Tesamorelin improves fat quality independent of changes in fat quantity.
Ontology highlight
ABSTRACT: Objectives
Fat quality and quantity may affect health similarly or differently. Fat quality can be assessed by measuring fat density on CT scan (greater density = smaller, higher quality adipocytes). We assessed the effects of tesamorelin, a growth hormone-releasing hormone analogue that reduces visceral fat (VAT) quantity in some people living with HIV (PWH), on fat density.Design
Participants from two completed, placebo-controlled, randomized trials of tesamorelin for central adiposity treatment in PWH were included if they had either a clinical response to tesamorelin (VAT decrease ≥8%, ≈70% of participants) or were placebo-treated.Methods
CT VAT and subcutaneous fat (SAT) density (Hounsfield Units, HU) were measured by a central blinded reader.Results
Participants (193 responders, 148 placebo) were 87% male and 83% white. Baseline characteristics were similar across arms, including VAT (-91 HU both arms, P = 0.80) and SAT density (-94 HU tesamorelin, -95 HU placebo, P = 0.29). Over 26 weeks, mean (SD) VAT and SAT density increased in tesamorelin-treated participants only [VAT: +6.2 (8.7) HU tesamorelin, +0.3 (4.2) HU placebo, P < 0.0001; SAT: +4.0 (8.7) HU tesamorelin, +0.3 (4.8) HU placebo, P < 0.0001]. The tesamorelin effects persisted after controlling for baseline VAT or SAT HU and area, and VAT [+2.3 HU, 95% confidence interval (4.5-7.3), P = 0.001) or SAT (+3.5 HU, 95% confidence interval (2.3-4.7), P < 0.001] area change.Conclusion
In PWH with central adiposity who experienced VAT quantity reductions on tesamorelin, VAT and SAT density increased independent of changes in fat quantity, suggesting that tesamorelin also improves VAT and SAT quality in this group.
SUBMITTER: Lake JE
PROVIDER: S-EPMC8243807 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BackgroundSubcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) are associated with adverse cardiometabolic risk profiles.ObjectivesThis study explored the degree to which changes in abdominal fat quantity and quality are associated with changes in cardiovascular disease (CVD) risk factors.MethodsStudy participants (n = 1,106; 44.1% women; mean baseline age 45.1 years) were drawn from the Framingham Heart Study Third Generation cohort who participated in the computed tomography (CT) substudy Exams 1 and 2. Participants were followed for 6.1 years on average. Abdominal adipose tissue volume in cm(3) and attenuation in Hounsfield units (HU) were determined by CT-acquired abdominal scans.ResultsThe mean fat volume change was an increase of 602 cm(3) for SAT and an increase of 703 cm(3) for VAT; the mean fat attenuation change was a decrease of 5.5 HU for SAT and an increase of 0.07 HU for VAT. An increase in fat volume and decrease in fat attenuation were associated with adverse changes in CVD risk factors. An additional 500 cm(3) increase in fat volume was associated with incident hypertension (odds ratio [OR]: 1.21 for SAT; OR: 1.30 for VAT), hypertriglyceridemia (OR: 1.15 for SAT; OR: 1.56 for VAT), and metabolic syndrome (OR: 1.43 for SAT; OR: 1.82 for VAT; all p < 0.05). Similar trends were observed for each additional 5 HU decrease in abdominal adipose tissue attenuation. Most associations remained significant even after further accounting for body mass index change, waist circumference change, or respective abdominal adipose tissue volumes.ConclusionsIncreasing accumulation of fat quantity and decreasing fat attenuation are associated with worsening of CVD risk factors beyond the associations with generalized adiposity, central adiposity, or respective adipose tissue volumes.
| S-EPMC5599249 | biostudies-literature
Project description:The type and the amount of dietary fat have a significant influence on the metabolic pathways involved in the development of obesity, metabolic syndrome, diabetes type 2 and cardiovascular diseases. However, it is unknown to what extent this modulation is achieved through DNA methylation. We assessed the effects of cholesterol intake, the proportion of energy intake derived from fat, the ratio of polyunsaturated fatty acids (PUFA) to saturated fatty acids (SFA), the ratio of monounsaturated fatty acids (MUFA) to SFA, and the ratio of (MUFA+PUFA) to SFA on genome-wide DNA methylation patterns in normal-weight and obese children. We determined the genome-wide methylation profile in blood of 69 Greek preadolescents (~10 y old), as well as their dietary intake for two consecutive weekdays and one weekend day. The methylation levels of four sites and a CpG island were significantly correlated with total fat intake. The methylation levels of 13 islands and 16 sites were significantly correlated with PUFA/SFA; of 35 islands and 158 sites with MUFA/SFA; and of 50 islands and 130 sites with (MUFA+PUFA)/SFA. We found significant gene enrichment in 26 pathways for PUFA/SFA, including the leptin pathway, and a significant enrichment in three pathways for (MUFA+PUFA)/SFA. Our results suggest that the quality, and to a lesser extent the quantity of fat intake, influences DNA methylation, including genes involved in metabolism. Thus, specific changes in DNA methylation may play an important role in the mechanisms involved in the physiological responses to different types of dietary fat. Bisulphite converted DNA from 22 boys were hybridised to the Illumina Infinium 27k Human Methylation Beadchip v1.2.Both obese and normal-weight indiviudals were included.
