RESUMEN
Young adults (18-25) with severe obesity constitute a challenging patient group, and there is limited evidence about their mental health status compared to population controls. Mental distress in treatment seeking young adults with severe obesity (n = 121, mean body mass index [BMI] = 39.8 kg m-2 ) was compared with matched (1:3 for age, gender and socioeconomic status) population controls of normal weight (n = 363, mean BMI = 22.4 kg m-2 ), as well as unmatched population controls with class I obesity (n = 105, mean BMI = 32.1 kg m-2 ) or severe obesity (n = 41, mean BMI = 39.7 kg m-2 ). Mental distress was measured by the General Health Questionnaire-12 (GHQ-12), and we quantified physician-diagnosed depression, present anxiety and suicide attempts. Poisson regression and linear regression analysis were used for analysing differences in mental distress between groups. Treatment seekers experienced more mental distress than normal weight controls as measured by continuous (adjusted mean: 3.9 vs. 2.2 points, P <0.001) and categorical (cut-off for mental distress ≥3 points, RR: 1.76, P <0.001) GHQ-12 scores, depression (RR: 2.18, P < 0.001), anxiety (RR: 1.97, P < 0.001) and suicide attempts (RR: 2.04; P = 0.034). Treatment seekers also experienced more mental distress as measured by continuous GHQ-12 than controls with class I obesity (adjusted mean: 2.3 points) or severe obesity (adjusted mean: 2.1; both, P < 0.001). Young adult treatment seekers with severe obesity constitute a risk group for mental distress compared to population controls of different BMI levels.
Asunto(s)
Índice de Masa Corporal , Trastornos Mentales/epidemiología , Obesidad/psicología , Delgadez/psicología , Adolescente , Adulto , Estudios de Cohortes , Femenino , Estado de Salud , Humanos , Masculino , Trastornos Mentales/psicología , Obesidad/epidemiología , Prevalencia , Calidad de Vida , Factores de Riesgo , Factores Socioeconómicos , Suecia/epidemiología , Delgadez/epidemiología , Adulto JovenRESUMEN
Controversy exists surrounding the role of childhood abuse in obesity development. This is a meta-analysis of observational studies on the role of childhood abuse in adult obesity. Systematic searches of PubMed, PsycInfo, Medline and CINAHL resulted in 23 cohort studies (4 prospective, 19 retrospective) with n=112,708 participants, containing four abuse types (physical, emotional, sexual, general). Four studies reported dose-response effects. A random effects model was used to quantify effect sizes, meta-regression/subgroup analysis for identifying potential moderating variables and Egger's test for publication bias. Adults who reported childhood abuse were significantly more likely to be obese (odds ratio [OR]: 1.34, 95% confidence interval [CI]: 1.24-1.45, P<0.001). All four types of abuse were significantly associated with adult obesity: physical (OR: 1.28, 95% CI: 1.13-1.46), emotional (OR: 1.36, 95% CI: 1.08-1.71), sexual (OR: 1.31, 95% CI: 1.13-1.53) and general abuse (OR: 1.45, 95% CI: 1.25-1.69). Severe abuse (OR: 1.50, 95% CI: 1.27-1.77) was significantly more associated with adult obesity (P=0.043) compared with light/moderate abuse (OR: 1.13, 95% CI: 0.91-1.41). We found no significant effects of study design (prospective vs. retrospective, P=0.07), age (P=0.96) or gender (P=0.92). Publication bias was evident (Egger's test P=0.007), but effect sizes remained statistically significant in sensitivity analyses. Childhood abuse was clearly associated with being obese as an adult, including a positive dose-response association. This suggests that adverse life experiences during childhood plays a major role in obesity development, potentially by inducing mental and emotional perturbations, maladaptive coping responses, stress, inflammation and metabolic disturbances.
