scholarly journals Lack of adipose-specific hexose-6-phosphate dehydrogenase causes inactivation of adipose glucocorticoids and improves metabolic phenotype in mice

2019 ◽  
Vol 133 (21) ◽  
pp. 2189-2202
Author(s):  
Jian Wang ◽  
Ying Wang ◽  
Limei Liu ◽  
Kabirullah Lutfy ◽  
Theodore C. Friedman ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fasting Blood Glucose ◽  
Visceral Obesity ◽  
Conditional Knockout ◽  
Hormone Sensitive Lipase ◽  
Metabolic Phenotype ◽  
Mrna Levels ◽  
Obesity And Diabetes ◽  
Factor C

Abstract Excessive glucocorticoid (GC) production in adipose tissue promotes the development of visceral obesity and metabolic syndrome (MS). 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is critical for controlling intracellular GC production, and this process is tightly regulated by hexose-6-phosphate dehydrogenase (H6PDH). To better understand the integrated molecular physiological effects of adipose H6PDH, we created a tissue-specific knockout of the H6PDH gene mouse model in adipocytes (adipocyte-specific conditional knockout of H6PDH (H6PDHAcKO) mice). H6PDHAcKO mice exhibited almost complete absence of H6PDH expression and decreased intra-adipose corticosterone production with a reduction in 11β-HSD1 activity in adipose tissue. These mice also had decreased abdominal fat mass, which was paralleled by decreased adipose lipogenic acetyl-CoA carboxylase (ACC) and ATP-citrate lyase (ACL) gene expression and reduction in their transcription factor C/EBPα mRNA levels. Moreover, H6PDHAcKO mice also had reduced fasting blood glucose levels, increased glucose tolerance, and increased insulin sensitivity. In addition, plasma free fatty acid (FFA) levels were decreased with a concomitant decrease in the expression of lipase adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) in adipose tissue. These results indicate that inactivation of adipocyte H6PDH expression is sufficient to cause intra-adipose GC inactivation that leads to a favorable pattern of metabolic phenotypes. These data suggest that H6PDHAcKO mice may provide a good model for studying the potential contributions of fat-specific H6PDH inhibition to improve the metabolic phenotype in vivo. Our study suggests that suppression or inactivation of H6PDH expression in adipocytes could be an effective intervention for treating obesity and diabetes.

scholarly journals SAT-591 Lack of Adipose-Specific Hexose-6-Phosphate Dehydrogenase Improves Fat Metabolic Phenotype and Increases Insulin Sensitivity in Mice

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Jian Wang ◽  
Xinxiang Wang ◽  
Samuel Kim ◽  
Xiwen Liu ◽  
Theodore C Friedman ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Visceral Obesity ◽  
Metabolic Phenotype ◽  
Potential Contribution ◽  
Mrna Levels ◽  
Glucose Levels ◽  
Lipogenic Gene Expression ◽  
Factor C

Abstract Lack of adipose-specific hexose-6-phosphate dehydrogenase improves fat metabolic phenotype and increases insulin sensitivity in mice. ABSTRACT Increased glucocorticoids (GCs) production in adipose tissue promotes the development of visceral obesity and the MS. The action of GCs in adipose tissue is tightly regulated by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) coupled with hexose-6-phosphate dehydrogenase (H6PDH). However, the phenotypic consequences of reduction of fat-specific GC action caused by inactivation of H6PDH specifically in adipose tissue have not been explored. To better understand the physiological effects of adipose H6PDH, we generated a tissue-specific animal model of adipocyte-specific H6PDH deletion under the control of the murine adipocyte-specific adiponectin promoter (H6PDHAcKO mice). H6PDHAcKO mice exhibited complete absence of H6PDH expression and decreased GC production with reduction of 11β-HSD1 in adipose tissue. These mice had decreased abdominal fat mass with decreased adipose lipogenic gene expression associated with reduction of their transcription factor C/EBPs mRNA levels. Moreover, H6PDHAcKO mice also decreased adipose lipolysis and reduced plasma FFA levels. In addition, H6PDHAcKO mice decreased fasting glucose levels and increase tolerance to glucose and insulin. These data suggest that H6PDHAcKO mice may provide a good model for study the potential contribution of fat-specific H6PDH inhibition to improve the metabolic phenotype in vivo.

scholarly journals Dopamine receptor D1- and D2-agonists do not spark brown adipose tissue thermogenesis in mice

