scholarly journals Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue

2016 ◽  
Vol 113 (12) ◽  
pp. 3377-3382 ◽  
Author(s):  
Xinran Ma ◽  
Lingyan Xu ◽  
Elisabetta Mueller
Keyword(s):  
Adipose Tissue ◽  
Side Effects ◽  
Glucocorticoid Receptor ◽  
Computational Prediction ◽  
Dependent Manner ◽  
Gene Promoters ◽  
Long Term Effects ◽  
Adipose Tissues ◽  
Fat Depots ◽  
Forkhead Box

Glucocorticoids (GCs) are widely prescribed anti-inflammatory agents, but their chronic use leads to undesirable side effects such as excessive expansion of adipose tissue. We have recently shown that the forkhead box protein A3 (Foxa3) is a calorie-hoarding factor that regulates the selective enlargement of epididymal fat depots and suppresses energy expenditure in a nutritional- and age-dependent manner. It has been demonstrated that Foxa3 levels are elevated in adipose depots in response to high-fat diet regimens and during the aging process; however no studies to date have elucidated the mechanisms that control Foxa3’s expression in fat. Given the established effects of GCs in increasing visceral adiposity and in reducing thermogenesis, we assessed the existence of a possible link between GCs and Foxa3. Computational prediction analysis combined with molecular studies revealed that Foxa3 is regulated by the glucocorticoid receptor (GR) in preadipocytes, adipocytes, and adipose tissues and is required to facilitate the binding of the GR to its target gene promoters in fat depots. Analysis of the long-term effects of dexamethasone treatment in mice revealed that Foxa3 ablation protects mice specifically against fat accretion but not against other pathological side effects elicited by this synthetic GC in tissues such as liver, muscle, and spleen. In conclusion our studies provide the first demonstration, to our knowledge, that Foxa3 is a direct target of GC action in adipose tissues and point to a role of Foxa3 as a mediator of the side effects induced in fat tissues by chronic treatment with synthetic steroids.

scholarly journals Distinct infrastructure of lipid networks in visceral and subcutaneous adipose tissues in overweight humans

2020 ◽  
Vol 112 (4) ◽  
pp. 979-990
Author(s):  
Anish Zacharia ◽  
Daniel Saidemberg ◽  
Chanchal Thomas Mannully ◽  
Natalya M Kogan ◽  
Alaa Shehadeh ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Visceral Adipose Tissue ◽  
Metabolic Diseases ◽  
Cell Model ◽  
Subcutaneous Tissue ◽  
Embryonic Stem ◽  
Adipose Tissues ◽  
Fat Depots ◽  
Visceral Adipose ◽  
Subcutaneous Adipose

ABSTRACT Background Adipose tissue plays important roles in health and disease. Given the unique association of visceral adipose tissue with obesity-related metabolic diseases, the distribution of lipids between the major fat depots located in subcutaneous and visceral regions may shed new light on adipose tissue–specific roles in systemic metabolic perturbations. Objective We sought to characterize the lipid networks and unveil differences in the metabolic infrastructure of the 2 adipose tissues that may have functional and nutritional implications. Methods Paired visceral and subcutaneous adipose tissue samples were obtained from 17 overweight patients undergoing elective abdominal surgery. Ultra-performance LC-MS was used to measure 18,640 adipose-derived features; 520 were putatively identified. A stem cell model for adipogenesis was used to study the functional implications of the differences found. Results Our analyses resulted in detailed lipid metabolic maps of the 2 major adipose tissues. They point to a higher accumulation of phosphatidylcholines, triacylglycerols, and diacylglycerols, although lower ceramide concentrations, in subcutaneous tissue. The degree of unsaturation was lower in visceral adipose tissue (VAT) phospholipids, indicating lower unsaturated fatty acid incorporation into adipose tissue. The differential abundance of phosphatidylcholines we found can be attributed at least partially to higher expression of phosphatidylethanolamine methyl transferase (PEMT). PEMT-deficient embryonic stem cells showed a dramatic decrease in adipogenesis, and the resulting adipocytes exhibited lower accumulation of lipid droplets, in line with the lower concentrations of glycerolipids in VAT. Ceramides may inhibit the expression of PEMT by increased insulin resistance, thus potentially suggesting a functional pathway that integrates ceramide, PEMT, and glycerolipid biosynthetic pathways. Conclusions Our work unveils differential infrastructure of the lipid networks in visceral and subcutaneous adipose tissues and suggests an integrative pathway, with a discriminative flux between adipose tissues.