Asunto(s)
Maltrato a los Niños/psicología , Obesidad/psicología , Trastornos Relacionados con Sustancias/psicología , Aumento de Peso , Adaptación Psicológica , Adulto , Edad de Inicio , Niño , Preescolar , Humanos , Salud Mental , Obesidad/etiología , Estudios Observacionales como Asunto , Oportunidad Relativa , Estudios Prospectivos , Estudios Retrospectivos , Factores de Riesgo , Trastornos Relacionados con Sustancias/etiología , Factores de TiempoRESUMEN
OBJECTIVE: The aim of this study was to explore the outcome and the problems of drop-out in the treatment of obese outpatients at an academic obesity unit. DESIGN: A two-year clinical treatment evaluation. SUBJECTS: A total of 117 obese subjects, 83 women and 34 men, mean aged 50 (23-70) years, with an average body mass index (BMI) of 39.0 kg/m2 (28.8- 64.7). INTERVENTION: All treatment was based on group therapy and included behaviour modification and nutrition counselling. A team of nurses, dieticians, a physiotherapist, a psychotherapist and a physician supervised the treatment. Two programmes were used. Group 1 initially received a low-calorie diet (LCD) for seven weeks combined with the behaviour treatment programme. Group 2 was treated with the behaviour treatment programme only. All subjects were offered complementary treatment according to their medical needs. RESULTS: There was a continuous drop-out of subjects during the two-year treatment period with an overall drop-out rate of 53%. Anthropometric characteristics, medical history or reasons for drop-out had no impact on the drop-out rate. In completers the weight reduction after two years was 9.2 [+/-10.8 standard deviation (S.D.) kg. In non-completers the weight reduction of the last observed weight measurement was 4.7 (+/-7.9 S.D.) kg. After year two, the weight reduction in Group 1 was 8.8 (+/-12.2 S.D.) kg, and in Group 2 was 9.7 (+/-8.0 S.D.) kg. CONCLUSION: This study has showed the difficulties of long-term clinical treatment of obese outpatients, even in a specialised obesity clinic. The findings demonstrate that educated and experienced staff together with an extended package of treatment options is not enough to keep patients in treatment for two years. However though the drop-out rate was high, two thirds of the included subjects reduced their weight, which is a satisfactory result in a clinical setting. The drop-out rate and the reasons for dropping out could give a clue in which direction the diagnostics and analysis of the subject's individual needs in health care should be directed.
Asunto(s)
Terapia Conductista , Dieta Reductora , Obesidad/terapia , Pacientes Desistentes del Tratamiento , Psicoterapia de Grupo , Adulto , Anciano , Índice de Masa Corporal , Terapia Combinada , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/dietoterapia , Pacientes Desistentes del Tratamiento/estadística & datos numéricos , Evaluación de Programas y Proyectos de Salud , Pérdida de PesoRESUMEN
A lipolytic process in skeletal muscle has recently been demonstrated. However, the physiological importance of this process is unknown. We investigated the role of skeletal muscle lipolysis for lipid utilization during caloric restriction in eight obese women before and after 11 days of very low-calorie diet (VLCD) (2.2 MJ per day). Subjects were studied with indirect calorimetry and microdialysis of skeletal muscle and adipose tissue in order to analyze substrate utilization and glycerol (lipolysis index) in connection with a two-step euglycemic-hyperinsulinemic (12 and 80 mU/m(2). min) clamp. Local blood flow rates in the two tissues were determined with (133)Xe-clearance. Circulating free fatty acids and glycerol decreased to a similar extent during insulin infusion before and during VLCD, and there was a less marked insulin-induced reduction in lipid oxidation during VLCD. Adipose tissue glycerol release was hampered by insulin infusion to the same extent ( approximately 40%) before and during VLCD. Skeletal muscle glycerol release was not influenced by insulin before VLCD. However, during VLCD insulin caused a marked (fivefold) (P < 0.01) increase in skeletal muscle glycerol release. The effect was accompanied by a fourfold stimulation of skeletal muscle blood flow (P < 0.01). We propose that, during short-term caloric restriction, the reduced ability of insulin to inhibit lipids, despite a preserved antilipolytic effect of the hormone in adipose tissue, is caused by an augmented mobilization of fat from skeletal muscle, and that a physiological role of muscle lipolysis provides a local source of fatty acids.
Asunto(s)
Metabolismo de los Lípidos , Lipólisis , Músculo Esquelético/metabolismo , Tejido Adiposo/metabolismo , Adulto , Calorimetría Indirecta , Metabolismo Energético , Ácidos Grasos no Esterificados/sangre , Femenino , Privación de Alimentos , Glicerol/sangre , Humanos , Insulina/sangre , Insulina/farmacología , Microdiálisis , Persona de Mediana Edad , Músculo Esquelético/irrigación sanguínea , Oxidación-Reducción , Flujo Sanguíneo RegionalRESUMEN
OBJECTIVE: To investigate in obese subjects the relationship between angiotensinogen gene expression in the abdominal omental and subcutaneous adipose tissue on the one hand and body fat distribution as measured by waist-to-hip ratio (WHR) on the other hand and to compare angiotensinogen gene expression between the two adipose tissue regions. SUBJECTS: Twenty obese subjects undergoing weight reduction surgery with adjustable gastric banding (12 men, eight women; WHR 0.89-1.09; body mass index (BMI) 29-51 kg/m2, age 26-54 y). MEASUREMENTS: Omental and subcutaneous adipose angiotensinogen mRNA and 18S ribosomal RNA (reference gene) levels were measured by competitive quantitative reverse transcriptase-polymerase chain reaction. RESULTS: Angiotensinogen mRNA levels were one-third higher in the omental than in the subcutaneous adipose tissue region (P=0.02). The 18S rRNA levels did not differ significantly between the two adipose tissue regions. WHR correlated positively and significantly with angiotensinogen mRNA in both the subcutaneous and the omental adipose tissue (r=0.5). This relationship was independent of age and BMI. However, WHR did not correlate with 18S rRNA in any of the adipose tissue regions. CONCLUSION: The angiotensinogen gene in adipose tissue might be involved in the development of upper-body obesity.