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Francesca-Maria Raffaelli ◽  
Julia Resch ◽  
Rebecca Oelkrug ◽  
K. Alexander Iwen ◽  
Jens Mittag
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Dopamine Receptor ◽  
Ex Vivo ◽  
Potential Target ◽  
D2 Agonist ◽  
Obesity And Diabetes ◽  
Brown Adipose

AbstractBrown adipose tissue (BAT) thermogenesis is considered a potential target for treatment of obesity and diabetes. In vitro data suggest dopamine receptor signaling as a promising approach; however, the biological relevance of dopamine receptors in the direct activation of BAT thermogenesis in vivo remains unclear. We investigated BAT thermogenesis in vivo in mice using peripheral administration of D1-agonist SKF38393 or D2-agonist Sumanirole, infrared thermography, and in-depth molecular analyses of potential target tissues; and ex vivo in BAT explants to identify direct effects on key thermogenic markers. Acute in vivo treatment with the D1- or D2-agonist caused a short spike or brief decrease in BAT temperature, respectively. However, repeated daily administration did not induce lasting effects on BAT thermogenesis. Likewise, neither agonist directly affected Ucp1 or Dio2 mRNA expression in BAT explants. Taken together, the investigated agonists do not seem to exert lasting and physiologically relevant effects on BAT thermogenesis after peripheral administration, demonstrating that D1- and D2-receptors in iBAT are unlikely to constitute targets for obesity treatment via BAT activation.

Regulation of obese gene expression in KK mice and congenic lethal yellow obese KKAy mice

1996 ◽  
Vol 271 (2) ◽  
pp. E333-E339 ◽  
Author(s):  
M. Hayase ◽  
Y. Ogawa ◽  
G. Katsuura ◽  
H. Shintaku ◽  
K. Hosoda ◽  
...  
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Tissue Expression ◽  
Mouse Strains ◽  
Mrna Levels ◽  
Ob Gene ◽  
Kk Mice ◽  
Kkay Mice ◽  
Obesity And Diabetes ◽  
Lethal Yellow

To elucidate the regulation of obese (ob) gene expression in obesity and diabetes, we examined ob gene expression in KK mice and congenic lethal yellow obese KKAy mice. Northern blot analysis revealed that the ob mRNA levels are roughly equivalent in each of the epididymal, mesenteric, and subcutaneous white adipose tissue (WAT) from KK and KKAy mice at 4 wk of age, when the obese phenotype of KKAy mice was not apparent. Expression of the ob gene was augmented in the mesenteric and subcutaneous WAT but was unchanged in the epididymal WAT in KKAy mice at 12 wk of age, when KKAy mice developed marked obesity with hyperglycemia, hyperlipidemia, and hyperinsulinemia. The ob gene expression was also examined during fasting in 12-wk-old KK and KKAy mice. After 24 or 72 h of fasting in both mouse strains, ob gene expression was downregulated in the epididymal and mesenteric WAT but was unchanged in the subcutaneous WAT. The present study demonstrates that adipose tissue expression of the ob gene is regulated depending on the nutritional status in KK and KKAy mice.

scholarly journals Tart Cherry Reduces Inflammation in Adipose Tissue of Zucker Fatty Rats and Cultured 3T3-L1 Adipocytes

Nutrients ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 1576 ◽  
Author(s):  
Shasika Jayarathne ◽  
April Stull ◽  
Alexandra Miranda ◽  
Shane Scoggin ◽  
Kate Claycombe-Larson ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid Synthase ◽  
Related Factor ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Adipose Tissue Inflammation ◽  
Tart Cherry ◽  
Tissue Inflammation ◽  
Anti Inflammatory

