The effects of moderate weight gain in adipose tissue gene expression in metabolically-normal (MNO) and metabolically-abnormal (MAO) subjects
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: E-GEOD-62832 | BioStudies |
REPOSITORIES: biostudies
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Project description:Obesity is associated with insulin resistance and increased intrahepatic triglyceride (IHTG) content, which are key risk factors for diabetes and cardiovascular disease. However, a subset of obese people does not develop these metabolic complications. We tested the hypothesis that MNO, but not MAO, people are protected from the adverse metabolic effects of weight gain. To this end, global transcriptional profile in adipose tissue before and after weight gain was evaluated by microarray analyses. We collected subcutaneous adipose tissue samples from MNO (n=11) and MAO (n=7) subjects before and after moderate (~6%) weight gain (total 36 samples). We evaluated the effects of weight gain on adipose tissue gene expression in both MNO and MNO subjects.We used the GeneChip Human Gene 1.0 ST array (Affymetrix, Santa Clara, CA, USA).
2015-01-09 | E-GEOD-62832 | ArrayExpress
Project description:BACKGROUND. Obesity is associated with insulin resistance and increased intrahepatic triglyceride (IHTG) content, both of which are key risk factors for diabetes and cardiovascular disease. However, a subset of obese people does not develop these metabolic complications. Here, we tested the hypothesis that people defined by IHTG content and insulin sensitivity as "metabolically normal obese" (MNO), but not those defined as "metabolically abnormal obese" (MAO), are protected from the adverse metabolic effects of weight gain. METHODS. Body composition, multiorgan insulin sensitivity, VLDL apolipoprotein B100 (apoB100) kinetics, and global transcriptional profile in adipose tissue were evaluated before and after moderate (~6%) weight gain in MNO (n = 12) and MAO (n = 8) subjects with a mean BMI of 36 ± 4 kg/m2 who were matched for BMI and fat mass. RESULTS. Although the increase in body weight and fat mass was the same in both groups, hepatic, skeletal muscle, and adipose tissue insulin sensitivity deteriorated, and VLDL apoB100 concentrations and secretion rates increased in MAO, but not MNO, subjects. Moreover, biological pathways and genes associated with adipose tissue lipogenesis increased in MNO, but not MAO, subjects. CONCLUSIONS. These data demonstrate that MNO people are resistant, whereas MAO people are predisposed, to the adverse metabolic effects of moderate weight gain and that increased adipose tissue capacity for lipogenesis might help protect MNO people from weight gain-induced metabolic dysfunction. TRIAL REGISTRATION. ClinicalTrials.gov NCT01184170. FUNDING. This work was supported by NIH grants UL1 RR024992 (Clinical Translational Science Award), DK 56341 (Nutrition and Obesity Research Center), DK 37948 and DK 20579 (Diabetes Center Grant), and UL1 TR000450 (KL2 Award); a Central Society for Clinical and Translational Research Early Career Development Award; and by grants from the Longer Life Foundation and the Kilo Foundation.
| S-EPMC4319438 | BioStudies
Project description:<h4>Objective</h4>Nonalcoholic fatty liver disease (i.e., increased intrahepatic triglyceride [IHTG] content), predisposes to type 2 diabetes and cardiovascular disease. Adipose tissue lipolysis and hepatic de novo lipogenesis (DNL) are the main pathways contributing to IHTG. We hypothesized that dietary macronutrient composition influences the pathways, mediators, and magnitude of weight gain-induced changes in IHTG.<h4>Research design and methods</h4>We overfed 38 overweight subjects (age 48 ± 2 years, BMI 31 ± 1 kg/m<sup>2</sup>, liver fat 4.7 ± 0.9%) 1,000 extra kcal/day of saturated (SAT) or unsaturated (UNSAT) fat or simple sugars (CARB) for 3 weeks. We measured IHTG (<sup>1</sup>H-MRS), pathways contributing to IHTG (lipolysis ([<sup>2</sup>H<sub>5</sub>]glycerol) and DNL (<sup>2</sup>H<sub>2</sub>O) basally and during euglycemic hyperinsulinemia), insulin resistance, endotoxemia, plasma ceramides, and adipose tissue gene expression at 0 and 3 weeks.<h4>Results</h4>Overfeeding SAT increased IHTG more (+55%) than UNSAT (+15%, <i>P</i> < 0.05). CARB increased IHTG (+33%) by stimulating DNL (+98%). SAT significantly increased while UNSAT decreased lipolysis. SAT induced insulin resistance and endotoxemia and significantly increased multiple plasma ceramides. The diets had distinct effects on adipose tissue gene expression.<h4>Conclusions</h4>Macronutrient composition of excess energy influences pathways of IHTG: CARB increases DNL, while SAT increases and UNSAT decreases lipolysis. SAT induced the greatest increase in IHTG, insulin resistance, and harmful ceramides. Decreased intakes of SAT could be beneficial in reducing IHTG and the associated risk of diabetes.