Asunto(s)
Abdomen , Tejido Adiposo/metabolismo , Angiotensinógeno/genética , Composición Corporal , Expresión Génica , Obesidad/genética , Tejido Adiposo/patología , Adulto , Biopsia , Constitución Corporal , Índice de Masa Corporal , Femenino , Gastroplastia , Humanos , Masculino , Persona de Mediana Edad , Obesidad/cirugía , ARN Mensajero/análisis , ARN Ribosómico 18S/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Some animal models suggest that tumor necrosis factor (TNF)-alpha is a key component in obesity-linked insulin resistance because it inhibits insulin receptor signaling and glucose transport in insulin-sensitive tissues. However, in vivo data in humans have given conflicting results regarding the relationship between circulating TNF-alpha levels and insulin sensitivity. In the present study, the potential local role of TNF-alpha on insulin action in human subcutaneous adipose tissue was studied in 42 obese women (BMI 39+/-10 kg/m2). We found a strong inverse correlation between adipose TNF-alpha secretion and maximum insulin-stimulated glucose transport in adipocytes that was independent of fat cell volume, age, and BMI (P < 0.001, r = 0.58). As much as one-third of the variation in insulin-stimulated glucose transport could be accounted for by variations in TNF-alpha secretion. There was no significant correlation (r = 0.11) between secretion of adipose plasminogen activator inhibitor 1 and glucose transport. Furthermore, subcutaneous adipose tissue of 4 obese women (BMI 40+/-4) incubated with TNF-A for 24 h showed a one-third concentration-dependent inhibition of insulin-stimulated glucose transport (P < 0.01). In conclusion, adipose TNF-alpha may be an important specific and local factor in adipose tissue that influences the ability of insulin to stimulate glucose transport in human fat cells, at least in obese women.
Asunto(s)
Tejido Adiposo/metabolismo , Glucosa/metabolismo , Insulina/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Tejido Adiposo/efectos de los fármacos , Adulto , Transporte Biológico/efectos de los fármacos , Femenino , Humanos , Persona de Mediana Edad , Obesidad/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
OBJECTIVES: To investigate gender differences in circulating leptin levels and adipose tissue production of leptin. DESIGN SETTING AND SUBJECTS: Thirty-two men and 63 women with a large interindividual variation in body mass index (BMI), but otherwise healthy, were investigated after an overnight fast. Body fat (bioimpedance), abdominal subcutaneous adipose tissue secretion of leptin in vitro and serum leptin were determined. RESULTS: Although there was no gender difference in mean BMI or fat cell size, mean percentage body fat was 49 in women and 36 in men (P < 0.001). At each level of BMI, serum leptin levels were about two times higher in women than in men (P < 0.001). Adipose tissue secretion rate of leptin in men was two-thirds of that in women (P < 0.05). The gender differences in body fat content, serum leptin and leptin secretion were observed in obese (BMI > 27 kg m-2) as well as non-obese subjects. Serum leptin levels (P < 0.001) and leptin secretion rate (P < 0.01) correlated positively with body fat content in either sex. However, the gender differences in serum leptin (P < 0.001) and leptin secretion rate (P < 0.01) remained statistically significantly different even when the values were adjusted for body fat. CONCLUSION: The gender difference in circulating leptin concentrations can be due to at least two different mechanisms. A higher proportion of adipose tissue and increased production rate of leptin per unit mass of adipose tissue might explain why women have higher circulating leptin levels than men.
Asunto(s)
Leptina/sangre , Caracteres Sexuales , Tejido Adiposo/metabolismo , Adulto , Índice de Masa Corporal , Tamaño de la Célula , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/sangreRESUMEN
OBJECTIVE: To evaluate a possible influence of a hereditary trait for obesity on the regulation of adipocyte metabolism in vitro in subcutaneous fat cells in obese and non-obese subjects. DESIGN: A biopsy from abdominal subcutaneous fat was obtained from consecutive subjects with or without a family trait for obesity. A positive family history of obesity was considered present if one or more of the first degree relatives had a BMI of 27 kg/m2 or more. SUBJECTS: 67 non-obese and 60 obese subjects, age 19-60 y. A family trait for overweight was present in 42 of the lean subjects and in 50 of the obese subjects. MEASUREMENTS: Fat cells were isolated and incubated in vitro with isoprenaline (a non-selective beta-adrenoceptor agonist), forskolin (activates the adenylyl cyclase) and dibutyryl cyclic AMP (stimulates the protein kinase hormone-sensitive lipase complex). Glycerol release was measured and used as lipolytic index. RESULTS: Maximal lipolytic response per g triglycerides was about 50% lower in obese subjects both with and without a positive heredity and in non-obese subjects with a family trait for obesity as compared to non-obese subjects without such trait (P=0.0001). Fat cell volume was twice as high in obese as compared to lean subjects. Drug-induced maximal glycerol release per fat cell in the obese subjects, regardless of family history of obesity, reached a similar level, but did not exceed that of the lean group without heredity. CONCLUSIONS: Obesity is associated with catecholamine resistance with a relatively ineffective lipolysis in fat cells, and presence of a family history of obesity was not associated with a further suppression of lipolysis. In the lean subjects, heredity for obesity significantly influenced lipolysis to similar low levels as in the obese subjects.