2014-05-09 | E-GEOD-57484 | biostudies-arrayexpress
Project description:The type and the amount of dietary fat have a significant influence on the metabolic pathways involved in the development of obesity, metabolic syndrome, diabetes type 2 and cardiovascular diseases. However, it is unknown to what extent this modulation is achieved through DNA methylation. We assessed the effects of cholesterol intake, the proportion of energy intake derived from fat, the ratio of polyunsaturated fatty acids (PUFA) to saturated fatty acids (SFA), the ratio of monounsaturated fatty acids (MUFA) to SFA, and the ratio of (MUFA+PUFA) to SFA on genome-wide DNA methylation patterns in normal-weight and obese children. We determined the genome-wide methylation profile in blood of 69 Greek preadolescents (~10 y old), as well as their dietary intake for two consecutive weekdays and one weekend day. The methylation levels of four sites and a CpG island were significantly correlated with total fat intake. The methylation levels of 13 islands and 16 sites were significantly correlated with PUFA/SFA; of 35 islands and 158 sites with MUFA/SFA; and of 50 islands and 130 sites with (MUFA+PUFA)/SFA. We found significant gene enrichment in 26 pathways for PUFA/SFA, including the leptin pathway, and a significant enrichment in three pathways for (MUFA+PUFA)/SFA. Our results suggest that the quality, and to a lesser extent the quantity of fat intake, influences DNA methylation, including genes involved in metabolism. Thus, specific changes in DNA methylation may play an important role in the mechanisms involved in the physiological responses to different types of dietary fat.
2014-05-09 | GSE57484 | GEO
Project description:Purpose: Dietary fat-driven hyperphagia increase intestinal growth and permeability and create microbial imbalance in the gut. Over-nutrition coupled with increase in intestinal nutrient absorbance capacity then lead to nutrient overload in the liver, visceral adipose tissue followed by ectopic fat deposition with consequential lipotoxicity and inflammation. We investigated how protein quantity (10-30%) and quality (casein and whey) interact with dietary fat (20-55%) to affect these outcomes in adult mice. High (30%) protein groups showed differential response to high fat diets (40 and 55% fat) and these groups were selected for RNA-seq experiments. RNA-seq was performed on RNA extracted from the jejunum, liver and hypothalami of mice exposed to the different diets. Methods: C57BL/6J male mice used in this work. All mice were fed a 20% kcal casein, 10% kcal fat and 70% kcal carbohydrate diet (Research Diets; USA; D12450Bi), until they were aged 20 weeks. Following 15 weeks of intake of the latter diet (at age 20 weeks), all animals were weight matched and randomly allocated to different groups and switched to experimental diets for 12 weeks. After 12 weeks of dietary interventions all animals were sacrificed and dissected. Methods: The dietary treatments consisted of 3 different levels of dietary fat (20, 40 and 55%) combined with 3 different levels of protein (10, 20 and 30%), each replicated with the protein coming from either casein (CAS) (diet codes: D17052701- D17052709) or whey protein isolate (WPI) (diet codes: D17052710- D17052718). The levels of cellulose and sucrose were fixed at 5% by weight and energy respectively. The carbohydrate (starch) amount was reduced in parallel with increase of dietary protein and fat. All these diets can be ordered direct from research diets (www.researchdiets.com) using the diet codes provided. The 18 different treatments with 12 mice per group, where mice were housed in cages of 3 animals. Methods: The hypothalamus, liver, and jejunum of all animals from 30% protein groups (6 diets [D17052703, D17052706, D17052709, D17052712, D17052715, D17052718], 71 animals) were collected. Total RNA was extracted from hypothalamic blocks using Tri-reagent (Sigma) and from liver and jejunum using the RNeasy Mini Kit (QIAGEN, 74104) according to manufacture instructions. Hypothalamic RNA was paired-end (PE) sequenced by PE100 on BGISEQ-500 platform at Beijing Genomic Institute (PE 2 x 75 bp, 150 bp per fragment, 20M read-pairs per sample). Sequencing of liver and jejunal RNA was performed using the NovaSeq 6000 platform (chemistry V4.0 Illumina) at Macrogen Inc Seoul, South Korea (PE 2 x 75 bp, 150 bp per fragment, 25M read-pairs per sample). Raw sequence reads were obtained in FASTQ format and these sequence reads were quality assessed using the software