Potential regulators of adipogenesis include microRNAs (miRNAs), small non-coding RNAs that have been recently shown related to adiposity and differentially expressed in fat depots. However, to date ...no study is available, to our knowledge, regarding miRNAs expression profile during human adipogenesis. Thereby, the aim of this study was to investigate whether miRNA pattern in human fat cells and subcutaneous adipose tissue is associated to obesity and co-morbidities and whether miRNA expression profile in adipocytes is linked to adipogenesis.
We performed a global miRNA expression microarray of 723 human and 76 viral mature miRNAs in human adipocytes during differentiation and in subcutaneous fat samples from non-obese (n = 6) and obese with (n = 9) and without (n = 13) Type-2 Diabetes Mellitus (DM-2) women. Changes in adipogenesis-related miRNAs were then validated by RT-PCR. Fifty of 799 miRNAs (6.2%) significantly differed between fat cells from lean and obese subjects. Seventy miRNAs (8.8%) were highly and significantly up or down-regulated in mature adipocytes as compared to pre-adipocytes. Otherwise, 17 of these 799 miRNAs (2.1%) were correlated with anthropometrical (BMI) and/or metabolic (fasting glucose and/or triglycerides) parameters. We identified 11 miRNAs (1.4%) significantly deregulated in subcutaneous fat from obese subjects with and without DM-2. Interestingly, most of these changes were associated with miRNAs also significantly deregulated during adipocyte differentiation.
The remarkable inverse miRNA profile revealed for human pre-adipocytes and mature adipocytes hints at a closely crosstalk between miRNAs and adipogenesis. Such candidates may represent biomarkers and therapeutic targets for obesity and obesity-related complications.
Context:
Circulating microRNAs (miRNAs) are valuable biomarkers of metabolic diseases and potential therapeutic targets in this field.
Objective:
Our objective was to define the circulating pattern ...of miRNAs in childhood obesity.
Design, Settings, and Main Outcome Measure:
The genome-wide circulating miRNA profile was assessed by RT-PCR in 10 boys (5 lean and 5 obese children). The most relevant miRNAs were cross-sectionally validated in 85 lean versus 40 obese children (63 boys and 62 girls) and longitudinally evaluated in samples from the same children when they were ∼7 and ∼10 years old (23 boys and 22 girls).
Results:
The cross-sectional validation study disclosed that 15 specific circulating miRNAs were significantly deregulated in prepubertal obesity, including the decreased miR-221 and miR-28-3p and increased concentrations in plasma of miR-486-5p, miR-486-3p, miR-142-3p, miR-130b, and miR-423-5p (all P < .0001). The circulating concentration of these miRNAs was significantly associated with body mass index and other measures of obesity such as percent fat mass, waist, regional fat distribution and with laboratory parameters such as homeostasis model assessment of insulin resistance, high-molecular-weight adiponectin, C-reactive protein, and circulating lipids in concordance with anthropometric associations. Plasma concentrations of 10 of these circulating miRNAs changed significantly and differently during the 3-year follow-up in children who increased or decreased their normalized weight.
Conclusion:
This study provides the first evidence that circulating miRNAs are deregulated in prepubertal obese children. Thus, the very early detection of an abnormal circulating miRNA profile may be a promising strategy to identify obese children who may suffer from metabolic abnormalities.
Thyroid hormones induce browning of white fat Martínez-Sánchez, Noelia; Moreno-Navarrete, José M; Contreras, Cristina ...
Journal of endocrinology,
02/2017, Letnik:
232, Številka:
2
Journal Article
Recenzirano
Odprti dostop
The canonical view about the effect of thyroid hormones (THs) on thermogenesis assumes that the hypothalamus acts merely as a modulator of the sympathetic outflow on brown adipose tissue (BAT). ...Recent data have challenged that vision by demonstrating that THs act on the ventromedial nucleus of the hypothalamus (VMH) to inhibit AMP-activated protein kinase (AMPK), which regulates the thermogenic program in BAT, leading to increased thermogenesis and weight loss. Current data have shown that in addition to activation of brown fat, the browning of white adipose tissue (WAT) might also be an important thermogenic mechanism. However, the possible central effects of THs on the browning of white fat remain unclear. Here, we show that 3,3′,5,5′ tetraiodothyroxyne (T4)-induced hyperthyroidism promotes a marked browning of WAT. Of note, central or VMH-specific administration of 3,3′,5-triiodothyronine (T3) recapitulates that effect. The specific genetic activation of hypothalamic AMPK in the VMH reversed the central effect of T3 on browning. Finally, we also showed that the expression of browning genes in human WAT correlates with serum T4. Overall, these data indicate that THs induce browning of WAT and that this mechanism is mediated via the central effects of THs on energy balance.
Extreme weight conditions (EWC) groups along a continuum may share some biological risk factors and intermediate neurocognitive phenotypes. A core cognitive trait in EWC appears to be executive ...dysfunction, with a focus on decision making, response inhibition and cognitive flexibility. Differences between individuals in these areas are likely to contribute to the differences in vulnerability to EWC. The aim of the study was to investigate whether there is a common pattern of executive dysfunction in EWC while comparing anorexia nervosa patients (AN), obese subjects (OB) and healthy eating/weight controls (HC).