Asunto(s)
Adipocitos/metabolismo , Lipólisis , Obesidad/genética , Adulto , Glucemia/análisis , Presión Sanguínea , Índice de Masa Corporal , Bucladesina/farmacología , HDL-Colesterol/sangre , Colforsina/farmacología , Femenino , Glicerol/metabolismo , Humanos , Insulina/sangre , Isoproterenol/farmacología , Lipólisis/efectos de los fármacos , Masculino , Persona de Mediana Edad , Obesidad/metabolismoRESUMEN
High plasma plasminogen activator inhibitor-1 (PAI-1) activity is a frequent finding in obesity and adipose tissue has recently been suggested to be a source of circulating PAI-1 in humans. In the present study, differences in adipose tissue gene expression and protein secretion rate of PAI-1 between subcutaneous and visceral adipose tissue was analysed in specimens obtained from 22 obese individuals. The secretion rate of PAI-1 was two-fold higher in subcutaneous adipose tissue than in visceral adipose tissue (292 +/- 50 vs 138 +/- 24 ng PAI-1/10(7) cells, P <0.05). In accordance with the secretion data, subcutaneous adipose tissue contained about three-fold higher levels of PAI-1 mRNA than visceral adipose tissue (2.43 +/- 0.37 vs 0.81 +/- 0.12 attomole PAI-1 mRNA/microg total RNA, P <0.00 ). PAI-1 secretion from subcutaneous but not from visceral adipose tissue correlated significantly with cell size (r = 0.43, P<0.05). In summary, subcutaneous adipose tissue secreted greater amounts of PAI-1 and had a higher PAI-1 gene expression than visceral adipose tissue from the same obese individuals. Bearing in mind that subcutaneous adipose tissue is the largest fat depot these finding may be important for the coagulation abnormalities associated with obesity.
Asunto(s)
Tejido Adiposo/metabolismo , Regulación de la Expresión Génica , Obesidad/metabolismo , Inhibidor 1 de Activador Plasminogénico/biosíntesis , Tejido Adiposo/patología , Adulto , Índice de Masa Corporal , Tamaño de la Célula , Susceptibilidad a Enfermedades , Femenino , Humanos , Masculino , Persona de Mediana Edad , Obesidad/patología , Especificidad de Órganos , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , ARN Mensajero/biosíntesis , Piel/patología , Factor de Necrosis Tumoral alfa/metabolismo , Vísceras/patologíaRESUMEN
The pathogenetic mechanisms behind familial combined hyperlipidemia (FCHL) are unknown. However, exaggerated postprandial lipemia and excessive serum free fatty acid (FFA) concentrations have drawn attention to altered lipid storage and lipolysis in peripheral adipose tissue. Hormone-sensitive lipase (HSL) is the enzyme responsible for intracellular lipolysis in adipocytes and a decrease of adipocyte HSL activity has been demonstrated in Swedish FCHL subjects. The aim of the study was to investigate if adipose tissue HSL activity had any effect on lipid phenotype and if low HSL activity and FCHL were linked in Finnish FCHL families. A total of 48 family members from 13 well-characterized Finnish FCHL families and 12 unrelated spouses participated in the study. FCHL patients with different lipid phenotypes (IIA, IIB, IV) did not differ in adipose tissue HSL activity from each other or from the 12 normolipidemic spouses (P = 0.752). In parametric linkage analysis using an affecteds-only strategy the low adipose tissue HSL activity was not significantly linked with FCHL phenotype. However, we found a significant sibling-sibling correlation for the HSL trait (0.51, P < 0.01). Thus, a modifying or interacting role of HSL in the pathogenesis of FCHL could not be excluded.