| S-EPMC7082640 | BioStudies
Project description:<h4>Objective</h4>Weight loss among metabolically healthy obese (MHO) individuals may be unnecessary or result in elevated cardio-metabolic risk. We studied the effects of exercise- or diet-induced weight loss on cardio-metabolic risk among MHO and metabolically abnormal obese (MAO) adults.<h4>Research design and methods</h4>Participants were 63 MHO and 43 MAO adults who took part in 3 to 6 months of exercise- or diet-induced weight loss intervention. Changes in anthropometry, adipose tissue distribution, and cardio-metabolic risk factors were assessed.<h4>Results</h4>Body weight, waist circumference, and total abdominal and visceral adipose tissue were reduced in all subjects (P < 0.05). Improvements in insulin sensitivity were observed in MHO and MAO men and women (P < 0.05), but were greater in the MAO individuals (P < 0.05). Fasting insulin was the only other cardio-metabolic improvement among MHO individuals (P < 0.05).<h4>Conclusions</h4>Lifestyle-induced weight loss among MHO subjects is associated with a reduction in total and abdominal obesity and improvement in selected cardio-metabolic risk factors.
| S-EPMC2928342 | BioStudies
Project description:An increased number of macrophages in adipose tissue is associated with insulin resistance and metabolic dysfunction in obese people. However, little is known about other immune cells in adipose tissue from obese people, and whether they contribute to insulin resistance. We investigated the characteristics of T cells in adipose tissue from metabolically abnormal insulin-resistant obese (MAO) subjects, metabolically normal insulin-sensitive obese (MNO) subjects, and lean subjects. Insulin sensitivity was determined by using the hyperinsulinemic euglycemic clamp procedure.We assessed plasma cytokine concentrations and subcutaneous adipose tissue CD4(+) T-cell populations in 9 lean, 12 MNO, and 13 MAO subjects. Skeletal muscle and liver samples were collected from 19 additional obese patients undergoing bariatric surgery to determine the presence of selected cytokine receptors.Adipose tissue from MAO subjects had 3- to 10-fold increases in numbers of CD4(+) T cells that produce interleukin (IL)-22 and IL-17 (a T-helper [Th] 17 and Th22 phenotype) compared with MNO and lean subjects. MAO subjects also had increased plasma concentrations of IL-22 and IL-6. Receptors for IL-17 and IL-22 were expressed in human liver and skeletal muscle samples. IL-17 and IL-22 inhibited uptake of glucose in skeletal muscle isolated from rats and reduced insulin sensitivity in cultured human hepatocytes.Adipose tissue from MAO individuals contains increased numbers of Th17 and Th22 cells, which produce cytokines that cause metabolic dysfunction in liver and muscle in vitro. Additional studies are needed to determine whether these alterations in adipose tissue T cells contribute to the pathogenesis of insulin resistance in obese people.
| S-EPMC3756481 | BioStudies
Project description:BACKGROUND AND PURPOSE:Phenelzine is an antidepressant drug known to increase the risk of hypertensive crisis when dietary tyramine is not restricted. However, this MAO inhibitor inhibits other enzymes not limited to the nervous system. Here we investigated if its antiadipogenic and antilipogenic effects in cultured adipocytes could contribute to decreased body fat in vivo, without unwanted hypertensive or cardiovascular effects. EXPERIMENTAL APPROACH:Mice were fed a standard chow and given 0.028% phenelzine in drinking water for 12 weeks. Body composition was determined by NMR. Cardiovascular dysfunction was assessed by heart rate variability analyses and by evaluation of cardiac oxidative stress markers. MAO activity, hydrogen peroxide release and triacylglycerol turnover were assayed in white adipose tissue (WAT), alongside determination of glucose and lipid circulating levels. KEY RESULTS:Phenelzine-treated mice exhibited lower body fat content, subcutaneous WAT mass and lipid content in skeletal muscles than control, without decreased body weight gain or food consumption. A modest alteration of cardiac sympathovagal balance occurred without depressed aconitase activity. In WAT, phenelzine impaired the lipogenic but not the antilipolytic actions of insulin, MAO activity and hydrogen peroxide release. Phenelzine treatment lowered non-fasting blood glucose and phosphoenolpyruvate carboxykinase expression. In vitro, high doses of phenelzine decreased both lipolytic and lipogenic responses in mouse adipocytes. CONCLUSION AND IMPLICATIONS:As phenelzine reduced body fat content without affecting cardiovascular function in mice, it may be of benefit in the treatment of obesity-associated complications, with the precautions of use recommended for antidepressant therapy.