Identification of genes expressed differentially in subcutaneous and visceral fat of cattle, pig, and mouse

2005 ◽  
Vol 21 (3) ◽  
pp. 343-350 ◽  
Author(s):  
Daisuke Hishikawa ◽  
Yeon-Hee Hong ◽  
Sang-gun Roh ◽  
Hisae Miyahara ◽  
Yukihiko Nishimura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
High Fat Diet ◽  
Animal Species ◽  
Fat Deposition ◽  
High Fat ◽  
Adipose Tissues ◽  
Fat Accumulation ◽  
Fat Depots ◽  
Visceral Adipose

The factors that control fat deposition in adipose tissues are poorly understood. It is known that visceral adipose tissues display a range of biochemical properties that distinguish them from adipose tissues of subcutaneous origin. However, we have little information on gene expression, either in relation to fat deposition or on interspecies variation in fat deposition. The first step in this study was to identify genes expressed in fat depot of cattle using the differential display RT-PCR method. Among the transcripts identified as having differential expression in the two adipose tissues were cell division cycle 42 homolog (CDC42), prefoldin-5, decorin, phosphate carrier, 12S ribosomal RNA gene, and kelch repeat and BTB domain containing 2 (Kbtbd2). In subsequent experiments, we determined the expression levels of these latter genes in the pig and in mice fed either a control or high-fat diet to compare the regulation of fat accumulation in other animal species. The levels of CDC42 and decorin mRNA were found to be higher in visceral adipose tissue than in subcutaneous adipose tissue in cattle, pig, and mice. However, the other genes studied did not show consistent expression patterns between the two tissues in cattle, pigs, and mice. Interestingly, all genes were upregulated in subcutaneous and/or visceral adipose tissues of mice fed the high-fat diet compared with the control diet. The data presented here extend our understanding of gene expression in fat depots and provide further proof that the mechanisms of fat accumulation differ significantly between animal species.

scholarly journals Adipocyte-specific modulation of KLF14 expression in mice leads to sex-dependent impacts in adiposity and lipid metabolism

2021 ◽  
Author(s):  
Qianyi Yang ◽  
Jameson Hinkle ◽  
Jordan N Reed ◽  
Redouane Aherrahrou ◽  
Zhiwen Xu ◽  
...  
Keyword(s):  
Fat Mass ◽  
Risk Allele ◽  
Lipid Storage ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Male Mice ◽  
Adipose Tissues ◽  
Female Mice ◽  
Fat Depots ◽  
Deficient Mice

Genome-wide association studies identified single nucleotide polymorphisms on chromosome 7 upstream of KLF14 to be associated with metabolic syndrome traits and increased risk for Type 2 Diabetes (T2D). The associations were more significant in women than in men. The risk allele carriers expressed lower levels of the transcription factor KLF14 in adipose tissues than non-risk allele carriers. To investigate how adipocyte KLF14 regulates metabolic traits in a sex-dependent manner, we characterized high-fat diet fed male and female mice with adipocyte-specific Klf14 deletion or overexpression. Klf14 deletion resulted in increased fat mass in female mice and decreased fat mass in male mice. Female Klf14-deficient mice had overall smaller adipocytes in subcutaneous fat depots but larger adipocytes in parametrial depots, indicating a shift in lipid storage from subcutaneous to visceral fat depots. They had reduced metabolic rates and increased respiratory exchange ratios consistent with increased utilization of carbohydrates as an energy source. Fasting and isoproterenol-induced adipocyte lipolysis was defective in female Klf14-deficient mice and concomitantly adipocyte triglycerides lipase mRNA levels were downregulated. Female Klf14-deficient mice cleared blood triglyceride and NEFA less efficiently than wild type. Finally, adipocyte-specific overexpression of Klf14 resulted in lower total body fat in female but not male mice. Taken together, consistent with human studies, adipocyte KLF14 deficiency in female but not in male mice causes increased adiposity and redistribution of lipid storage from subcutaneous to visceral adipose tissues. Increasing KLF14 abundance in adipocytes of females with obesity and T2D may provide a novel treatment option to alleviate metabolic abnormalities.