FastQC (v 0.111.58; http://www.bioinformatics.babraham.ac.uk/projects/fastqc/). Sequences from all samples were quality trimmed, and cleaned of adaptor sequences using BBDuk java package to trim Illumina adapter sequences. On average 0.1% of the bases were trimmed per sample. Trimmed reads were aligned to the Mus musculus reference genome assembly GRCm38 (ftp://ftp.ensembl.org/pub/release-96/fasta/mus_musculus/dna/) using STAR RNA-seq aligner v2.5.2, and uniquely mapped read counts per Ensembl annotated gene/ transcript were estimated using the STAR -- quantMode option. Genes with zero read counts across all samples as well as non-protein coding genes were removed prior to subsequent analysis. Differential gene expression analysis and data transformations and visualization were carried out using DeSeq2 v1.18.1 in R 3.5.2. Sample clustering was carried out on variance stabilizing transformed data and visualised using PCA. Differentially expressed genes lists were generated using a negative binomial generalized linear model and pairwise comparisons using each combination of fat and protein content in each tissue. P values were adjusted for multiple comparisons using a Benjamini and Hochberg (B-H) method. DE genes with an adjusted P value < 0.05 were used for further DE gene data exploration and pathway analysis. The fold changes and p values were loaded into the Ingenuity Pathway Analysis (IPA) program (Ingenuity Systems; http://www.ingenuity.com/) for core analysis. IPA Knowledge Database was used to analyse the dietary impacts on canonical pathways and upstream regulators available in IPA. Results: Differential gene expression and IPA results revealed that jejunal immunity of the high (30%) CAS fed groups at 40 and 55% fat was oriented toward pro-inflammatory responses, whereas the corresponding WPI fed groups showed a reduction of inflammation. The liver transcriptome reveals genes involved in FA/lipid uptake and synthesis to be upregulated and genes involved in FA/lipid degradation were downregulated following a proportional increase of dietary fat (20 to 55%) in 30% CAS fed animals and these effects were not seen in WPI fed animals. In the hypothalamus, the intake of 40 and 55% fat significantly increased the number of differentially expressed genes compared to 20% fat. The effect of protein quality on hypothalamic gene expression (CAS vs WPI) was only seen at the highest fat content (55%), where several changes in signalling pathways were seen in WPI relative to CAS. These include a decreased reactive oxygen species production, reduction interleukin and chemokine inflammatory pathways and increased oxidative phosphorylation compared with mice fed CAS and 55% fat. Conclusions: Analysis of jejunal, liver and hypothalamic transcriptomic revealed that the intake of high WPI impeded the negative effects of high fat feeding (increased lipogenesis in the liver, inflammation, activation of disease-related pathways etc.), whereas the intake of high CAS exacerbated these effects. The data highlight the importance of selecting proteins rich in essential amino acids, for improving the metabolic outcomes of high fat diet.
2021-04-01 | GSE167498 | GEO
Project description:Aims/hypothesisFibroblast growth factor 21 (FGF21) is considered to be a promising therapeutic candidate for the treatment of type 2 diabetes. However, as FGF21 levels are elevated in obese and diabetic conditions we aimed to test if exogenous FGF21 is sufficient to prevent diabetes and beta cell loss in New Zealand obese (NZO) mice, a model for polygenetic obesity and type 2 diabetes.MethodsMale NZO mice were treated with a specific dietary regimen that leads to the onset of diabetes within 1 week. Mice were treated subcutaneously with PBS or FGF21 to assess changes in glucose homeostasis, energy expenditure, food intake and other metabolic endpoints.ResultsFGF21 treatment prevented islet destruction and the onset of hyperglycaemia, and improved glucose clearance. FGF21 increased energy expenditure by inducing browning in subcutaneous white adipose tissue. However, as a result of a compensatory increased food intake, body fat did not decrease in response to FGF21 treatment, but exhibited elevated Glut4 expression.Conclusions/interpretationFGF21 prevents the onset of diet-induced diabetes, without changing body fat mass. Beneficial effects are mediated via white adipose tissue browning and elevated thermogenesis. Furthermore, these data indicate that obesity does not induce FGF21 resistance in NZO mice.