Asunto(s)
Hiperlipidemia Familiar Combinada/metabolismo , Esterol Esterasa/metabolismo , Tejido Adiposo/metabolismo , Adulto , Anciano , Regulación hacia Abajo , Femenino , Finlandia/epidemiología , Humanos , Hiperlipidemia Familiar Combinada/epidemiología , Masculino , Persona de Mediana Edad , LinajeRESUMEN
Decreased lipolytic effect of catecholamines in adipose tissue has repeatedly been demonstrated in obesity and may be a cause of excess accumulation of body fat. However, the mechanisms behind this lipolysis defect are unclear. The role of hormone-sensitive lipase was examined using abdominal subcutaneous adipocytes from 34 obese drug-free and otherwise healthy males or females and 14 non-obese control subjects. The enzyme catalyzes the rate-limiting step of the lipolysis pathway. The maximum lipolytic capacity of fat cells was significantly decreased in obesity when measured using either a non-selective beta-adrenergic receptor agonist (isoprenaline) or a phosphodiesterase resistant cyclic AMP analogue (dibutyryl cyclic AMP). Likewise, enzyme activity, protein expression, and mRNA of hormone-sensitive lipase were significantly decreased in adipocytes of obese subjects. The findings were not influenced by age or gender. The data suggest that a decreased expression of hormone-sensitive lipase in subcutaneous fat cells, which in turn causes decreased enzyme function and impaired lipolytic capacity of adipocytes, is present in obesity. Impaired expression of the hormone-sensitive lipase gene might at least in part explain the enzyme defect.
Asunto(s)
Tejido Adiposo/enzimología , Obesidad/enzimología , Esterol Esterasa/genética , Tejido Adiposo/química , Tejido Adiposo/citología , Adulto , Factores de Edad , Anciano , Índice de Masa Corporal , Pesos y Medidas Corporales , Tamaño de la Célula , Femenino , Regulación de la Expresión Génica , Glicerol/metabolismo , Humanos , Insulina/sangre , Lipólisis/genética , Masculino , Persona de Mediana Edad , Mutación , Obesidad/etiología , Obesidad/metabolismo , ARN Mensajero/análisis , Factores Sexuales , Esterol Esterasa/análisisRESUMEN
The effects of acylation-stimulating protein (ASP) and insulin on free fatty acid (FFA) release from isolated human fat cells and the signal transduction pathways to induce these effects were studied. ASP and insulin inhibited basal and norepinephrine-induced FFA release by stimulating fractional FFA re-esterification (both to the same extent) and by inhibiting FFA produced during lipolysis (ASP to a lesser extent than insulin). Protein kinase C inhibition influenced none of the effects of ASP or insulin. Phosphatidylinositol 3-kinase inhibition counteracted the effects of insulin but not of ASP. Phosphodiesterase 3 (PDE3) activity was stimulated by ASP and insulin, whereas PDE4 activity was slightly increased by ASP only. Selective PDE3 inhibition reversed the effects of both ASP and insulin on fractional FFA re-esterification and lipolysis. Selective PDE4 inhibition slightly counteracted the ASP but not the effect of insulin on fractional FFA re-esterification and did not prevent the action of ASP or insulin on lipolysis. Thus, ASP and insulin play a major role in regulating FFA release from fat cells as follows: insulin by stimulating fractional FFA re-esterification and inhibiting lipolysis and ASP mainly by stimulating fractional FFA re-esterification. For both ASP and insulin these effects on FFA release are mediated by PDE3, and for ASP PDE4 might also be involved. The signaling pathway preceding PDE is not known for ASP but involves phosphatidylinositol 3-kinase for insulin.
Asunto(s)
Tejido Adiposo/metabolismo , Apolipoproteínas B/metabolismo , Proteínas Sanguíneas/metabolismo , Complemento C3a/análogos & derivados , Ácidos Grasos no Esterificados/metabolismo , Insulina/metabolismo , 3',5'-AMP Cíclico Fosfodiesterasas/metabolismo , Acilación , Tejido Adiposo/citología , Androstadienos/farmacología , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3 , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Inhibidores Enzimáticos/farmacología , Humanos , Técnicas In Vitro , Lipólisis , Naftalenos/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Proteína Quinasa C/antagonistas & inhibidores , WortmaninaRESUMEN
The influence of weight reduction and female sex hormones on the regulation of lipolysis was investigated in isolated abdominal sc adipocytes from 20 obese hyperandrogenic women with polycystic ovary syndrome (PCOS). Nine PCOS women were reinvestigated after 8-12 weeks of weight reduction therapy (WR) with a very low calorie diet, inducing a mean loss of 8 +/- 3 kg, and 8 PCOS women were reinvestigated after 12 weeks of treatment with combined oral contraceptives (OC), containing ethinyl estradiol and norethisterone; the remaining 3 subjects were drop-outs. Both WR and OC normalized hyperandrogenicity. WR caused a 50% reduction of basal lipolysis rate and a 5- to 7-fold increased noradrenaline and terbutaline sensitivity (P < 0.02); the latter could be ascribed to a 2-fold increased beta2-adrenoceptor density (P < 0.02) as determined with radioligand binding. There was no change with regard to dobutamine (beta1-adrenoceptor sensitivity) or clonidine, (alpha2-adrenoceptor sensitivity) or to beta1-adrenoceptor density. OC treatment did not influence the basal lipolysis rate or beta2- or alpha2-adrenoceptor sensitivity, but lowered the beta1-adrenoceptor sensitivity 7-fold (P < 0.03) without a reduction in beta1-adrenoceptor density. The OC treatment effect was not observed when forskolin and dibutyryl cAMP, acting on adenylate cyclase or protein kinase A, respectively, were used, suggesting a partial uncoupling of beta1-adrenoceptors. WR therapy, but not OC therapy, caused, in addition to changes in lipolysis function, improved in vivo insulin sensitivity and lower plasma noradrenaline levels. These findings suggest that factors other than hyperandrogenicity modulate lipolysis regulation in obese subjects with PCOS. Disturbances in sympathetic pathways could be of pathogenic importance.
