518 research outputs found
Thyroid hormone status defines brown adipose tissue activity and browning of white adipose tissues in mice
The present study aimed to determine the effect of thyroid hormone dysfunction
on brown adipose tissue activity and white adipose tissue browning in mice.
Twenty randomized female C57BL/6NTac mice per treatment group housed at room
temperature were rendered hypothyroid or hyperthyroid. In-vivo small animal
18F-FDG PET/MRI was performed to determine the effects of hypo- and
hyperthyroidism on BAT mass and BAT activity. Ex-vivo14C-acetate loading assay
and assessment of thermogenic gene and protein expression permitted analysis
of oxidative and thermogenic capacities of WAT and BAT of eu-, hyper and
hypothyroid mice. 18F-FDG PET/MRI revealed a lack of brown adipose tissue
activity in hypothyroid mice, whereas hyperthyroid mice displayed increased
BAT mass alongside enhanced 18F-FDG uptake. In white adipose tissue of both,
hyper- and hypothyroid mice, we found a significant induction of thermogenic
genes together with multilocular adipocytes expressing UCP1. Taken together,
these results suggest that both the hyperthyroid and hypothyroid state
stimulate WAT thermogenesis most likely as a consequence of enhanced
adrenergic signaling or compensation for impaired BAT function, respectively
Electronic properties of curved few-layers graphene: a geometrical approach
We show the presence of non-relativistic L\'evy-Leblond fermions in flat
three- and four-layers graphene with AB stacking, extending the results
obtained in [Curvatronics2017] for bilayer graphene. When the layer is curved
we obtain a set of equations for Galilean fermions that are a variation of
those of L\'evy-Leblond with a well defined combination of pseudospin, and that
admit L\'evy-Leblond spinors as solutions in an approriate limit. The local
energy of such Galilean fermions is sensitive to the intrinsic curvature of the
surface. We discuss the relationship between two-dimensional pseudospin,
labelling layer degrees of freedom, and the different energy bands. For
L\'evy-Leblond fermions an interpretation is given in terms of massless
fermions in an effective 4D spacetime, and in this case the pseudospin is
related to four dimensional chirality. A non-zero energy band gap between
conduction and valence electronic bands is obtained for surfaces with positive
curvature.Comment: 16 pages, 4 figures. Matches the published version. Refined theory
that describes the unique combination of isospin states ocurring in curved
bilayer graphene sheet
ADCY5 gene expression in adipose tissue is related to obesity in men and mice
Genome wide association studies revealed an association of the single nucleotide polymorphism rs11708067 within the ADCY5 geneâencoding adenylate cyclase 5âwith increased type 2 diabetes (T2D) risk and higher fasting glucose. However, it remains unclear whether the association between ADCY5 variants and glycemic traits may involve adipose tissue (AT) related mechanisms. We therefore tested the hypothesis that ADCY5 mRNA expression in human and mouse AT is related to obesity, fat distribution, T2D in humans and high fat diet (HFD) in mice. We measured ADCY5 mRNA expression in paired samples of visceral and subcutaneous adipose tissue from 244 individuals with a wide range of body weight and parameters of hyperglycemia, which have been genotyped for rs11708067. In addition, AT ADCY5 mRNA was assessed in C57BL/6NTac which underwent a 10 weeks standard
chow (n = 6) or high fat diet (HFD, n = 6). In humans, visceral ADCY5 expression is significantly higher in obese compared to lean individuals. ADCY5 expression correlates with BMI, body fat mass, circulating leptin, fat distribution, waist and hip circumference, but not with fasting plasma glucose and HbA1c. Adcy5 expression in mouse AT is significantly
higher after a HFD compared to chow (p<0.05). Importantly, rs11708067 is not associated with ADCY5 mRNA expression levels in either fat depot in any of the genetic models tested. Our results suggest that changes in AT ADCY5 expression are related to obesity and fat distribution, but not with impaired glucose metabolism and T2D. However, altered ADCY5 expression in AT does not seem to be the mechanism underlying the association between rs11708067 and increased T2D risk
Circulating cell adhesion molecules in metabolically healthy obesity
Background/Objectives
People with metabolically healthy obesity (MHO) may still have an increased risk for cardiovascular mortality compared to metabolically healthy lean (MHL) individuals. However, the mechanisms linking obesity to cardiovascular diseases are not entirely understood. We therefore tested the hypothesis that circulating cell adhesion molecules (CAMs) are higher in MHO compared to MHL individuals.
