animal , Animais , Tamanho Celular , Modelos Animais de Doenças , Metabolismo Energético/genética , Feminino , Regulação da Expressão Gênica , Hipertrofia , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Camundongos Endogâmicos C57BL , Estado Nutricional , Obesidade Materna/genética , Obesidade Materna/patologia , Obesidade Materna/fisiopatologia , Gravidez , Caracteres Sexuais , Fatores Sexuais , Transdução de Sinais , Fatores de Tempo
13.
Psychol Health ; 35(9): 1151-1161, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32275177

RESUMO

Objective: The present study examined whether physical activity, personality, cognition, education, and depressive symptoms mediate the association between polygenic scores (PGS) for body mass index (BMI) and waist circumference and the corresponding phenotypic adiposity measures.Design: Participants were 9,139 individuals aged 50 to 107 years (57% women; Mean Age: 68.17, SD: 10.06) from the Health and Retirement Study who were genotyped. Trained staff measured their height, weight, and waist circumference, and participants answered questions on physical activity, personality, education, cognitive function, and depressive symptoms.Main Outcome Measures: BMI and waist circumference.Results: A higher PGS for both BMI and waist circumference were related to higher phenotypic BMI and waist circumference, respectively, in part through their association with lower physical activity, conscientiousness, education, and higher depressive symptoms but not cognition. The mediators accounted for 6.6% of the association between PGS and BMI and 9.6% of the association between PGS and waist circumference.Conclusion: The present study provides new evidence on the multiple, distinct pathways through which genetic propensity to higher BMI and waist circumference may lead to higher adiposity in adulthood. Individuals with a higher genetic predisposition to obesity may gain more weight through less adaptive behavioral, personality and educational profiles.


Assuntos
Adiposidade/genética , Índice de Massa Corporal , Obesidade/genética , Obesidade/psicologia , Circunferência da Cintura/genética , Idoso , Idoso de 80 Anos ou mais , Cognição , Depressão , Escolaridade , Exercício Físico , Feminino , Predisposição Genética para Doença , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Personalidade , Fenótipo , Fatores de Risco , Estados Unidos
14.
J Endocrinol ; 245(1): 93-100, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32027602

RESUMO

Remodeling of energy-storing white fat into energy-consuming beige fat has led to a promising new approach to alleviate adiposity. Several studies have shown adipokines can induce white adipose tissue (WAT) beiging through autocrine or paracrine actions. Betatrophin, a novel adipokine, has been linked to energy expenditure and lipolysis but not clearly clarified. Here, we using high-fat diet-induced obesity to determine how betatrophin modulate beiging and adiposity. We found that betatrophin-knockdown mice displayed less white fat mass and decreased plasma TG and NEFA levels. Consistently, inhibition of betatrophin leads to the phenotype change of adipocytes characterized by increased mitochondria contents, beige adipocytes and mitochondria biogenesis-specific markers both in vivo and in vitro. Of note, blocking AMP-activated protein kinase (AMPK) signaling pathway is able to abolish enhanced beige-like characteristics in betatrophin-knockdown adipocytes. Collectively, downregulation of betatrophin induces beiging in white adipocytes through activation of AMPK signaling pathway. These processes suggest betatrophin as a latent therapeutic target for obesity.


Assuntos
Adipócitos Bege/metabolismo , Adipócitos Brancos/metabolismo , Tecido Adiposo Branco/metabolismo , Proteínas Semelhantes a Angiopoietina/metabolismo , Mitocôndrias/metabolismo , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos Bege/citologia , Adipócitos Brancos/citologia , Tecido Adiposo Branco/citologia , Adiposidade/genética , Proteínas Semelhantes a Angiopoietina/genética , Animais , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/genética , Ácidos Graxos não Esterificados/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Interferência de RNA , Transdução de Sinais , Triglicerídeos/sangue
15.
J Endocrinol ; 245(1): 115-127, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32027603

RESUMO

Proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus (ARC) are essential for normal energy homeostasis. Maximal ARC Pomc transcription is dependent on neuronal Pomc enhancer 1 (nPE1), located 12 kb upstream from the promoter. Selective deletion of nPE1 in mice decreases ARC Pomc expression by 70%, sufficient to induce mild obesity. Because nPE1 is located exclusively in the genomes of placental mammals, we questioned whether its hypomorphic mutation would also alter placental Pomc expression and the metabolic adaptations associated with pregnancy and lactation. We assessed placental development, pup growth, circulating leptin and expression of Pomc, Agrp and alternatively spliced leptin receptor (LepR) isoforms in the ARC and placenta of Pomc∆1/∆1 and Pomc+/+ dams. Despite indistinguishable body weights, lean mass, food intake, placental histology and Pomc expression and overall pregnancy outcomes between the genotypes, Pomc ∆1/∆1 females had increased pre-pregnancy fat mass that paradoxically decreased to control levels by parturition. However, Pomc∆1/∆1 dams had exaggerated increases in circulating leptin, up to twice of that of the typically elevated levels in Pomc+/+ mice at the end of pregnancy, despite their equivalent fat mass. Pomc∆1/∆1dams also had increased placental expression of soluble leptin receptor (LepRe), although the protein levels of LEPRE in circulation were the same as Pomc+/+ controls. Together, these data suggest that the hypomorphic Pomc∆1/∆1 allele is responsible for the perinatal super hyperleptinemia of Pomc∆1/∆1 dams, possibly due to upregulated leptin secretion from individual adipocytes.


Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Leptina/metabolismo , Neurônios/metabolismo , Pró-Opiomelanocortina/genética , Adiposidade/genética , Alelos , Animais , Núcleo Arqueado do Hipotálamo/citologia , Peso Corporal , Feminino , Leptina/sangue , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Placenta/embriologia , Placenta/metabolismo , Gravidez , Pró-Opiomelanocortina/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo
16.
Obesity (Silver Spring) ; 28(4): 772-782, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32108446

RESUMO

OBJECTIVE: Inactivity and inflammation are linked to obesity and insulin resistance. It was hypothesized that MyD88 (mediates inflammation) knockout from muscle (MusMyD88-/- ) would prevent, whereas miR146a-/- (MyD88 inhibitor) would exacerbate, inactivity-induced metabolic disturbances. METHODS: Cre-control, MusMyD88-/- , and miR146a-/- mice were given running wheels for 5 weeks to model an active phenotype. Afterward, half were placed into a small mouse cage (SMC) to restrict movement for 8 days. Body composition, muscle (3 H)2-deoxyglucose uptake, visceral fat histology, and tissue weight (hind limb muscles, visceral fat, and liver) were assessed. In skeletal muscle and visceral fat, RNA sequencing and mitochondrial function were performed on female MusMyD88-/- and Cre-control SMC mice. RESULTS: The SMC induced adiposity, hyperinsulinemia, and muscle insulin-stimulated glucose uptake, which was worsened in miR146a-/- mice. In females, MusMyD88-/- mice were protected. Female MusMyD88-/- mice during the SMC period (vs. Cre-control) exhibited higher Igf1 and decreased Ip6k3 and Trim63 muscle expression. Visceral fat transcript changes corresponded to improved lipid metabolism, decreased adipose expansion (Gulp1↑, Anxa2↓, Ehd1↓) and meta-inflammation (Hmox1↓), and increased beiging (Fgf10↑). Ralgapa2, negative regulator of GLUT4 translocation, and inflammation-related gene 993011J21Rik2 were decreased in both muscle and fat. CONCLUSIONS: Whole-body miR146a-/- exacerbated inactivity-induced fat gain and muscle insulin resistance, whereas MusMyD88-/- prevented insulin resistance in female mice.


Assuntos
Adiposidade/genética , Resistência à Insulina/fisiologia , Músculo Esquelético/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo
17.
J Pediatr ; 219: 23-30.e1, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32037156

RESUMO

OBJECTIVE: To examine the association between polymorphisms of the ciliary neurotrophic factor gene (CNTF) and total and central adiposity markers in adolescents. STUDY DESIGN: This cross-sectional study involved 1057 European adolescents aged 12-18 years enrolled in the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study. Five polymorphisms of CNTF were genotyped, and the weight, height, waist and hip circumference, and triceps and subscapular skinfold thickness of the subjects were measured and recorded. RESULTS: The T allele of rs2509914, the C allele of rs2515363, and the G allele of rs2515362 were significantly associated (after Bonferroni correction) with higher values for several adiposity markers under different inheritance models. The CNTF CCGGA haplotype (rs2509914, rs17489568, rs2515363 rs1800169, and rs2515362) was also significantly associated with lower body mass index, waist circumference, waist/height ratio, and waist/hip ratio values compared with the TCCGG haplotype under several inheritance models. CONCLUSIONS: Three polymorphisms-rs2509914, rs2515363, and rs2515362-and the CCGGA haplotype of CNTF were significantly associated with adiposity in European adolescents. These results suggest the potential role of CTNF in the development of obesity-related phenotypes.


Assuntos
Adiposidade/genética , Fator Neurotrófico Ciliar/sangue , Obesidade/genética , Adolescente , Índice de Massa Corporal , Estudos de Casos e Controles , Criança , Estudos Transversais , Europa (Continente)/epidemiologia , Feminino , Marcadores Genéticos , Humanos , Masculino , Obesidade/sangue , Obesidade/epidemiologia , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Distribuição por Sexo
18.
J Endocrinol ; 245(1): 165-178, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32053493