Retinoids and retinoid-metabolic gene expression in mouse adipose tissues

2011 ◽  
Vol 89 (6) ◽  
pp. 578-584 ◽  
Author(s):  
Aurelia Sima ◽  
Daniel-Constantin Manolescu ◽  
Pangala Bhat
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Adipocyte Differentiation ◽  
Binding Protein ◽  
Retinol Binding Protein ◽  
Retinol Dehydrogenase ◽  
Adipose Tissues ◽  
Fat Depots ◽  
Retinoid Metabolism ◽  
Metabolic Gene Expression

Vitamin A and its analogs (retinoids) regulate adipocyte differentiation. Recent investigations have demonstrated a relationship among retinoids, retinoid-binding-protein 4 (RBP4) synthesized in adipose tissues, and insulin-resistance status. In this study, we measured retinoid levels and analyzed the expression of retinoid homeostatic genes associated with retinol uptake, esterification, oxidation, and catabolism in subcutaneous (Sc) and visceral (Vis) mouse fat tissues. Both Sc and Vis depots were found to contain similar levels of all-trans retinol. A metabolite of retinol with characteristic ultraviolet absorption maxima for 9-cis retinol was observed in these 2 adipose depots, and its level was 2-fold higher in Sc than in Vis tissues. Vis adipose tissue expressed significantly higher levels of RBP4, CRBP1 (intracellular retinol-binding protein 1), RDH10 (retinol dehydrogenase), as well as CYP26A1 and B1 (retinoic acid (RA) hydroxylases). No differences in STRA6 (RBP4 receptor), LRAT (retinol esterification), CRABP1 and 2 (intracellular RA-binding proteins), and RALDH1 (retinal dehydrogenase) mRNA expressions were discerned in both fat depots. RALDH1 was identified as the only RALDH expressed in both Sc and Vis adipose tissues. These results indicate that Vis is more actively involved in retinoid metabolism than Sc adipose tissue.

scholarly journals 1,25-Dihydroxyvitamin D3 upregulates leptin expression in mouse adipose tissue

2012 ◽  
Vol 216 (2) ◽  
pp. 265-271 ◽  
Author(s):  
Juan Kong ◽  
Yunzi Chen ◽  
Guojun Zhu ◽  
Qun Zhao ◽  
Yan Chun Li
Keyword(s):  
Vitamin D ◽  
Adipose Tissue ◽  
Energy Homeostasis ◽  
Ex Vivo ◽  
Critical Role ◽  
Dependent Manner ◽  
Adipose Tissues ◽  
Dihydroxyvitamin D ◽  
1,25 Dihydroxyvitamin D ◽  
Leptin Expression

Leptin is an adipose tissue-derived hormone that plays a critical role in energy homeostasis. Vitamin D has been shown to regulate energy metabolism, but the relationship between vitamin D and leptin is unclear. Leptin expression and secretion was reduced in vitamin D receptor (VDR)-null mice and increased in transgenic (Tg) mice overexpressing the VDR in adipocytes; however, as leptin is mainly determined by fat mass, it is unclear whether the vitamin D hormone directly regulates leptin expression. To address this question, we determined the effect of vitamin D on leptin expressionin vivoandex vivo. One-week treatment of WT mice with the vitamin D analog RO-27-5646 led to a significant increase in adipose leptin mRNA transcript and serum leptin levels. Moreover, in adipose tissue cultures, 1,25-dihydroxyvitamin D markedly stimulated mRNA expression and secretion of leptin, but not resistin, in adipose tissues obtained from WT mice, but not from VDR-null mice, and leptin upregulation induced by 1,25-dihydroxyvitamin D was more robust in adipose tissues obtained from VDR Tg mice compared with WT mice. These data demonstrate that 1,25-dihydroxyvitamin D stimulates adipose leptin production in a VDR-dependent manner, suggesting that vitamin D may affect energy homeostasis through direct regulation of leptin expression.