Thirty five AN patients, fifty two OB and one hundred thirty seven HC were compared using the Wisconsin Card Sorting Test (WCST); Stroop Color and Word Test (SCWT); and Iowa Gambling Task (IGT). All participants were female, aged between 18 and 60 years.
There was a significant difference in IGT score (F(1.79); p<.001), with AN and OB groups showing the poorest performance compared to HC. On the WCST, AN and OB made significantly more errors than controls (F(25.73); p<.001), and had significantly fewer correct responses (F(2.71); p<.001). Post hoc analysis revealed that the two clinical groups were not significantly different from each other. Finally, OB showed a significant reduced performance in the inhibition response measured with the Stroop test (F(5.11); p<.001) compared with both AN and HC.
These findings suggest that EWC subjects (namely AN and OB) have similar dysfunctional executive profile that may play a role in the development and maintenance of such disorders.
Aims/hypothesis
Adipocyte lipopolysaccharide-binding protein (LBP) biosynthesis is associated with obesity-induced adipose tissue dysfunction. Our purpose was to study the role of LBP in regulating ...the browning of adipose tissue.
Methods
Adult mice were maintained at 4°C for 3 weeks or treated with the β
3
-adrenergic agonist, CL316,243, for 1 week to induce the browning of white fat. Precursor cells from brown and white adipose tissues were cultured under differentiation-inducing conditions to yield brown and beige/brite adipocytes, respectively. In vitro,
Lbp
was knocked down in 3T3-L1 adipocytes, and cells were treated with recombinant LBP or co-cultured in transwells with control 3T3-L1 adipocytes. Wild-type and
Lbp
-null mice, fed a standard or high fat diet (HFD) for 15 weeks, were also used in investigations. In humans, subcutaneous and visceral adipose tissue samples were obtained from a cohort of morbidly obese participants.
Results
The induction of white fat browning by exposure of mice to cold or CL316,243 treatment was strongly associated with decreased
Lbp
mRNA expression in white adipose tissue. The acquisition of the beige/brite phenotype in cultured cells was associated with downregulation of
Lbp
. Moreover, silencing of
Lbp
induced the expression of brown fat-related genes in adipocytes, whereas LBP treatment reversed this effect.
Lbp
-null mice exhibited the spontaneous induction of subcutaneous adipose tissue browning, as evidenced by a remarkable increase in
Ucp1
and
Dio2
gene expression and the appearance of multivacuolar adipocyte clusters. The amount of brown adipose tissue, and brown adipose tissue activity were also increased in
Lbp
-null mice. These changes were associated with decreased weight gain in
Lbp
-null mice and protection against HFD-induced inflammatory responses, as shown by reduced IL-6 levels. However, rather than improving glucose homeostasis, these effects led to glucose intolerance and insulin resistance.
Conclusions/interpretation
LBP is identified as a negative regulator of the browning process, which is likely to contribute to the obesity-promoting action of LBP. The deleterious metabolic effects of LBP deletion are compatible with the concept that the appropriate regulation of inflammatory pathways is necessary for a healthy systemic metabolic profile, regardless of body weight regulation.
Scope
Changes in genetic variations affecting the taste receptor, type 2, member 38 (TAS2R38) may identify the interacting mechanism leading to obesity and potential associations with proteins ...partaking in innate immunity, such as surfactant protein D (SPD) and mannan‐binding lectin (MBL).
Methods and results
We evaluated haplotypes of the bitter‐taste receptor TAS2R38 in an identification sample of 210 women in different weight conditions, including anorexia nervosa and obesity. The association with SPD and MBL was tested in an independent sample picturing general population (n = 534). The relationship with obesity was validated in an extended final sample of 1319 participants. In the sample comprised of women in extreme weight conditions, increased obesity was identified in AVI/AVI subjects (OR = 2.5 1.06–6.11, p = 0.035). In the sample picturing general population, increased SPD and MBL concentrations were found in nonsmoking AVI carriers. In this cohort, smoking and obesity blunted associations between TAS2R38 haplotypes and SPD and MBL. In the extended sample, the association of AVI/AVI haplotypes with increased obesity was also identified (OR = 1.4 0.99/1.85, p = 0.049), being more robust in subjects aged <40 years (OR = 1.9 1.06/3.42, p = 0.031).
Conclusion
Current data reinforce the impact of TAS2R38 gene on phenotypic and clinical outputs affecting obesity, showing significant associations with extreme weight conditions (i.e., obesity and anorexia nervosa), and changes in both olfactory capacity and immune traits.
Here, we demonstrate that genetic variations that underlie functionality of the TAS2R38, a receptor that regulates the ability to identify bitter‐tasting compounds, may impact on phenotypic and clinical outputs affecting extreme weight conditions (i.e., obesity and anorexia nervosa), being also associated with proteins partaking in innate immunity (i.e., surfactant protein D (SPD) and mannanbinding lectin (MBL)).
