scholarly journals Obesogens: How They Are Identified and Molecular Mechanisms Underlying Their Action

2021 ◽  
Vol 12 ◽  
Author(s):  
Nicole Mohajer ◽  
Chrislyn Y. Du ◽  
Christian Checkcinco ◽  
Bruce Blumberg
Keyword(s):  
Adipose Tissue ◽  
Gut Microbiome ◽  
Molecular Mechanisms ◽  
Endocrine Function ◽  
Future Generations ◽  
Metabolic Disturbances ◽  
Metabolic System ◽  
Chemical Screening ◽  
Brown Adipose

Adult and childhood obesity have reached pandemic level proportions. The idea that caloric excess and insufficient levels of physical activity leads to obesity is a commonly accepted answer for unwanted weight gain. This paradigm offers an inconclusive explanation as the world continually moves towards an unhealthier and heavier existence irrespective of energy balance. Endocrine disrupting chemicals (EDCs) are chemicals that resemble natural hormones and disrupt endocrine function by interfering with the body’s endogenous hormones. A subset of EDCs called obesogens have been found to cause metabolic disruptions such as increased fat storage, in vivo. Obesogens act on the metabolic system through multiple avenues and have been found to affect the homeostasis of a variety of systems such as the gut microbiome and adipose tissue functioning. Obesogenic compounds have been shown to cause metabolic disturbances later in life that can even pass into multiple future generations, post exposure. The rising rates of obesity and related metabolic disease are demanding increasing attention on chemical screening efforts and worldwide preventative strategies to keep the public and future generations safe. This review addresses the most current findings on known obesogens and their effects on the metabolic system, the mechanisms of action through which they act upon, and the screening efforts through which they were identified with. The interplay between obesogens, brown adipose tissue, and the gut microbiome are major topics that will be covered.

scholarly journals Autocrine effects of transgenic resistin reduce palmitate and glucose oxidation in brown adipose tissue

2016 ◽  
Vol 48 (6) ◽  
pp. 420-427 ◽  
Author(s):  
Michal Pravenec ◽  
Petr Mlejnek ◽  
Václav Zídek ◽  
Vladimír Landa ◽  
Miroslava Šimáková ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Glucose Oxidation ◽  
Expression Profiles ◽  
Relative Weight ◽  
Gene Expression Profiles ◽  
Metabolic Disturbances ◽  
Brown Adipose

Resistin has been originally identified as an adipokine that links obesity to insulin resistance in mice. In our previous studies in spontaneously hypertensive rats (SHR) expressing a nonsecreted form of mouse resistin ( Retn) transgene specifically in adipose tissue (SHR- Retn), we have observed an increased lipolysis and serum free fatty acids, ectopic fat accumulation in muscles, and insulin resistance. Recently, brown adipose tissue (BAT) has been suggested to play an important role in the pathogenesis of metabolic disturbances. In the current study, we have analyzed autocrine effects of transgenic resistin on BAT glucose and lipid metabolism and mitochondrial function in the SHR- Retn vs. nontransgenic SHR controls. We observed that interscapular BAT isolated from SHR- Retn transgenic rats compared with SHR controls showed a lower relative weight (0.71 ± 0.05 vs. 0.91 ± 0.08 g/100 g body wt, P < 0.05), significantly reduced both basal and insulin stimulated incorporation of palmitate into BAT lipids (658 ± 50 vs. 856 ± 45 and 864 ± 47 vs. 1,086 ± 35 nmol/g/2 h, P ≤ 0.01, respectively), and significantly decreased palmitate oxidation (37.6 ± 4.5 vs. 57 ± 4.1 nmol/g/2 h, P = 0.007) and glucose oxidation (277 ± 34 vs. 458 ± 38 nmol/g/2 h, P = 0.001). In addition, in vivo microPET imaging revealed significantly reduced 18F-FDG uptake in BAT induced by exposure to cold in SHR- Retn vs. control SHR (232 ± 19 vs. 334 ± 22 kBq/ml, P < 0.05). Gene expression profiles in BAT identified differentially expressed genes involved in skeletal muscle and connective tissue development, inflammation and MAPK and insulin signaling. These results provide evidence that autocrine effects of resistin attenuate differentiation and activity of BAT and thus may play a role in the pathogenesis of insulin resistance in the rat.

scholarly journals Inflammation of adipose tissue. Is there a place for statins to correct adiposopathy?