scholarly journals The selective glucocorticoid receptor antagonist CORT125281 has tissue-specific activity

2020 ◽  
Vol 246 (1) ◽  
pp. 79-92
Author(s):  
Lisa L Koorneef ◽  
Jan Kroon ◽  
Eva M G Viho ◽  
Lucas F Wahl ◽  
Kim M L Heckmans ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Glucocorticoid Receptor ◽  
Transcriptional Activity ◽  
Specific Activity ◽  
Pcr Analysis ◽  
High Dose ◽  
Dependent Manner ◽  
Tissue Specific ◽  
Brown Adipose ◽  
Neuroendocrine Axis

Glucocorticoids mediate numerous essential processes in the human body via binding to the glucocorticoid receptor (GR). Excessive GR signaling can cause disease, and GR antagonists can be used to treat many symptoms of glucocorticoid-induced pathology. The purpose of this study was to characterize the tissue-specific properties of the selective GR antagonist CORT125281. We evaluated the antagonistic effects of CORT125281 upon acute and subchronic corticosterone exposure in mice. In the acute corticosterone setting, hypothalamus-pituitary-adrenal-axis activity was investigated by measurement of basal- and stress-induced corticosterone levels, adrenocorticotropic hormone levels and pituitary proopiomelanocortin expression. GR signaling was evaluated by RT-PCR analysis of GR-responsive transcripts in liver, muscle, brown adipose tissue (BAT), white adipose tissue (WAT) and hippocampus. Pretreatment with a high dose of CORT125281 antagonized GR activity in a tissue-dependent manner. We observed complete inhibition of GR-induced target gene expression in the liver, partial blockade in muscle and BAT and no antagonism in WAT and hippocampus. Tissue distribution only partially explained the lack of effective antagonism. CORT125281 treatment did not disinhibit the hypothalamus-pituitary-adrenal neuroendocrine axis. In the subchronic corticosterone setting, CORT125281 partially prevented corticosterone-induced hyperinsulinemia, but not hyperlipidemia and immune suppression. In conclusion, CORT125281 antagonizes GR transcriptional activity in a tissue-dependent manner and improves corticosterone-induced hyperinsulinemia. Tailored dosing of CORT125281 may allow tissue-specific inhibition of GR transcriptional activity.

scholarly journals Gene expression of PPARγ and PGC-1α in human omental and subcutaneous adipose tissues is related to insulin resistance markers and mediates beneficial effects of physical training

2010 ◽  
Vol 162 (3) ◽  
pp. 515-523 ◽  
Author(s):  
Karen Ruschke ◽  
Lauren Fishbein ◽  
Arne Dietrich ◽  
Nora Klöting ◽  
Anke Tönjes ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Cardiovascular Risk ◽  
Mrna Expression ◽  
Physical Training ◽  
Adipose Tissues ◽  
Beneficial Effects ◽  
Fat Depots

ObjectiveObesity and type 2 diabetes (T2D) are reaching epidemic proportions in Western societies, and they contribute to substantial morbidity and mortality. The peroxisome proliferator-activated receptor γ (PPARγ) and PPARγ coactivator-1α (PGC-1α) system plays an important role in the regulation of efficient energy utilization and oxidative phosphorylation, both of which are decreased in obesity and insulin resistance.Design and methodsWe measured the metabolic parameters and the expression of PPARγ and PGC-1α mRNA using quantitative real-time PCR in omental and subcutaneous (SC) adipose tissues in an observational study of 153 individuals as well as in SC fat and skeletal muscle in an interventional study of 60 subjects (20 each with normal glucose tolerance, impaired glucose tolerance, and T2D) before and after intensive physical training for 4 weeks.ResultsPPARγ and PGC-1α mRNA expression in both fat depots as well as in skeletal muscle is associated with markers of insulin resistance and cardiovascular risk. PGC-1α mRNA expression is significantly higher in SC fat than in omental fat, whereas PPARγ mRNA expression is not significantly different between these fat depots. Skeletal muscle and SC fat PPARγ and PGC-1α mRNA expression increased significantly in response to physical training.ConclusionsGene expression of PPARγ and PGC-1α in human adipose tissue is related to markers of insulin resistance and cardiovascular risk. Increased muscle and adipose tissue PPARγ and PGC-1α expression in response to physical training may mediate the beneficial effects of exercise on insulin sensitivity.