Addictions are associated with decision making impairments. The present study explores decision making in Substance use disorder (SUD), Gambling disorder (GD) and Obesity (OB) when assessed by Iowa ...Gambling Task (IGT) and compares them with healthy controls (HC).
For the aims of this study, 591 participants (194 HC, 178 GD, 113 OB, 106 SUD) were assessed according to DSM criteria, completed a sociodemographic interview and conducted the IGT.
SUD, GD and OB present impaired decision making when compared to the HC in the overall task and task learning, however no differences are found for the overall performance in the IGT among the clinical groups. Results also reveal some specific learning across the task patterns within the clinical groups: OB maintains negative scores until the third set where learning starts but with a less extend to HC, SUD presents an early learning followed by a progressive although slow improvement and GD presents more random choices with no learning.
Decision making impairments are present in the studied clinical samples and they display individual differences in the task learning. Results can help understanding the underlying mechanisms of OB and addiction behaviors as well as improve current clinical treatments.
Sensory factors may play an important role in the determination of appetite and food choices. Also, some adipokines may alter or predict the perception and pleasantness of specific odors. We aimed to ...analyze differences in smell-taste capacity between females with different weights and relate them with fat and fat-free mass, visceral fat, and several adipokines.
179 females with different weights (from low weight to morbid obesity) were studied. We analyzed the relation between fat, fat-free mass, visceral fat (indirectly estimated by bioelectrical impedance analysis with visceral fat rating (VFR)), leptin, adiponectin and visfatin. The smell and taste assessments were performed through the "Sniffin' Sticks" and "Taste Strips" respectively.
We found a lower score in the measurement of smell (TDI-score (Threshold, Discrimination and Identification)) in obese subjects. All the olfactory functions measured, such as threshold, discrimination, identification and the TDI-score, correlated negatively with age, body mass index (BMI), leptin, fat mass, fat-free mass and VFR. In a multiple linear regression model, VFR mainly predicted the TDI-score. With regard to the taste function measurements, the normal weight subjects showed a higher score of taste functions. However a tendency to decrease was observed in the groups with greater or lesser BMI. In a multiple linear regression model VFR and age mainly predicted the total taste scores.
We show for the first time that a reverse relationship exists between visceral fat and sensory signals, such as smell and taste, across a population with different body weight conditions.
Abstract
Plakophilin-2 (PKP2) is a key component of desmosomes, which, when defective, is known to promote the fibro-fatty infiltration of heart muscle. Less attention has been given to its role in ...adipose tissue. We report here that levels of PKP2 steadily increase during fat cell differentiation, and are compromised if adipocytes are exposed to a pro-inflammatory milieu. Accordingly, expression of PKP2 in subcutaneous adipose tissue diminishes in patients with obesity, and normalizes upon mild-to-intense weight loss. We further show defective PKP2 in adipocytes to break cell cycle dynamics and yield premature senescence, a key rheostat for stress-induced adipose tissue dysfunction. Conversely, restoring PKP2 in inflamed adipocytes rewires E2F signaling towards the re-activation of cell cycle and decreased senescence. Our findings connect the expression of PKP2 in fat cells to the physiopathology of obesity, as well as uncover a previously unknown defect in cell cycle and adipocyte senescence due to impaired PKP2.
Consumption of long-chain polyunsaturated fatty acids (PUFAs), which are abundant in seafood and nuts, ameliorates components of the metabolic syndrome. Circulating microRNAs (miRNAs) have ...demonstrated to be valuable biomarkers of metabolic diseases. Here, we investigated whether a sustained nuts-enriched diet can lead to changes in circulating miRNAs, in parallel to the dietary modification of fatty acids (FAs).
The profile of 192 common miRNAs was assessed (TaqMan low-density arrays) in plasma from 10 healthy women before and after an 8-week trial with a normocaloric diet enriched with PUFAs (30 g/day of almonds and walnuts). The most relevant miRNAs were validated in an extended sample of 30 participants (8 men and 22 women). Adiponectin was measured by immunoassay and FAs by gas liquid chromatography coupled to mass spectrometry. The percentage of both ω-3 (P=.01) and ω-6 (P=.029) PUFAs of dietary origin (as inferred from plasma FA concentrations) increased, whereas saturated FAs decreased (P=.0008). Concomitantly with changes in circulating FAs, several miRNAs were modified by treatment, including decreased miR-328, miR-330-3p, miR-221 and miR-125a-5p, and increased miR-192, miR-486-5p, miR-19b, miR-106a, miR-769-5p, miR-130b and miR-18a. Interestingly, miR-106a variations in plasma correlated with changes in PUFAs, while miR-130b (r=0.58, P=.003) and miR-221 (r=0.46, P=.03) reflected changes in C-reactive protein. The dietary modulation of miR-125a-5p mirrored changes in fasting triglycerides (r=−0.44, P=.019) and increased adiponectin (r=0.43, P=.026).
Dietary FAs (as inferred from plasma FA concentration) are linked to changes in circulating miRNAs, which may be modified by a PUFAs-enriched diet.
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