2019 ◽  
Vol 16 (1) ◽  
pp. 12-19
Author(s):  
Daria A. Borodkina ◽  
Olga V. Gruzdeva ◽  
Elena V. Palicheva ◽  
Olga L. Barbarash
Keyword(s):  
Adipose Tissue ◽  
Molecular Mechanisms ◽  
Cholesterol Biosynthesis ◽  
Living Organism ◽  
Endocrine Function ◽  
Clinical Effects ◽  
Key Factor ◽  
Coa Reductase

This review is devoted to the analysis of data on the effect of inhibitors of 3-hydroxy-3-methylglutaryl coenzymate-reductase on the endocrine function of adipose tissue in obesity. Violation of metabolism of adipose tissue, as well as the amount of fat, are a a key factor in the pathophysiology of obesity and the development of concomitant diseases. Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl-kofermenta reductase (HMG-COA reductase) that catalyze the initial stage of cholesterol biosynthesis in the liver. Therefore, traditionally, the liver is considered as the main target organ for statins. The results of studies of molecular mechanisms of action of statins on carbohydrate and lipid metabolism, adipokine and inflammatory balance in adipose tissue on the example of isolated adipocytes (in vivo) and in living organism (in vitro) are presented. Effect of statins on the action of insulin, as well as the possibility of developing pathological conditions associated with insulin resistance and the development of type 2 diabetes mellitus (DM 2). The proven clinical effects of cholesterol-lowering action of statins, allow new insights and to further explore their possible impact on other links in the development of obesity, and potentially to use them as therapeutic agents for pharmacological correction of obesity and the fight against cardiovascular diseases.

scholarly journals Bisphenol A effects on gene expression in adipocytes from children: association with metabolic disorders

2015 ◽  
Vol 54 (3) ◽  
pp. 289-303 ◽  
Author(s):  
Ciro Menale ◽  
Maria Teresa Piccolo ◽  
Grazia Cirillo ◽  
Raffaele A Calogero ◽  
Alfonso Papparella ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Bisphenol A ◽  
Metabolic Disorders ◽  
Molecular Mechanisms ◽  
Endocrine Function ◽  
Human Adipocytes ◽  
Fat Cell ◽  
Endocrine Disrupting Chemical

Bisphenol A (BPA) is a xenobiotic endocrine-disrupting chemical.In vitroandin vivostudies have indicated that BPA alters endocrine-metabolic pathways in adipose tissue, which increases the risk of metabolic disorders and obesity. BPA can affect adipose tissue and increase fat cell numbers or sizes by regulating the expression of the genes that are directly involved in metabolic homeostasis and obesity. Several studies performed in animal models have accounted for an obesogen role of BPA, but its effects on human adipocytes – especially in children – have been poorly investigated. The aim of this study is to understand the molecular mechanisms by which environmentally relevant doses of BPA can interfere with the canonical endocrine function that regulates metabolism in mature human adipocytes from prepubertal, non-obese children. BPA can act as an estrogen agonist or antagonist depending on the physiological context. To identify the molecular signatures associated with metabolism, transcriptional modifications of mature adipocytes from prepubertal children exposed to estrogen were evaluated by means of microarray analysis. The analysis of deregulated genes associated with metabolic disorders allowed us to identify a small group of genes that are expressed in an opposite manner from that of adipocytes treated with BPA. In particular, we found that BPA increases the expression of pro-inflammatory cytokines and the expression ofFABP4andCD36, two genes involved in lipid metabolism. In addition, BPA decreases the expression ofPCSK1, a gene involved in insulin production. These results indicate that exposure to BPA may be an important risk factor for developing metabolic disorders that are involved in childhood metabolism dysregulation.

scholarly journals CCAAT/Enhancer Binding Proteinβin relation to ER Stress, Inflammation, and Metabolic Disturbances

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Sophie E. van der Krieken ◽  
Herman E. Popeijus ◽  
Ronald P. Mensink ◽  
Jogchum Plat
Keyword(s):  
Er Stress ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Developed Countries ◽  
Metabolic Disturbances ◽  
Metabolic System ◽  
Physiological Level ◽  
The Metabolic Syndrome ◽  
Brown Adipose

The prevalence of the metabolic syndrome and underlying metabolic disturbances increase rapidly in developed countries. Various molecular targets are currently under investigation to unravel the molecular mechanisms that cause these disturbances. This is done in attempt to counter or prevent the negative health consequences of the metabolic disturbances. Here, we reviewed the current knowledge on the role of C/EBP-βin these metabolic disturbances. C/EBP-βdeletion in mice resulted in downregulation of hepatic lipogenic genes and increased expression ofβ-oxidation genes in brown adipose tissue. Furthermore, C/EBP-βis important in the differentiation and maturation of adipocytes and is increased during ER stress and proinflammatory conditions. So far, studies were only conducted in animals and in cell systems. The results found that C/EBP-βis an important transcription factor within the metabolic disturbances of the metabolic system. Therefore, it is interesting to examine the potential role of C/EBP-βat molecular and physiological level in humans.