Postnatal development of uncoupling protein, uncoupling protein mRNA, and GLUT4 in adipose tissues of goats

1993 ◽  
Vol 265 (3) ◽  
pp. R676-R682 ◽  
Author(s):  
P. Trayhurn ◽  
M. E. Thomas ◽  
J. S. Keith
Keyword(s):  
Adipose Tissue ◽  
Glucose Transporter ◽  
Uncoupling Protein ◽  
Subcutaneous Fat ◽  
Brown Fat ◽  
Postnatal Life ◽  
Mitochondrial Uncoupling ◽  
Adipose Tissues ◽  
Perirenal Adipose Tissue ◽  
Fat Depots

Adipose tissues have been characterized in newborn goats on the basis of the presence of the 32,000-M(r) mitochondrial uncoupling protein (UCP) diagnostic of brown fat, and early postnatal developmental changes have been determined. Both internal (perirenal, pericardial, and omental) and subcutaneous (hindlimb and neck regions) adipose tissues in newborn goats contained UCP and are therefore brown fat. The insulin-sensitive glucose transporter, GLUT4, was also present in adipose tissues of newborn goats, implying a potential for insulin-stimulated glucose uptake at birth. UCP was still evident in the perirenal fat of goats at 3 wk of age, but the mitochondrial concentration was only 4%, and the amount per cell a mere 0.2%, of that in the newborn. UCP was not detectable, however, in either the omental or subcutaneous adipose tissue at 3 wk of age and had disappeared from the subcutaneous fat before 2 wk. In contrast to UCP, GLUT4 remained throughout the initial 3 wk of postnatal life. The mRNA for UCP was detected in perirenal adipose tissue of newborn goats, indicating that the gene coding for the protein is being expressed at around birth. UCP mRNA was not, however, detectable in the other fat depots; nor was it evident in the perirenal adipose tissue at > or = 2.5 days of age. It is concluded that the adipose tissues of newborn goats (both internal and subcutaneous) represent brown fat and that there is a rapid transition toward white fat over the first weeks of life. This transition occurs at different rates in different depots but is not markedly faster in goats than in other ruminants.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Adipose tissue growth and development: the modulating role of ambient temperature

2021 ◽  
Vol 248 (1) ◽  
pp. R19-R28
Author(s):  
Michael E Symonds ◽  
Mark Pope ◽  
Ian Bloor ◽  
James Law ◽  
Reham Alagal ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Ambient Temperature ◽  
Uncoupling Protein ◽  
Tissue Growth ◽  
Long Term Effects ◽  
Mitochondrial Uncoupling ◽  
Fat Depots ◽  
Brown Adipose ◽  
Beige Fat ◽  
And Function

Adipose tissue is usually laid down in small amounts in the foetus and is characterised as possessing small amounts of the brown adipose tissue-specific mitochondrial uncoupling protein (UCP)1. In adults, a primary factor determining the abundance and function of UCP1 is ambient temperature. Cold exposure causes activation and the rapid generation of heat through the free flow of protons across the mitochondria with no requirement to convert ADP to ATP. In rodents, housing at an ambient temperature below thermoneutrality promotes the appearance of beige like adipocytes. These arise as discrete regions of UCP1 containing cells in white fat depots. There is increasing evidence to show that to gain credible translational results on brown and beige fat function in rodent models that they should be housed at thermoneutrality. This not only reflects the type of environment in which humans spend a majority of their time, but is in accord with the rise of global temperature caused by industrialisation and the uncontrolled burning of fossil fuels. There is now good evidence in adult humans, that stimulating brown fat can improve glucose homeostasis which can be achieved either by nutritional or pharmacological interventions. The challenge, therefore, is to establish credible developmental models in animals maintained at thermoneutrality which will elucidate the true impact of nutrition. The primary focus should fall specifically on the components of breast milk and how these modulate long term effects on brown or beige fat development and function.

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