Obesity increases adipose tissue inflammation and secretion of pro-inflammatory adipokines, which have systemic effects on the organism’s health status. Our objective was to dissect mechanisms of anti-inflammatory effects of tart cherry (TC) in adipose tissue of Zucker fatty rats, and cultured 3T3-L1 adipocytes. Rats were fed either a control diet, or 4% TC powder diets for eight weeks. Body and epididymal fat pad weights were not significantly different between control and TC groups. However, rats fed the TC diet had significantly reduced adipose tissue inflammation (p < 0.05), as determined by reduced mRNA levels of pro-inflammatory markers including interleukin-6 (IL-6), tumor necrosis factor alpha (TNFα), interleukin-1beta (IL-1β), monocyte chemoattractant protein 1 (MCP-1), inducible nitric oxide synthase (iNOS), and CD-11b, and increased mRNA levels of type-1 arginase (Arg-1) anti-inflammatory marker. Consistent with these in vivo results, TC significantly decreased expression of IL-6 mRNA and protein levels in lipopolysaccharide (LPS) stimulated adipocytes compared to those stimulated with LPS, but no TC. Moreover, both in vivo (rat adipose tissue) and in vitro (3T3-L1 adipocytes), phosphorylation of p65-NF-κB subunit was significantly reduced by TC. Additionally, TC decreased mRNA expression of fatty acid synthase (FASN), and increased expression of peroxisome proliferator-activated receptor alpha (PPARα), master regulator of lipid oxidation, and anti-oxidant markers nuclear factor erythroid-derived 2-related factor (NRFs) in both models. In conclusion, our findings indicate that TC downregulates inflammation in part via the nuclear factor kappa B (NF-κB) pathway in adipose tissue. Thus, TC may serve as a potential intervention to reduce obesity-associated inflammation.

scholarly journals St. John’s Wort Has Metabolically Favorable Effects on AdipocytesIn Vivo

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Scott Fuller ◽  
Allison J. Richard ◽  
David M. Ribnicky ◽  
Robbie Beyl ◽  
Randall Mynatt ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
White Adipose Tissue ◽  
Critical Role ◽  
Fasting Blood Glucose ◽  
Serine Phosphorylation ◽  
Whole Body ◽  
Storage Site ◽  
St John’S Wort ◽  
St John's Wort

In addition to serving as a storage site for reserve energy, adipocytes play a critical role in whole-body insulin sensitivity and glucose metabolism. St. John’s Wort (SJW) is a botanical supplement widely used as an over-the-counter treatment of depression and a variety of other conditions associated with anxiety and nerve pain. Previous studies in our laboratory demonstrated that SJW inhibits insulin-stimulated glucose uptake and adipocyte differentiation in cultured murine and mature human adipocytes. To investigate the effects of SJW on adipocyte functionin vivo, we utilized C57BL/6J mice. In our studies, mice were administered SJW extract (200 mg/kg) once daily by gavage for two weeks. In contrast to ourin vitrostudies, mice treated with SJW extract showed increased levels of adiponectin in white adipose tissue in a depot specific manner(P<0.01). SJW also exerted an insulin-sensitizing effect as indicated by a significant increase in insulin-stimulated Akt serine phosphorylation in epididymal white adipose tissue(P<0.01). Food intake, body weight, fasting blood glucose, and fasting insulin did not differ between the two groups. These results are important as they indicate that SJW does not promote metabolic dysfunction in adipose tissuein vivo.

Selective inhibition of sphingosine kinase-1 protects adipose tissue against LPS-induced inflammatory response in Zucker diabetic fatty rats

2014 ◽  
Vol 307 (5) ◽  
pp. E437-E446 ◽  
Author(s):  
Monica Tous ◽  
Raquel Ferrer-Lorente ◽  
Lina Badimon
Keyword(s):  
Adipose Tissue ◽  
Inflammatory Response ◽  
Sphingosine Kinase ◽  
Selective Inhibition ◽  
Mrna Levels ◽  
Sphingosine Kinase 1 ◽  
Zucker Diabetic Fatty Rats ◽  
Cc Chemokines ◽  
Interfering Rna

Obesity is associated with a state of chronic inflammation. The chemokine (C-C motif) ligand 5 (CCL5) has been proposed to modulate the inflammatory response in adipose tissue (AT). However, the mechanisms underlying CCL5 upregulation in AT remain undefined. The objective of the present study was to evaluate whether the enzyme sphingosine kinase-1 (SK1) would modulate the expression of CCL5 and other inflammatory biomarkers in primary adipocytes and its potential role in lipopolysaccharide (LPS)-induced AT inflammation in a rat model of diabetes. To address this, LPS-stimulated primary adipocytes and 3T3-L1 cells were treated with a SK inhibitor, and the expression of Ccl5 and other CC chemokines were studied. Moreover, the effect of SK1 knockdown on cytokine production was analyzed in 3T3-L1 cells by transfection of SK1-specific small-interfering RNA (siRNA). The anti-inflammatory effects of SK inhibitor in AT were also investigated in vivo using the Zucker lean normoglycemic control (ZLC) rats. LPS treatment stimulated Ccl5, IL-6, pentraxin 3 ( Ptx3), and Tnfα mRNA expression in primary adipocytes and 3T3-L1 cells, whereas pharmacologically and siRNA-mediated SK1 inhibition strongly reduced mRNA levels of proinflammatory cytokines in these cells. Similarly, administration of SK inhibitor to ZLC rats prevented the LPS-induced inflammatory response in AT. Our data demonstrate a role for SK1 in endotoxin-induced cytokine expression in adipocytes and suggest that inhibition of SK1 may be a potential therapeutic tool in the prevention and treatment of chronic and common metabolic disorders, including obesity, insulin-resistance, and type 2 diabetes.