RESUMO

Loss of ovarian hormones leads to increased adiposity and insulin resistance (IR), increasing the risk for cardiovascular and metabolic diseases. The purpose of this study was to investigate whether the molecular mechanism behind the adverse systemic and adipose tissue-specific metabolic effects of ovariectomy requires loss of signaling through estrogen receptor alpha (ERα) or estrogen receptor ß (ERß). We examined ovariectomized (OVX) and ovary-intactwild-type (WT), ERα-null (αKO), and ERß-null (ßKO) female mice (age ~49 weeks; n = 7-12/group). All mice were fed a phytoestrogen-free diet (<15 mg/kg) and either remained ovary-intact (INT) or were OVX and followed for 12 weeks. Body composition, energy expenditure, glucose tolerance, and adipose tissue gene and protein expression were analyzed. INT αKO were ~25% fatter with reduced energy expenditure compared to age-matched INT WT controls and ßKO mice (all P < 0.001). Following OVX, αKO mice did not increase adiposity or experience a further increase in IR, unlike WT and ßKO, suggesting that loss of signaling through ERα mediates OVX-induced metabolic dysfunction. In fact, OVX in αKO mice (i.e., signaling through ERß in the absence of ERα) resulted in reduced adiposity, adipocyte size, and IR (P < 0.05 for all). ßKO mice responded adversely to OVX in terms of increased adiposity and development of IR. Together, these findings challenge the paradigm that ERα mediates metabolic protection over ERß in all settings. These findings lead us to suggest that, following ovarian hormone loss, ERß may mediate protective metabolic benefits.


Assuntos
Adiposidade/genética , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Resistência à Insulina/genética , Ovariectomia , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Composição Corporal/genética , Metabolismo Energético/genética , Receptor alfa de Estrogênio/deficiência , Receptor beta de Estrogênio/deficiência , Feminino , Expressão Gênica , Humanos , Leptina/genética , Leptina/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/genética
19.
PLoS One ; 15(2): e0228400, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32027667

RESUMO

Obesity is a multifactorial disease caused by complex interactions between genes and dietary factors. Salt-rich diet is related to the development and progression of several chronic diseases including obesity. However, the molecular basis of how salt sensitivity genes (SSG) contribute to adiposity in obesity patients remains unexplored. In this study, we used the microarray expression data of visceral adipose tissue samples and constructed a complex protein-interaction network of salt sensitivity genes and their co-expressed genes to trace the molecular pathways connected to obesity. The Salt Sensitivity Protein Interaction Network (SSPIN) of 2691 differentially expressed genes and their 15474 interactions has shown that adipose tissues are enriched with the expression of 23 SSGs, 16 hubs and 84 bottlenecks (p = 2.52 x 10-16) involved in diverse molecular pathways connected to adiposity. Fifteen of these 23 SSGs along with 8 other SSGs showed a co-expression with enriched obesity-related genes (r ≥ 0.8). These SSGs and their co-expression partners are involved in diverse metabolic pathways including adipogenesis, adipocytokine signaling pathway, renin-angiotensin system, etc. This study concludes that SSGs could act as molecular signatures for tracing the basis of adipogenesis among obese patients. Integrated network centered methods may accelerate the identification of new molecular targets from the complex obesity genomics data.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes/efeitos dos fármacos , Obesidade Pediátrica/genética , Estresse Salino/genética , Cloreto de Sódio na Dieta/farmacologia , Adiposidade/efeitos dos fármacos , Adiposidade/genética , Adolescente , Estudos de Casos e Controles , Epistasia Genética/efeitos dos fármacos , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Análise em Microsséries/métodos , Obesidade Pediátrica/metabolismo , Obesidade Pediátrica/patologia , Estresse Salino/efeitos dos fármacos , Integração de Sistemas , Adulto Jovem
20.
Anim Genet ; 51(2): 314-318, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31909836

RESUMO

Growth and fatness traits are complex and economically important traits in the pig industry. The molecular basis underlying porcine growth and fatness traits remains largely unknown. To uncover genetic loci and candidate genes for these traits, we explored the GeneSeek GGP Porcine 80K SNP chip to perform a GWAS for seven growth and fatness traits in 365 individuals from the Sujiang pig, a recently developed breed in China. We identified two, 17, one and 11 SNPs surpassing the suggestively significant threshold (P < 1.86 × 10-5 ) for body weight, chest circumference, chest width and backfat thickness respectively. Of these SNPs, 20 represent novel genetic loci, and five and four SNPs were respectively associated with chest circumference and backfat thickness at a genome-wide significant threshold (P < 9.31 × 10-7 ). Eight SNPs had a pleiotropic effect on both chest circumference and backfat thickness. The most remarkable locus resided in a region between 72.95 and 76.27 Mb on pig chromosome 4, harboring a number of previously reported quantitative trait loci related to backfat deposition. In addition to two reported genes (PLAG1 and TAS2R38), we identified four genes including GABRB3, ZNF106, XKR4 and MGAM as novel candidates for body weight and backfat thickness at the mapped loci. Our findings provide insights into the genetic architecture of porcine growth and fatness traits and potential markers for selective breeding of Chinese Sujiang pigs.


Assuntos
Adiposidade/genética , Peso Corporal/genética , Estudo de Associação Genômica Ampla/veterinária , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Sus scrofa/genética , Animais , China , Sus scrofa/crescimento & desenvolvimento , Sus scrofa/metabolismo
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