| S-EPMC6448882 | biostudies-literature
Project description:BackgroundThe accumulation of mitochondrial DNA (mtDNA) mutations, and the reduction of mtDNA copy number, both disrupt mitochondrial energetics, and may contribute to aging and age-associated phenotypes. However, there are few genetic and epidemiological studies on the spectra of blood mtDNA heteroplasmies, and the distribution of mtDNA copy numbers in different age groups and their impact on age-related phenotypes. In this work, we used whole-genome sequencing data of isolated peripheral blood mononuclear cells (PBMCs) from the UK10K project to investigate in parallel mtDNA heteroplasmy and copy number in 1511 women, between 17 and 85 years old, recruited in the TwinsUK cohorts.ResultsWe report a high prevalence of pathogenic mtDNA heteroplasmies in this population. We also find an increase in mtDNA heteroplasmies with age (β = 0.011, P = 5.77e-6), and showed that, on average, individuals aged 70-years or older had 58.5% more mtDNA heteroplasmies than those under 40-years old. Conversely, mtDNA copy number decreased by an average of 0.4 copies per year (β = -0.395, P = 0.0097). Multiple regression analyses also showed that age had independent effects on mtDNA copy number decrease and heteroplasmy accumulation. Finally, mtDNA copy number was positively associated with serum bicarbonate level (P = 4.46e-5), and inversely correlated with white blood cell count (P = 0.0006). Moreover, the aggregated heteroplasmy load was associated with blood apolipoprotein B level (P = 1.33e-5), linking the accumulation of mtDNA mutations to age-related physiological markers.ConclusionsOur population-based study indicates that both mtDNA quality and quantity are influenced by age. An open question for the future is whether interventions that would contribute to maintain optimal mtDNA copy number and prevent the expansion of heteroplasmy could promote healthy aging.
| S-EPMC5697406 | biostudies-literature
Project description:Adeno-associated virus (AAV) vectors are promising tools for gene therapy. The current AAV vector system produces an abundance of empty capsids that are eliminated before clinical use, leading to increased costs for gene therapy. In the present study, we established an AAV production system that regulates the timing of capsid expression using a tetracycline-dependent promoter. Tetracycline-regulating capsid expression increased viral yield and reduced empty capsids in various serotypes without altering AAV vector infectivity in vitro and in vivo. The replicase expression pattern change observed in the developed AAV vector system improved viral quantity and quality, whereas timing control of capsid expression reduced empty capsids. These findings provide a new perspective on the development of AAV vector production systems in gene therapy.
| S-EPMC10122016 | biostudies-literature
Project description:OBJECTIVE:Tesamorelin reduces visceral adipose tissue (VAT) in HIV. We investigated whether reductions in VAT with tesamorelin are associated with changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST). DESIGN AND METHODS:We utilized data from two multicenter Phase III trials of tesamorelin among 806 HIV-infected patients with abdominal obesity. These studies showed that the majority of patients treated with tesamorelin are 'responders', defined a priori by the Food and Drug Administration as achieving at least 8% reduction in VAT. In the current analysis, we sought to examine the impact of VAT reduction on ALT and AST among patients participating in the Phase III trials with baseline elevated ALT or AST. Within this group, we compared changes in ALT and AST in VAT responders vs. nonresponders after 26 weeks of treatment, and then assessed the effects of drug discontinuation on these endpoints over a subsequent 26-week period. RESULTS:At baseline, VAT was positively associated with ALT (P?=?0.01). In study participants assigned to tesamorelin with baseline ALT or AST more than 30?U/l, VAT responders experienced greater reductions in ALT (-8.9?±?22.6 vs. 1.4?±?34.7?U/l, P?=?0.004) and AST (-3.8?±?12.9 vs. 0.4?±?22.4?U/l, P?=?0.04) compared with nonresponders over 26 weeks. This improvement among VAT responders persisted over 52 weeks even in those switched to placebo despite a partial reaccumulation of VAT. CONCLUSION:A clinically significant VAT reduction with tesamorelin was associated with improved liver enzymes among HIV-infected patients with abdominal obesity and elevated baseline transaminases.