scholarly journals AMPK Phosphorylates Desnutrin/ATGL and Hormone-Sensitive Lipase To Regulate Lipolysis and Fatty Acid Oxidation within Adipose Tissue

2016 ◽  
Vol 36 (14) ◽  
pp. 1961-1976 ◽  
Author(s):  
Sun-Joong Kim ◽  
Tianyi Tang ◽  
Marcia Abbott ◽  
Jose A. Viscarra ◽  
Yuhui Wang ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Hydrolase Activity ◽  
Hormone Sensitive Lipase ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Hormone Sensitive

The role of AMP-activated protein kinase (AMPK) in promoting fatty acid (FA) oxidation in various tissues, such as liver and muscle, has been well understood. However, the role of AMPK in lipolysis and FA metabolism in adipose tissue has been controversial. To investigate the role of AMPK in the regulation of adipose lipolysisin vivo, we generated mice with adipose-tissue-specific knockout of both the α1 and α2 catalytic subunits of AMPK (AMPK-ASKO mice) by using aP2-Cre and adiponectin-Cre. Both models of AMPK-ASKO ablation show no changes in desnutrin/ATGL levels but have defective phosphorylation of desnutrin/ATGL at S406 to decrease its triacylglycerol (TAG) hydrolase activity, lowering basal lipolysis in adipose tissue. These mice also show defective phosphorylation of hormone-sensitive lipase (HSL) at S565, with higher phosphorylation at protein kinase A sites S563 and S660, increasing its hydrolase activity and isoproterenol-stimulated lipolysis. With higher overall adipose lipolysis, both models of AMPK-ASKO mice are lean, having smaller adipocytes with lower TAG and higher intracellular free-FA levels. Moreover, FAs from higher lipolysis activate peroxisome proliferator-activated receptor delta to induce FA oxidative genes and increase FA oxidation and energy expenditure. Overall, for the first time, we providein vivoevidence of the role of AMPK in the phosphorylation and regulation of desnutrin/ATGL and HSL and thus adipose lipolysis.

scholarly journals Expression of peroxisome proliferator-activated receptors in lean and obese Zucker rats

2000 ◽  
pp. 71-78 ◽  
Author(s):  
A Gorla-Bajszczak ◽  
C Siegrist-Kaiser ◽  
O Boss ◽  
AG Burger ◽  
CA Meier
Keyword(s):  
Adipose Tissue ◽  
Fiber Type ◽  
Zucker Rats ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Rnase Protection ◽  
Brown Adipose ◽  
Obese Zucker Rats

OBJECTIVE: Examination of the pattern of expression of peroxisome proliferator-activated receptor (PPAR) isoforms alpha and gamma in a model of obesity. DESIGN: Examination of adipose tissue and primary adipocyte cultures from lean and obese Zucker rats at different ages (28 days and 12 weeks). METHODS: mRNA levels were measured by RNase protection assay.RESULTS: The highest levels of PPARalpha and gamma mRNA were present in brown adipose tissue (BAT), followed by liver and white adipose tissue (WAT) for the alpha and gamma subtypes, respectively, at both ages examined. PPARalpha was expressed 100-fold higher in BAT compared with WAT, and PPARgamma mRNA levels were 2-fold higher in the WAT of obese compared with lean rats. PPARalpha and gamma expression was minimal in m. soleus, although higher levels of PPARgamma were found in the diaphragm. In marked contrast to the findings in vivo, virtually no PPARalpha mRNA could be detected in BAT cultures differentiated in vitro. CONCLUSION: PPARalpha and gamma are most highly expressed in BAT in vivo. However, PPARalpha is undetectable in brown adipose cells in vitro, suggesting that the expression of this receptor is induced by some external stimuli. In addition, the expression of PPARgamma was increased in WAT from young obese animals, compatible with an early adaptive phenomenon. Finally, the presence of PPARgamma mRNA is detectable only in particular muscles, such as the diaphragm, suggesting the possibility of an influence of fiber type on its expression, although exercise did not influence the expression of PPARgamma in other skeletal muscles.