Subjects/Methods
Serum concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), E-selectin and P-selectin were measured in age- and sex-matched groups of MHL (nâ=â32), MHO categorized into BMI-matched insulin sensitive (IS, nâ=â32) or insulin resistant (IR) obesity (nâ=â32) and people with metabolically unhealthy obesity (MUO, nâ=â32).
Results
Indeed, individuals with MHO have significantly higher sICAM-1, E-selectin, and P-selectin serum concentrations compared to MHL people. However, these CAMs are still significantly lower in IS compared to IR MHO. There was no difference between the groups in sVCAM-1 serum concentrations. Compared to all other groups, circulating adhesion molecules were significantly higher in individuals with MUO.
Conclusions
These findings suggest that obesity-related increased cardiovascular risk is reflected and may be mediated by significantly higher CAMs. The mechanisms causing elevated adhesion molecules even in the absence of overt cardio-metabolic risk factors and whether circulating CAMs could predict cardiovascular events need to be explored
Vaspin inhibits kallikrein 7 by serpin mechanism
The molecular target of the adipokine vaspin (visceral adipose tissue-derived serpin; serpinA12) and its mode of action are unknown. Here, we provide the vaspin crystal structure and identify human kallikrein 7 (hK7) as a first protease target of vaspin inhibited by classical serpin mechanism with high specificity in vitro. We detect vaspinâhK7 complexes in human plasma and find co-expression of both proteins in murine pancreatic ÎČ-cells. We further demonstrate that hK7 cleaves human insulin in the A- and B-chain. Vaspin treatment of isolated pancreatic islets leads to increased insulin concentration in the media upon glucose stimulation without influencing insulin secretion. By application of vaspin and generated inactive mutants, we find the significantly improved glucose tolerance in C57BL/6NTac and db/db mice treated with recombinant vaspin fully dependent on the vaspin serpin activity and not related to vaspin-mediated changes in insulin sensitivity as determined by euglycemic-hyperinsulinemic clamp studies. Improved glucose metabolism could be mediated by increased insulin plasma concentrations 150Â min after a glucose challenge in db/db mice, supporting the hypothesis that vaspin may inhibit insulin degradation by hK7 in the circulation. In conclusion, we demonstrate the inhibitory serpin nature and the first protease target of the adipose tissue-derived serpin vaspin, and our findings suggest hK7 inhibition by vaspin as an underlying physiological mechanism for its compensatory actions on obesity-induced insulin resistance. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00018-013-1258-8) contains supplementary material, which is available to authorized users
Identification of a regulatory pathway inhibiting adipogenesis via RSPO2
Healthy adipose tissue remodeling depends on the balance between de novo adipogenesis from adipogenic progenitor cells and the hypertrophy of adipocytes. De novo adipogenesis has been shown to promote healthy adipose tissue expansion, which confers protection from obesity-associated insulin resistance. Here, we define the role and trajectory of different adipogenic precursor subpopulations and further delineate the mechanism and cellular trajectory of adipogenesis, using single-cell RNA-sequencing datasets of murine adipogenic precursors. We identify Rspo2 as a functional regulator of adipogenesis, which is secreted by a subset of CD142âcells to inhibit maturation of early progenitors through the receptor Lgr4. Increased circulating RSPO2 in mice leads to adipose tissue hypertrophy and insulin resistance and increased RSPO2 levels in male obese individuals correlate with impaired glucose homeostasis. Taken together, these findings identify a complex cellular crosstalk that inhibits adipogenesis and impairs adipose tissue homeostasis
Extensive weight loss reveals distinct gene expression changes in human subcutaneous and visceral adipose tissue
Weight loss has been shown to significantly improve Adipose tissue (AT) function, however changes in AT gene expression profiles particularly in visceral AT (VAT) have not been systematically studied. Here, we tested the hypothesis that extensive weight loss in response to bariatric surgery (BS) causes AT gene expression changes, which may affect energy and lipid metabolism, inflammation and secretory function of AT. We assessed gene expression changes by whole genome expression chips in AT samples obtained from six morbidly obese individuals, who underwent a two step BS