scholarly journals HAND2 is a novel obesity-linked adipogenic transcription factor regulated by glucocorticoid signaling

2020 ◽  
Author(s):  
Maude Giroud ◽  
Foivos-Filippos Tsokanos ◽  
Giorgio Caratti ◽  
Sajjad Khani ◽  
Elena Sophie Vogl ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Adipose Tissue ◽  
Mouse Model ◽  
Molecular Mechanisms ◽  
Adipocyte Differentiation ◽  
Gene Clusters ◽  
Metabolic Disturbances ◽  
Primary Mouse

AbstractAdipocytes are critical cornerstones of energy metabolism. While obesity-induced adipocyte dysfunction is associated with insulin resistance and systemic metabolic disturbances, adipogenesis, the formation of new adipocytes and healthy adipose tissue expansion are associated with metabolic benefits. Understanding the molecular mechanisms governing adipogenesis is of great clinical potential to efficiently restore metabolic health in obesity. Here we show that Heart- and neural crest derivatives-expressed protein 2 (HAND2) is an obesity-linked adipocyte transcription factor regulated by glucocorticoids and required for adipocyte differentiation in vitro. In a large cohort of humans with obesity, white adipose tissue (WAT) HAND2 expression was correlated to body-mass-index (BMI). The HAND2 gene was enriched in white adipocytes, induced early in differentiation and responded to dexamethasone, a typical glucocorticoid receptor (GR, encoded by NR3C1) agonist. Silencing of NR3C1 in human multipotent adipose-derived stem cells (hMADS) or deletion of GR in a transgenic conditional mouse model results in diminished HAND2 expression, establishing that adipocyte HAND2 is regulated by glucocorticoids via GR in vitro and in vivo. Using a combinatorial RNAseq approach we identified gene clusters regulated by the GR-HAND2 pathway. Interestingly, silencing of HAND2 impaired adipocyte differentiation in hMADS and primary mouse adipocytes. However, a conditional adipocyte Hand2 deletion mouse model using Cre under control of the Adipoq promoter did not mirror these effects on adipose tissue differentiation, indicating that Hand2 was required at stages prior to Adipoq expression. In summary, our study identifies HAND2 as a novel obesity-linked adipocyte transcription factor, highlighting new mechanisms of GR-dependent adipogenesis in human and mice.

Functional characterization of human brown adipose tissue metabolism

2020 ◽  
Vol 477 (7) ◽  
pp. 1261-1286 ◽  
Author(s):  
Marie Anne Richard ◽  
Hannah Pallubinsky ◽  
Denis P. Blondin
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Functional Characterization ◽  
Human Infants ◽  
Positron Emission ◽  
Brown Adipose ◽  
Treatment Of Obesity ◽  
And Function

Brown adipose tissue (BAT) has long been described according to its histological features as a multilocular, lipid-containing tissue, light brown in color, that is also responsive to the cold and found especially in hibernating mammals and human infants. Its presence in both hibernators and human infants, combined with its function as a heat-generating organ, raised many questions about its role in humans. Early characterizations of the tissue in humans focused on its progressive atrophy with age and its apparent importance for cold-exposed workers. However, the use of positron emission tomography (PET) with the glucose tracer [18F]fluorodeoxyglucose ([18F]FDG) made it possible to begin characterizing the possible function of BAT in adult humans, and whether it could play a role in the prevention or treatment of obesity and type 2 diabetes (T2D). This review focuses on the in vivo functional characterization of human BAT, the methodological approaches applied to examine these features and addresses critical gaps that remain in moving the field forward. Specifically, we describe the anatomical and biomolecular features of human BAT, the modalities and applications of non-invasive tools such as PET and magnetic resonance imaging coupled with spectroscopy (MRI/MRS) to study BAT morphology and function in vivo, and finally describe the functional characteristics of human BAT that have only been possible through the development and application of such tools.

scholarly journals Gpr1 is an active chemerin receptor influencing glucose homeostasis in obese mice

2014 ◽  
Vol 222 (2) ◽  
pp. 201-215 ◽  
Author(s):  
Jillian L Rourke ◽  
Shanmugam Muruganandan ◽  
Helen J Dranse ◽  
Nichole M McMullen ◽  
Christopher J Sinal
Keyword(s):  
Adipose Tissue ◽  
Glucose Homeostasis ◽  
Stromal Vascular Fraction ◽  
Tolerance Test ◽  
Glucose Levels ◽  
Brown Adipose ◽  
Elevated Glucose ◽  
And Function ◽  
G Protein Coupled