Asunto(s)
Anticonceptivos Orales Combinados/farmacología , Lipólisis , Obesidad/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Sistema Nervioso Simpático/fisiología , Pérdida de Peso , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/patología , Agonistas alfa-Adrenérgicos/farmacología , Agonistas Adrenérgicos beta/farmacología , Adulto , Anticonceptivos Secuenciales Orales/farmacología , Dieta Reductora , Congéneres del Estradiol/farmacología , Estrógenos/farmacología , Etinilestradiol/farmacología , Femenino , Humanos , Lipólisis/efectos de los fármacos , Noretindrona/farmacología , Obesidad/dietoterapia , Síndrome del Ovario Poliquístico/fisiopatología , Ensayo de Unión Radioligante , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
OBJECTIVES: To investigate the role of a polymorphism in codon 27 (Gln27Glu) of the beta 2-adrenoceptor gene for obesity in males compared to previously investigated females with an association of this polymorphism to obesity. DESIGN: Population-based study. SETTING: Medical department at a University Hospital. SUBJECTS: A total of 138 non-related Swedish males with body mass indexes (BMI) in the range 19.4-53.4 kg m-2 were recruited as: healthy volunteers, healthy obese subjects and subjects undergoing surgery for uncomplicated gallstone or abdominal hernia. In order to investigate the impact of gender, the results were compared with a subset of an earlier investigated female population of 109 Swedish females. Obesity was defined as a BMI > 27 kg m-2. MAIN OUTCOME MEASURES: Genotype examination of beta 2-adrenoceptor polymorphism in codon 27 with polymerase chain reaction and restriction fragment length polymorphism. RESULTS: The allele frequency of Gln27 and Glu27 did not differ between males and females when obese and non-obese subjects were investigated together. However, in obese males, the frequency of the Glu27 allele was significantly decreased (P = 0.034), whereas the frequency of this allele was increased in obese females (P = 0.013). No impact of the female androgen status on the distribution of the Gln27Glu polymorphism could be demonstrated in the obese females. CONCLUSION: A positive association between obesity and the Glu27 genetic variant in the beta 2-adrenoceptor exists in females, whereas in males there is a negative correlation between Glu27 and obesity. The findings suggest that different genetic factors contribute to obesity in males and females.
Asunto(s)
Ácido Glutámico/genética , Mutación , Obesidad/genética , Polimorfismo de Longitud del Fragmento de Restricción , Receptores Adrenérgicos beta/genética , Adulto , Cartilla de ADN , Femenino , Humanos , Masculino , Reacción en Cadena de la PolimerasaRESUMEN
Increased mobilization of non-esterified fatty acids (NEFA) from visceral as opposed to peripheral fat depots can lead to metabolic disturbances because of the direct portal link between visceral fat and the liver. Compared with peripheral fat, visceral fat shows a decreased response to insulin. The mechanisms behind these site variations were investigated by comparing insulin action on NEFA metabolism with insulin receptor signal transduction through the insulin receptor substrate-1 (IRS-1) pathway in omental (visceral) and subcutaneous human fat obtained during elective surgery. Insulin inhibited lipolysis and stimulated NEFA re-esterification. This was counteracted by wortmannin, an inhibitor of phosphaditylinositol (PI) 3-kinase. The effects of insulin on antilipolysis and NEFA re-esterification were greatly reduced in omental fat cells. Insulin receptor binding capacity, mRNA and protein expression did not differ between the cell types. Insulin was four times more effective in stimulating tyrosine phosphorylation of the insulin receptor in subcutaneous fat cells (p < 0.001). Similarly, insulin was two to three times more effective in stimulating tyrosine phosphorylation of IRS-1 in subcutaneous fat cells (p < 0.01). This finding could be explained by finding that IRS-1 protein expression was reduced by 50 +/- 8% in omental fat cells (p < 0.01). In omental fat cells, maximum insulin-stimulated association of the p85 kDa subunit of PI 3-kinase to phosphotyrosine proteins and phosphotyrosine associated PI 3-kinase activity were both reduced by 50% (p < 0.05 or better). Thus, the ability of insulin to induce antilipolysis and stimulate NEFA re-esterification is reduced in visceral adipocytes. This reduction can be explained by reduced insulin receptor autophosphorylation and signal transduction through an IRS-1 associated PI 3-kinase pathway in visceral adipocytes.
