bluuebunny/crossref_metadata_2025_split huggingface dataset:
BAF60a Orchestrates Thermogenic Chromatin Accessibility in Brown Fat
Authors: LI SIMING , LIU TONGYU , MI LIN , MENG ZHUOXIAN , LIN JIANDIE 
Published: June 2018

Life Sciences Institute and Department of Cell and Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109
Brown fat thermogenesis is important for cold defense and systemic energy balance. The activation of the thermogenic gene program during development and in response to cold requires global reconfiguration of chromatin structure. Here we demonstrate that BAF60a, a component of SWI/SNF chromatin-remodeling complex, is indispensable for cold-induced thermogenesis. Mice with adipose tissue-specific inactivation of BAF60a exhibited impaired thermogenic gene expression and were exquisitely cold-sensitive. Assay for Transposase-Accessible Chromatin using sequencing (ATAC) revealed that chromatin accessibility of many brown fat-enriched genes was markedly reduced by Baf60a deficiency. Motif enrichment analysis indicated that these BAF60a-dependent chromatin regions are highly enriched for binding sites for PPARγ, EBF2, and C/EBPβ, key transcriptional regulators of thermogenic gene expression, suggesting that BAF60a likely serves an important role in orchestrating the thermogenic chromatin state. Adipose tissue inactivation of BAF60a augmented browning of inguinal adipose tissue following cold acclimation. Mechanistically, this browning response was linked to compensatory activation of the ACTH/Melanocortin 2 Receptor signaling. Our studies outline a mechanism of global control of chromatin accessibility during thermogenesis and reveal differential role of BAF60a in brown and beige fat biogenesis.

Disclosure
S. Li: None. T. Liu: None. L. Mi: None. Z. Meng: None. J. Lin: None.
Thiazolidinediones’ Insulin-Sensitizing Properties Depend on Adiponectin-Mediated Reductions in Certain Ceramide Species
Authors: GORDILLO RUTH , ZHANG KEHAO , SCHERER PHILIPP E. , HAWKINS MEREDITH 
Published: June 2018

Adiponectin release from adipocytes is stimulated by the thiazolidinedione (TZD) class of PPARγ agonists in a time-dependent fashion, with an increase within 10 days followed by a more robust effect within 3 weeks. Our previous work suggested that adiponectin exerts its metabolic effects in part by enhancing the deacylation of the sphingolipid ceramide, a lipotoxic metabolite stimulated by exposure to saturated fats or inflammatory mediators. Adiponectin receptors in fact display potent ceramidase activity. Ceramides and diacylglycerols correlate with impaired insulin action. The effects of 10 and 21 days’ pioglitazone (Pio; 45 mg/day) treatment on insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp studies in n=26 type 2 diabetic subjects (Diabetes. 62:1843, 2013). Total and high molecular weight (HMW) adiponectin levels in plasma were determined using a commercial sandwich ELISA kit. Sphingolipids in adipose tissue and plasma were quantified by liquid chromatography-tandem mass spectrometry. Improved hepatic and peripheral insulin sensitivity was seen after 21 days, but not 10 days, of Pio, and were highly correlated with an increased ratio of HMW adiponectin/total levels (r2=0.90). Variable responses in both total and HMW adiponectin defined subjects as Responders (R;≥1.5-fold increase with Pio) vs. Non-responders (NR; no change). Sphingosine-1P, a beneficial conversion product from ceramides, increased 2-fold and Sphinganine-1P increased 2.5-fold in R relative to NR and placebo (p=0.0286). Pio induced decreases in dihydroceramides and increases in lactosylceramides as a function of time and adiponectin levels, the functional significance of which needs to be further explored. This study suggests the insulin-sensitizing properties of TZDs critically depend on elevating circulating adiponectin levels, with an associated lowering of certain ceramide species involved in insulin resistance and inflammation.

Disclosure
R. Gordillo: None. K. Zhang: None. P.E. Scherer: None.
Fibroblast Growth Factor-9 Regulates Adaptive Brown Adipose Tissue Mass Expansion
Authors: SHAMSI FARNAZ , HUANG TIAN LIAN , TSENG YU-HUA 
Published: June 2018