| S-EPMC5633509 | biostudies-literature
Project description:ImportanceAmong patients infected with human immunodeficiency virus (HIV), visceral adiposity is associated with metabolic dysregulation and ectopic fat accumulation. Tesamorelin, a growth hormone-releasing hormone analog, specifically targets visceral fat reduction but its effects on liver fat are unknown.ObjectiveTo investigate the effect of tesamorelin on visceral and liver fat.Design, setting, and patientsDouble-blind, randomized, placebo-controlled trial conducted among 50 antiretroviral-treated HIV-infected men and women with abdominal fat accumulation at Massachusetts General Hospital in Boston. The first patient was enrolled on January 10, 2011; for the final patient, the 6-month study visit was completed on September 6, 2013.InterventionsParticipants were randomized to receive tesamorelin, 2 mg (n=28), or placebo (n=22), subcutaneously daily for 6 months.Main outcomes and measuresPrimary end points were changes in visceral adipose tissue and liver fat. Secondary end points included glucose levels and other metabolic end points.ResultsForty-eight patients received treatment with study drug. Tesamorelin significantly reduced visceral adipose tissue (mean change, -34 cm2 [95% CI, -53 to -15 cm2] with tesamorelin vs 8 cm2 [95% CI, -14 to 30 cm2] with placebo; treatment effect, -42 cm2 [95% CI, -71 to -14 cm2]; P = .005) and liver fat (median change in lipid to water percentage, -2.0% [interquartile range {IQR}, -6.4% to 0.1%] with tesamorelin vs 0.9% [IQR, -0.6% to 3.7%] with placebo; P = .003) over 6 months, for a net treatment effect of -2.9% in lipid to water percentage. Fasting glucose increased in the tesamorelin group at 2 weeks (mean change, 9 mg/dL [95% CI, 5-13 mg/dL] vs 2 mg/dL [95% CI, -3 to 8 mg/dL] in the placebo group; treatment effect, 7 mg/dL [95% CI, 1-14 mg/dL]; P = .03), but changes at 6 months in fasting glucose (mean change, 4 mg/dL [95% CI, -2 to 10 mg/dL] with tesamorelin vs 2 mg/dL [95% CI, -4 to 7 mg/dL] with placebo; treatment effect, 2 mg/dL [95% CI, -6 to 10 mg/dL]; P = .72 overall across time points) and 2-hour glucose (mean change, -1 mg/dL [95% CI, -18 to 15 mg/dL] vs -8 mg/dL [95% CI, -24 to 8 mg/dL], respectively; treatment effect, 7 mg/dL [95% CI, -16 to 29 mg/dL]; P = .53 overall across time points) were not significant.Conclusions and relevanceIn this preliminary study of HIV-infected patients with abdominal fat accumulation, tesamorelin administered for 6 months was associated with reductions in visceral fat and additionally with modest reductions in liver fat. Further studies are needed to determine the clinical importance and long-term consequences of these findings.Trial registrationclinicaltrials.gov Identifier: NCT01263717.
| S-EPMC4363137 | biostudies-literature
Project description:Macronutrient composition of the diet influences the development of obesity and insulin resistance. The aim of this study was to assess the role of dietary fat quantity and fatty acid composition in body composition, insulin resistance, and insulin secretion. An open parallel randomized trial design was used. Overweight participants (n = 75) were randomized to follow a low-fat vegan (n = 38) or control diet (n = 37) for 16 weeks. Dual X-ray absorptiometry was used to measure body composition. Insulin resistance was assessed with the Homeostasis Model Assessment (HOMA-IR) index. Insulin secretion was assessed after stimulation with a liquid breakfast (Boost Plus, Nestle, Vevey, Switzerland). Self-reported 3-day diet records were used to assess dietary intake. A linear regression model was used to test the relationship between fat intake and body composition, insulin resistance, and insulin secretion. Changes in fat intake expressed as percent of total energy consumed correlated positively with changes in fat mass (r = 0.52; p < 0.001; and 0.347; p = 0.006, respectively), even after adjustment for changes in body-mass index (BMI) and energy intake (0.33; p = 0.01). Decreased intakes of C18:0 (r = 0.37, p = 0.004) and CLA-trans-10-cis12 (r = 0.40, p = 0.002), but increased intake of C18:2 (r = -0.40, p = 0.002) and C18:3 (p = -0.36, p = 0.006), were associated with a decrease in HOMA-IR, independent on changes in BMI and energy intake. The main fatty acids associated with changes in fasting insulin secretion were C12:0 (r = -0.31, p = 0.03), and TRANS 16:1 (r = -0.33, p = 0.02), both independent on changes in BMI and energy intake. Our findings demonstrate that, in the context of a low-fat vegan diet, decreased intake of saturated and trans fats and increased relative content of polyunsaturated fatty acids, particularly linoleic and α-linolenic acids, are associated with decreased fat mass and insulin resistance, and enhanced insulin secretion.
| S-EPMC6472059 | biostudies-literature