Adipogenic and lipolytic effects of chronic glucocorticoid exposure

2011 ◽  
Vol 300 (1) ◽  
pp. C198-C209 ◽  
Author(s):  
Jonathan E. Campbell ◽  
Ashley J. Peckett ◽  
Anna M. D'souza ◽  
Thomas J. Hawke ◽  
Michael C. Riddell
Keyword(s):  
Adipose Tissue ◽  
Ex Vivo ◽  
Residual Effect ◽  
Hormone Sensitive Lipase ◽  
Maximum Effect ◽  
Dependent Manner ◽  
Sprague Dawley ◽  
Preadipocyte Differentiation ◽  
Concentration Dependent Manner

Glucocorticoids have been proposed to be both adipogenic and lipolytic in action within adipose tissue, although it is unknown whether these actions can occur simultaneously. Here we investigate both the in vitro and in vivo effects of corticosterone (Cort) on adipose tissue metabolism. Cort increased 3T3-L1 preadipocyte differentiation in a concentration-dependent manner, but did not increase lipogenesis in adipocytes. Cort increased lipolysis within adipocytes in a concentration-dependent manner (maximum effect at 1–10 μM). Surprisingly, removal of Cort further increased lipolytic rates (∼320% above control, P < 0.05), indicating a residual effect on basal lipolysis. mRNA and protein expression of adipose triglyceride lipase and phosphorylated status of hormone sensitive lipase (Ser563/Ser660) were increased with 48 h of Cort treatment. To test these responses in vivo, Sprague-Dawley rats were subcutaneously implanted with wax pellets with/without Cort (300 mg). After 10 days, adipose depots were removed and cultured ex vivo. Both free fatty acids and glycerol concentrations were elevated in fed and fasting conditions in Cort-treated rats. Despite increased lipolysis, Cort rats had more visceral adiposity than sham rats (10.2 vs. 6.9 g/kg body wt, P < 0.05). Visceral adipocytes from Cort rats were smaller and more numerous than those in sham rats, suggesting that adipogenesis occurred through preadipocyte differentiation rather than adipocyte hypertrophy. Visceral, but not subcutaneous, adipocyte cultures from Cort-treated rats displayed a 1.5-fold increase in basal lipolytic rates compared with sham rats ( P < 0.05). Taken together, our findings demonstrate that chronic glucocorticoid exposure stimulates both lipolysis and adipogenesis in visceral adipose tissue but favors adipogenesis primarily through preadipocyte differentiation.

scholarly journals RFX1, a transactivator of hepatitis B virus enhancer I, belongs to a novel family of homodimeric and heterodimeric DNA-binding proteins

1994 ◽  
Vol 14 (2) ◽  
pp. 1230-1244
Author(s):  
W Reith ◽  
C Ucla ◽  
E Barras ◽  
A Gaud ◽  
B Durand ◽  
...  
Keyword(s):  
Hepatitis B Virus ◽  
Dna Binding ◽  
Hepatitis B ◽  
Binding Proteins ◽  
Dna Binding Proteins ◽  
Mrna Levels ◽  
B Virus ◽  
Factor C

RFX1 is a transactivator of human hepatitis B virus enhancer I. We show here that RFX1 belongs to a previously unidentified family of DNA-binding proteins of which we have cloned three members, RFX1, RFX2, and RFX3, from humans and mice. Members of the RFX family constitute the nuclear complexes that have been referred to previously as enhancer factor C, EP, methylation-dependent DNA-binding protein, or rpL30 alpha. RFX proteins share five strongly conserved regions which include the two domains required for DNA binding and dimerization. They have very similar DNA-binding specificities and heterodimerize both in vitro and in vivo. mRNA levels for all three genes, particularly RFX2, are elevated in testis. In other cell lines and tissues, RFX mRNA levels are variable, particularly for RFX2 and RFX3. RFX proteins share several novel features, including new DNA-binding and dimerization motifs and a peculiar dependence on methylated CpG dinucleotides at certain sites.

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