Brown adipose tissue (BAT) plays an essential role in adaptive thermogenesis in response to environmental changes, such as cold and diet. Targeting BAT and modulating its mass and/or energy-dissipating capacity hold great promise for treatment of metabolic disorders. Expansion of BAT mass through increased cellular proliferation is a fundamental mechanism of cold adaptation. We have recently discovered Fibroblast Growth Factor 9 (FGF-9) as a cold-induced adipokine produced by BAT that regulates BAT mass. Adeno-associated virus (AAV)-mediated overexpression of FGF-9 in vivo increased BAT mass and improved glucose metabolism in obese mice. Additionally, using double thymidine analogue labeling we demonstrated that FGF-9 overexpression in BAT increased cellular proliferation and enhanced cold-induced BAT expansion. Using an adipose tissue-specific Cas9 knock-in mouse model coupled with the AAV-mediated delivery of gRNAs targeting FGF-9, we specifically deleted FGF-9 in BAT and demonstrated that loss of FGF-9 resulted in reduction of cold-induced proliferation of brown adipocyte progenitors, and led to impaired thermogenic capacity. Therefore, FGF-9 is essential for cold-induced formation of new brown adipocytes and long term cold adaptation. Combining the results from these gain- and loss-of-function studies, we conclude that FGF-9 acts as a growth factor for brown adipocyte progenitors to promote BAT expansion in response to cold. These findings provide a novel regulatory mechanism modulating BAT mass, and may ultimately contribute to the development of novel therapeutic strategies to combat obesity and its comorbidities.

Disclosure
F. Shamsi: None. T. Huang: None. Y. Tseng: Other Relationship; Self; Chugai Pharmaceutical Co., Ltd.. Research Support; Self; MedImmune.
Vitamin D Enhances Insulin Sensitivity in Neurons
Authors: TEIXEIRA SILVANIA , HE YANLIN , XU YONG , SISLEY STEPHANIE 
Published: June 2018

Vitamin D deficiency has been linked to diabetes but a causal relationship is not clear. We previously published hypothalamic vitamin D action is critical for glucose tolerance and insulin sensitivity in obese animals. We hypothesized vitamin D also enhanced insulin sensitivity within the brain. Indeed, 48 hours of 1,25D3 (aka calcitriol) increased phosphorylation of Akt in hypothalamic cells (GT1-7). This effect was not observed in the absence of insulin, indicating that vitamin D was enhancing insulin action rather than mediating phosphorylation independently. Phosphorylation of Akt is often mediated by phosphoinositide 3-kinase (PI3K). Wortmannin, a PI3K inhibitor, blocked the effects of vitamin D to enhance pAkt. This supports a PI3K-dependent mechanism of vitamin D action. Vitamin D increased mRNA concentrations of key components of the PI3K/Akt pathway, namely IRS2 and p85. p55 expression, a negative regulator of PI3K, was decreased. Vitamin D did not affect transcription of the insulin receptor, IRS1, Akt, or the vitamin D receptor. Together, these support vitamin D as a regulator of the PI3K pathway in hypothalamic neurons. Additionally, the PI3K pathway has previously been shown to be important in rapid effects of other nuclear hormones. Since we previously published vitamin D depolarizes hypothalamic neurons, we investigated whether the PI3K pathway was also necessary in rapid vitamin D actions. Indeed, vitamin D was unable to depolarize hypothalamic neurons in the presence of the PI3K inhibitor wortmannin. Together, these data support that the action of vitamin D in the brain to influence glucose homeostasis may be through altered insulin signaling in the brain and requires the PI3K pathway for effects. These results are important in light of the known association between vitamin D and insulin resistance. They suggest that although vitamin D enhances insulin sensitivity, its actions are dependent upon a functional PI3K pathway, which is likely altered in an obese, insulin-resistant individual.

Disclosure
S. Teixeira: None. Y. He: None. Y. Xu: None. S. Sisley: Consultant; Self; Alexion Pharmaceuticals, Inc..
VEGF-A-Expressing Adipose Tissue Shows Rapid Beiging, Enhanced Survival after Transplantation
Authors: KIM MIN , AN YU A. , BANG HYUN SEOK , SCHERER PHILIPP E. , PARK JIYOUNG 
Published: June 2018

Adipocyte-derived VEGF-A plays a crucial role in angiogenesis and contributes to adipocyte function and systemic metabolism, such as insulin resistance, chronic inflammation and beigeing of subcutaneous adipose tissue. Utilizing a doxycycline (Dox)-inducible adipocyte-specific VEGF-A overexpressing mouse model, we investigated the dynamics of local VEGF-A effects on tissue beiging of adipose tissue transplants. VEGF-A overexpression in adipocytes triggers angiogenesis. We also observe a rapid appearance of beige fat cells in subcutaneous white adipose tissue (sWATs) within as early as 2 days post induction of VEGF-A. In contrast to conventional cold-induced beiging, VEGF-A-induced beiging is independent of IL-4. We subjected metabolically healthy VEGF-A overexpressing adipose tissue to autologous transplantation. Transfer of subcutaneous adipose tissues taken from VEGF-A overexpressing mice into diet-induced obese mice resulted in systemic metabolic benefits, associated with improved survival of adipocytes and a concomitant reduced inflammatory response. These effects of VEGF-A are tissue autonomous, inducing WAT beigeing and angiogenesis within the transplanted tissue. Our findings indicate that manipulation of adipocyte functions with a bona fide angiogenic factor, such as VEGF-A, significantly improves the survival and volume retention of fat grafts and can convey metabolically favorable properties on the recipient on the basis of beiging.