Asunto(s)
Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Ácidos Grasos no Esterificados/metabolismo , Insulina/farmacología , Lipólisis/fisiología , Fosfoproteínas/metabolismo , Receptor de Insulina/fisiología , Adipocitos/efectos de los fármacos , Tejido Adiposo/efectos de los fármacos , Adulto , Anciano , Femenino , Glicerol/metabolismo , Humanos , Insulina/fisiología , Proteínas Sustrato del Receptor de Insulina , Cinética , Lipólisis/efectos de los fármacos , Masculino , Persona de Mediana Edad , Norepinefrina/farmacología , Epiplón , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Fosfotirosina/metabolismo , ARN Mensajero/genética , Receptor de Insulina/genética , Transducción de Señal , Piel , Transcripción GenéticaRESUMEN
Impaired lipolysis has been proposed as a pathogenic factor contributing to clustering of abdominal obesity and dyslipidaemia in Type II (non-insulin-dependent) diabetes mellitus--that is, the metabolic syndrome (MSDR). As this syndrome clusters in families, alterations in the hormone-sensitive lipase (HSL) gene could contribute to the genetic predisposition to MSDR. To test this hypothesis we carried out population and intrafamily association studies in individuals with MSDR, using a polymorphic marker (LIPE) in the HSL gene. There was a significant difference in allele frequency distribution between 235 Type II diabetic patients and 146 control subjects (p = 0.002), particularly between 78 abdominally obese Type II diabetic patients with MSDR and the control group (p = 0.010). An extended transmission disequilibrium test (TDT) showed transmission disequilibrium of 66 alleles to 42 nondiabetic, abdominally obese offspring in families with Type II diabetes (p < 0.05). A slight difference in allele frequency distribution was seen between 71 individuals from the lowest and 71 from the highest tertile of isoprenaline-induced lipolysis in fat tissue (p = 0.07). No missense mutations were found with single-strand conformational polymorphism (SSCP) in 20 abdominally obese subjects with MSDR. In conclusion, our population and intrafamily association studies suggest that the LIPE marker in the HSL gene is in linkage disequilibrium with an allele and/or gene which increases susceptibility to abdominal obesity and thereby possibly to Type II diabetes.
Asunto(s)
Constitución Corporal , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus/genética , Obesidad , Esterol Esterasa/genética , Abdomen , Tejido Adiposo/metabolismo , Agonistas Adrenérgicos beta/farmacología , Anciano , Alelos , Femenino , Frecuencia de los Genes , Humanos , Isoproterenol/farmacología , Desequilibrio de Ligamiento , Lipólisis/efectos de los fármacos , Masculino , Persona de Mediana EdadRESUMEN
Hormone-sensitive lipase (HSL) catalyzes the rate-limiting step in adipocyte lipolysis. The activity of HSL is thought to be primarily regulated by reversible phosphorylation. However, the regulation of HSL activity by pre-translational mechanisms has been poorly studied. The present studies were undertaken to explore the relationship between the levels of HSL protein and mRNA expressions and the lipolytic capacity. The study was performed in human abdominal subcutaneous adipocytes with identical sizes but having either a high (HL) or low (LL) lipolytic capacity (n = 16). Basal and maximal lipolysis induced by catecholamines, an adenylyl cyclase activator forskolin, and a cyclic AMP analogue dibutyryl cAMP were 50% lower in LL- in comparison with HL-fat cells (P < 0.05 or better). No differences in drug sensitivity were found. HSL activity and quantity were about 50% lower in LL- compared with HL-fat cells (P < 0.05). Moreover, the mRNA ratio between HSL and gamma-actin was 35% lower in LL- compared with HL-fat cells (P < 0.05). There was a strong linear correlation between the protein and enzymatic HSL measurements (r2 = 0.91). In addition, the maximum lipolytic capacity was significantly correlated with HSL activity (r2 = 0.75) and HSL protein amount (r2 = 0.64). It is concluded that hormone-sensitive lipase (HSL) expression, measured either as total HSL protein by Western blot analysis or as total amount of activatable HSL enzyme, is a major determinant of the maximum lipolytic capacity of human fat cells. In addition, HSL protein expression is at least, in part, determined by HSL mRNA expression.