strategy with sleeve gastrectomy as initial and a Roux-en-Y gastric bypass as second step surgery after 12 ± 2 months. Global gene expression differences in VAT and subcutaneous (S)AT were analyzed through the use of genome-scale metabolic model (GEM) for adipocytes. Significantly altered gene expressions were PCR-validated in 16 individuals, which also underwent a two-step surgery intervention. We found increased expression of cell death-inducing DFFA-like effector a
(CIDEA), involved in formation of lipid droplets in both fat depots in response to significant weight loss. We observed that expression of the genes associated with metabolic reactions involved in NAD+, glutathione and branched chain amino acid metabolism are significantly increased in AT
depots after surgery-induced weight loss
Two Patterns of Adipokine and Other Biomarker Dynamics in a Long-Term Weight Loss Intervention
Objective: Long-term dietary intervention frequently induces a rapid weight decline followed by weight stabilization/regain. Here, we sought to identify adipokine biomarkers that may reflect continued beneficial effects of dieting despite partial weight regain. Research design and methods: We analyzed the dynamics of fasting serum levels of 12 traditional metabolic biomarkers and novel adipokines among 322 participants in the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT) of low-fat, Mediterranean, or low-carbohydrate diets for weight loss. Results: We identified two distinct patterns: Pattern A includes biomarkers (insulin, triglycerides, leptin, chemerin, monocyte chemoattractant protein 1, and retinol-binding protein 4) whose dynamics tightly correspond to changes in body weight, with the trend during the weight loss phase (months 0â6) going in the opposite direction to that in the weight maintenance/regain phase (months 7â24) (P < 0.05 between phases, all biomarkers). Pattern B includes biomarkers (high molecular weight adiponectin, HDL cholesterol [HDL-C], high-sensitivity C-reactive protein [hsCRP], fetuin-A, progranulin, and vaspin) that displayed a continued, cumulative improvement (P < 0.05 compared with baseline, all biomarkers) throughout the intervention. These patterns were consistent across sex, diabetic groups, and diet groups, although the magnitude of change varied. Hierarchical analysis suggested similar clusters, revealing that the dynamic of leptin (pattern A) was most closely linked to weight change and that the dynamic of hsCRP best typified pattern B. Conclusions: hsCRP, HDL-C, adiponectin, fetuin-A, progranulin, and vaspin levels display a continued long-term improvement despite partial weight regain. This may likely reflect either a delayed effect of the initial weight loss or a continuous beneficial response to switching to healthier dietary patterns
Extensive weight loss reveals distinct gene expression changes in human subcutaneous and visceral adipose tissue
Weight loss has been shown to significantly improve Adipose tissue (AT) function, however changes in AT gene expression profiles particularly in visceral AT (VAT) have not been systematically studied. Here, we tested the hypothesis that extensive weight loss in response to bariatric surgery (BS) causes AT gene expression changes, which may affect energy and lipid metabolism, inflammation and secretory function of AT. We assessed gene expression changes by whole genome expression chips in AT samples obtained from six morbidly obese individuals, who underwent a two step BS
strategy with sleeve gastrectomy as initial and a Roux-en-Y gastric bypass as second step surgery after 12 ± 2 months. Global gene expression differences in VAT and subcutaneous (S)AT were analyzed through the use of genome-scale metabolic model (GEM) for adipocytes. Significantly altered gene expressions were PCR-validated in 16 individuals, which also underwent a two-step surgery intervention. We found increased expression of cell death-inducing DFFA-like effector a
(CIDEA), involved in formation of lipid droplets in both fat depots in response to significant weight loss. We observed that expression of the genes associated with metabolic reactions involved in NAD+, glutathione and branched chain amino acid metabolism are significantly increased in AT
depots after surgery-induced weight loss
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