Chemerin is an adipose-derived signaling protein (adipokine) that regulates adipocyte differentiation and function, immune function, metabolism, and glucose homeostasis through activation of chemokine-like receptor 1 (CMKLR1). A second chemerin receptor, G protein-coupled receptor 1 (GPR1) in mammals, binds chemerin with an affinity similar to CMKLR1; however, the function of GPR1 in mammals is essentially unknown. Herein, we report that expression of murineGpr1mRNA is high in brown adipose tissue and white adipose tissue (WAT) and skeletal muscle. In contrast to chemerin (Rarres2) andCmklr1,Gpr1expression predominates in the non-adipocyte stromal vascular fraction of WAT. Heterozygous and homozygousGpr1-knockout mice fed on a high-fat diet developed more severe glucose intolerance than WT mice despite having no difference in body weight, adiposity, or energy expenditure. Moreover, mice lackingGpr1exhibited reduced glucose-stimulated insulin levels and elevated glucose levels in a pyruvate tolerance test. This study is the first, to our knowledge, to report the effects ofGpr1deficiency on adiposity, energy balance, and glucose homeostasisin vivo. Moreover, these novel results demonstrate that GPR1 is an active chemerin receptor that contributes to the regulation of glucose homeostasis during obesity.

scholarly journals TAF7L modulates brown adipose tissue formation

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Haiying Zhou ◽  
Bo Wan ◽  
Ivan Grubisic ◽  
Tommy Kaplan ◽  
Robert Tjian
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Core Promoter ◽  
Uncoupling Protein ◽  
Dna Looping ◽  
Chromatin Interactions ◽  
Brown Adipose ◽  
Important Regulator

Brown adipose tissue (BAT) plays an essential role in metabolic homeostasis by dissipating energy via thermogenesis through uncoupling protein 1 (UCP1). Previously, we reported that the TATA-binding protein associated factor 7L (TAF7L) is an important regulator of white adipose tissue (WAT) differentiation. In this study, we show that TAF7L also serves as a molecular switch between brown fat and muscle lineages in vivo and in vitro. In adipose tissue, TAF7L-containing TFIID complexes associate with PPARγ to mediate DNA looping between distal enhancers and core promoter elements. Our findings suggest that the presence of the tissue-specific TAF7L subunit in TFIID functions to promote long-range chromatin interactions during BAT lineage specification.

Noradrenaline-induced calorigenesis in warm- or cold-acclimated rats. In vivo estimation of adrenoceptor concentration of noradrenaline effecting half-maximal response

1980 ◽  
Vol 58 (9) ◽  
pp. 1072-1077 ◽  
Author(s):  
Florent Depocas ◽  
Gloria Zaror-Behrens ◽  
Suzanne Lacelle
Keyword(s):  
Adipose Tissue ◽  
Steady State ◽  
Brown Adipose Tissue ◽  
Maximal Response ◽  
Brown Adipose ◽  
Acclimation Group ◽  
Arterial Plasma ◽  
State Concentration ◽  
Na Uptake

Desmethylimipramine (DMI, 1 mg DMI∙HCl kg−1) and normetanephrine (NMN, 1 μg min−1 g−0.74) were used to inhibit, respectively, neuronal and extraneuronal uptakes of noradrenaline (NA) during calorigenesis induced in barbital-sedated warm-acclimated (WA) or cold-acclimated (CA) rats by infusion of NA, a procedure which mimics the effects of NA released within calorigenic tissues in response to cold exposure. The doses of the inhibitors were selected for maximal effectiveness in potentiating calorigenic response and for minimal side effects. For rats of either acclimation group treated with DMI and NMN, with DMI only, or with neither inhibitor the doses of NA required to evoke approximately half-maximal calorigenic responses were, respectively, 0.5, 1.0, and 3.5 ng min−1 g−0.74. The corresponding steady-state concentrations of NA in arterial plasma averaged 14.3, 21.7, and 43.2 nM in the three groups of WA rats and 10.0, 14.8, and 31.9 nM in the three groups of CA rats. Reduction by NA uptake inhibitors of the circulating levels of NA necessary to stimulate calorigenesis, half-maximally, presumably in brown adipose tissue, indicates a reduction in the steepness of the NA concentration gradient between capillary plasma and synaptic clefts in that tissue. The steady-state concentration of NA in blood plasma of rats treated with DMI and NMN and infused with NA at a dose of 0.5 ng min−1 g−0.74 (~1 × 10−8 M) is a good estimate of the NA concentration required at calorigenic adrenoceptors to effect half-maximal activation. Presumably, this concentration is also an estimate of that resulting from NA released at nerve endings during cold-induced activation of nonshivering thermogenesis at half-maximal rates in brown adipose tissue.

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