Asunto(s)
Adipocitos/metabolismo , Lipólisis , Esterol Esterasa/metabolismo , Adipocitos/efectos de los fármacos , Adipocitos/patología , Adulto , Tamaño de la Célula , Femenino , Variación Genética , Humanos , Inmunoquímica , Técnicas In Vitro , Isoproterenol/farmacología , Cinética , Lipólisis/efectos de los fármacos , Masculino , Peso Molecular , Obesidad/enzimología , Obesidad/metabolismo , Obesidad/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Esterol Esterasa/química , Esterol Esterasa/genéticaRESUMEN
Upper body obesity is a risk factor for type 2 diabetes. Little is known about the regulation of body fat distribution, but leptin may be involved. This study examined the secretion of leptin in subcutaneous and omental fat tissue in 15 obese and 8 nonobese women. Leptin secretion rates were two to three times higher in subcutaneous than in omental fat tissue in both obese and nonobese women (P < 0.0001 and P < 0.001, respectively). There was a positive correlation between BMI and leptin secretion rates in both subcutaneous (r = 0.87, P < 0.0001) and omental (r = 0.74, P < 0.0001) fat tissue. Furthermore, leptin secretion rates in subcutaneous and omental fat tissue correlated well with serum leptin levels (r = 0.84, P < 0.0001 and r = 0.73, P = 0.001, respectively), although in multivariate analysis, the subcutaneous leptin secretion rate was the major regressor for serum leptin (F = 42). Subcutaneous fat cells were approximately 50% larger than omental fat cells, and there was a positive correlation between fat cell size and leptin secretion rate in both fat depots (r = 0.8, P < 0.01). Leptin (but not gamma-actin) mRNA levels were twofold higher in subcutaneous than in omental fat tissue (P < 0.05). Thus the subcutaneous fat depot is the major source of leptin in women owing to the combination of a mass effect (subcutaneous fat being the major depot) and a higher secretion rate in the subcutaneous than in the visceral region, which in turn could be due to increased cell size and leptin gene expression.
Asunto(s)
Tejido Adiposo/metabolismo , Obesidad/metabolismo , Biosíntesis de Proteínas , Tejido Adiposo/cirugía , Adulto , Índice de Masa Corporal , Peso Corporal , Femenino , Humanos , Cinética , Leptina , Persona de Mediana Edad , Obesidad/cirugía , Epiplón , Reacción en Cadena de la Polimerasa , Proteínas/metabolismo , ARN Mensajero/análisis , Valores de Referencia , Análisis de Regresión , Piel , VíscerasRESUMEN
High plasma plasminogen activator inhibitor-1 (PAI-1) activity is a frequent finding in obesity, and both PAI-1 and obesity are risk factors for cardiovascular disease. To study the mechanisms underlying increased PAI-1 levels in obese individuals, gene expression and secretion of PAI-1 were measured in human abdominal subcutaneous adipose tissue. A total of 32 obese, otherwise healthy subjects and 10 never-obese healthy subjects with a body mass index (BMI) of 42.6 +/- 1.2 and 24.3 +/- 1.9 kg/m2 (mean +/- SEM), respectively, were investigated. Plasma PAI-1 activity, adipose tissue PAI-1 secretion and adipocyte PAI-1 mRNA levels were increased seven-fold (p < 0.0001), sixfold (p < 0.0001) and twofold (p < 0.05), respectively, in the obese group. There were clear associations between adipose tissue secretion of PAI-1 and PAI-1 mRNA levels on the one hand and fat cell volume on the other (r = 0.68, p < 0.0001 and r = 0.51, p < 0.01, respectively, in the obese group). PAI-1 mRNA levels were also related to the amount of PAI-1 secreted among obese individuals (r = 0.31, p = 0.09). It is concluded that adipose tissue secretes significant amounts of PAI-1, that PAI-1 secretion from adipose tissue is increased in obesity, and that PAI-1 secretion is related to the lipid content and cell volume of fat cells. Plasma PAI-1 activity is elevated in obesity, at least in part due to increased gene expression in adipocytes, which, in turn, enhances PAI-1 secretion from adipose tissue.
Asunto(s)
Tejido Adiposo/metabolismo , Obesidad/metabolismo , Inhibidor 1 de Activador Plasminogénico/metabolismo , Tejido Adiposo/cirugía , Glucemia/metabolismo , Constitución Corporal , Índice de Masa Corporal , Peso Corporal , Femenino , Humanos , Insulina/sangre , Masculino , Obesidad/cirugía , Inhibidor 1 de Activador Plasminogénico/biosíntesis , ARN Mensajero/biosíntesis , Valores de Referencia , Transcripción Genética , Triglicéridos/sangreRESUMEN
The possible role of hormone-sensitive lipase (HSL) in determining regional differences in lipolysis activation in humans was studied in vitro. Small adipose tissue biopsies were obtained from the abdominal sc and omental regions during surgery in 21 subjects spanning a wide range of body mass index (22-50 kg/m2). In lipolysis experiments, isolated fat cells were incubated with lipolytic agents acting at different levels in the lipolytic cascade. The activity and messenger ribonucleic acid expression of HSL were determined. The maximum lipolytic capacity was higher in sc than in omental fat cells as were HSL activity and messenger ribonucleic acid expression. The maximum lipolysis rate was significantly correlated to HSL activity. This is in accordance with the role of HSL as the rate-limiting step of lipolysis. However, adipocytes were 24% larger in the sc than in the omental region, and the lipolysis rate was significantly correlated to fat cell size regardless of either the region of origin or gender. This indicates that the regulation of HSL activity in healthy subjects, which appears to occur at a transcriptional level, is to a large extent dependent on fat cell size.