| S-EPMC5980542 | BioStudies
Project description:The effects of moderate weight gain in adipose tissue gene expression in metabolically-normal (MNO) and metabolically-abnormal (MAO) subjects
| PRJNA265579 | ENA
Project description:Visceral adipose tissue (VAT) is an important risk factor for obesity-related metabolic disorders. Therefore, a reduction in VAT has become a key goal in obesity management. However, VAT is correlated with intrahepatic triglyceride (IHTG) content, so it is possible that IHTG, not VAT, is a better marker of metabolic disease. We determined the independent association of IHTG and VAT to metabolic function, by evaluating groups of obese subjects, who differed in IHTG content (high or normal) but matched on VAT volume or differed in VAT volume (high or low) but matched on IHTG content. Stable isotope tracer techniques and the euglycemic-hyperinsulinemic clamp procedure were used to assess insulin sensitivity and very-low-density lipoprotein-triglyceride (VLDL-TG) secretion rate. Tissue biopsies were obtained to evaluate cellular factors involved in ectopic triglyceride accumulation. Hepatic, adipose tissue and muscle insulin sensitivity were 41, 13, and 36% lower (P < 0.01), whereas VLDL-triglyceride secretion rate was almost double (P < 0.001), in subjects with higher than normal IHTG content, matched on VAT. No differences in insulin sensitivity or VLDL-TG secretion were observed between subjects with different VAT volumes, matched on IHTG content. Adipose tissue CD36 expression was lower (P < 0.05), whereas skeletal muscle CD36 expression was higher (P < 0.05), in subjects with higher than normal IHTG. These data demonstrate that IHTG, not VAT, is a better marker of the metabolic derangements associated with obesity. Furthermore, alterations in tissue fatty acid transport could be involved in the pathogenesis of ectopic triglyceride accumulation by redirecting plasma fatty acid uptake from adipose tissue toward other tissues.
| S-EPMC2741268 | BioStudies
Project description:Individuals with metabolically healthy obesity (MHO) are at relatively low risk for the development of metabolic abnormalities and subclinical atherosclerosis. This study aims to examine whether hepatic fat accumulation determines metabolic phenotype of obesity and associated with subclinical atherosclerosis. A total of 485 obese adults (aged 40-65 years) who received magnetic resonance spectroscopy were divided into metabolically abnormally obesity (MAO) and MHO groups according to metabolic status. MHO individuals had lower levels of intrahepatic triglyceride (IHTG) content and carotid intima-media thickness (CIMT) than MAO individuals. In multivariable linear regression analyses, IHTG content was independently associated with metabolic syndrome components and CIMT. Based on receiver operating characteristic curve analysis, the IHTG content displayed a higher area under the curve (AUC) for detecting the MAO phenotype (AUC = 0.70, 95%CI = 0.65-0.75) and increased CIMT (AUC = 0.60, 95%CI = 0.54-0.66) than BMI, waist circumference, and body fat percent. MHO individuals were 1.9 times (p < 0.001) more likely to have metabolic syndrome per 1 SD change in IHTG content in multivariable-adjusted models. Likewise, the risk for high CIMT increased 29% per 1 SD change in IHTG content [OR (95% CI):1.29(1.01-1.64)]. These findings suggest that hepatic fat is a potential predictor of metabolically unhealthy obesity phenotype and subclinical atherosclerosis.
2016-01-01 | S-EPMC4763213 | BioStudies
Project description:BACKGROUNDAn increase in intrahepatic triglyceride (IHTG) is the hallmark feature of nonalcoholic fatty liver disease (NAFLD) and is decreased by weight loss. Hepatic de novo lipogenesis (DNL) contributes to steatosis in individuals with NAFLD. The physiological factors that stimulate hepatic DNL and the effect of weight loss on hepatic DNL are not clear.METHODSHepatic DNL, 24-hour integrated plasma insulin and glucose concentrations, and both liver and whole-body insulin sensitivity were determined in individuals who were lean (n = 14), obese with normal IHTG content (n = 26), or obese with NAFLD (n = 27). Hepatic DNL was assessed using the deuterated water method corrected for the potential confounding contribution of adipose tissue DNL. Liver and whole-body insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp procedure in conjunction with glucose tracer infusion. Six subjects in the obese-NAFLD group were also evaluated before and after a diet-induced weight loss of 10%.RESULTSThe contribution of hepatic DNL to IHTG-palmitate was 11%, 19%, and 38% in the lean, obese, and obese-NAFLD groups, respectively. Hepatic DNL was inversely correlated with hepatic and whole-body insulin sensitivity, but directly correlated with 24-hour plasma glucose and insulin concentrations. Weight loss decreased IHTG content, in conjunction with a decrease in hepatic DNL and 24-hour plasma glucose and insulin concentrations.CONCLUSIONSThese data suggest hepatic DNL is an important regulator of IHTG content and that increases in circulating glucose and insulin stimulate hepatic DNL in individuals with NAFLD. Weight loss decreased IHTG content, at least in part, by decreasing hepatic DNL.TRIAL REGISTRATIONClinicalTrials.gov NCT02706262.FUNDINGThis study was supported by NIH grants DK56341 (Nutrition Obesity Research Center), DK20579 (Diabetes Research Center), DK52574 (Digestive Disease Research Center), and RR024992 (Clinical and Translational Science Award), and by grants from the Academy of Nutrition and Dietetics Foundation, the College of Natural Resources of UCB, and the Pershing Square Foundation.
| S-EPMC7269561 | BioStudies