Disclosure
M. Kim: None. Y.A. An: None. H. Bang: None. P.E. Scherer: None. J. Park: None.
p62 Deficiency Leads to Hypogonadism and Infertility via Pituitary Functions Loss in Young Female Mice before Metabolic Disorders Onset
Authors: LONG MIN , ZHENG HONGTING , LI XING 
Published: June 2018

p62/SQSTM1 is an essential protein adaptor that fine-tunes numerous biological processes by autophagy or related cell signaling pathway. Previous studies have proved that p62 loss lead to mature-onset metabolic disorders including obesity, diabetes and fatty liver in adult mice; and in younger human being those metabolic diseases are close to reproductive dysfunctions, such as PCOS. Here, the metabolism and reproductive function of younger (8 weeks) p62 deficient female mice was observed, and hypothalamus-pituitary-ovary axis was evaluated to explore the possible upstream mechanisms. We found that although p62 deficiency rarely exposes obvious metabolic influences during younger stage of female mice, the deteriorative reproductive function has exhibited, such as attenuated breeding success rate and number of pups per litter. In particular, genetic deletion of p62 causes impaired estrous cycle, thread-like atrophied uteri and low-weight ovary with the lack of corpus luteum, failure of folliculogenesis and ovulation. Next, the low levels of plasma sex steroid hormone estradiol and gonadotropic luteinizing hormone (LH) have also been detected. Furthermore, defected steroidogenesis signaling including decreased StAR and P450scc in p62 KO ovary reveals reduced cholesterol-to-pregnenolone transition, meanwhile, increased Lhcgr mRNA expression in ovarian suggests a compensatory reaction. Consistent with lower serum LH level, significantly decreased mRNA expression of Lhb as well as slightly reduced Fshb also were found in the pituitary of p62 KO female mice. In addition, the elevated expression of Kiss1 mRNA in hypothalamus might discover the compensatory for pituitary function loss. Our findings support the vital role p62 of pituitary on reproductive function in younger individuals, and this effect might be the direct consequence rather than by metabolic disorders induced by p62 deficiency.

Disclosure
M. Long: None. H. Zheng: None. X. Li: None.
Ablation of Adipose CREB3L3 Protects Mice from Obesity-Induced Metabolic Dysfunction
Authors: MCCANN MAXIMILIAN A. , QIANG GUIFEN , GIL VICTORIA , KONG HYERIM WHANG , ZHANG KEZHONG , LIEW CHONG WEE 
Published: June 2018

Metabolically healthy obesity (MHO) is a subtype of obesity where individuals lack the metabolic symptoms associated with obesity, despite being obese. Our lab has found that the fat-specific ablation of cyclic-AMP Responsive Element Binding Protein 3-like-3 (CREB3L3) creates a phenotype mimicking MHO in mice fed a high-fat diet (HFD). CREB3L3 is an ER-bound transcription factor that we have discovered to not only be expressed in adipose tissue, but selectively downregulated in obese subcutaneous fat from both mice and human patients. Subcutaneous fat is considered the more “metabolically-protective” subtype of white adipose tissue in obesity, so we hypothesized that this downregulation of CREB3L3 could contribute to the healthier phenotype of obese subcutaneous fat, and the ablation of this protein specifically in adipose tissue could be metabolically beneficial. We found that the fat-specific knockout (KO) of CREB3L3 significantly increased body weight and the mass of both the subcutaneous inguinal (iWAT) and visceral epididymal (eWAT) fat depots on HFD, as compared to wild type controls. However, the KO mice do not exhibit the insulin resistance or glucose intolerance expected with their more obese phenotype, likely due to enhanced lipid storage in adipose tissue, which sequesters lipids away from the circulation and liver. Indeed, the KO mice do not exhibit dyslipidemia and have reduced hepatic triglyceride content. The enhanced adipose lipid storage is achieved via the enlargement of the iWAT and eWAT in the KO mice. Morphometric analysis shows that both of these tissues have more adipocytes, and the eWAT has more large adipocytes. While adipocyte hypertrophy typically contributes to metabolic dysfunction, the KO eWAT, along with the iWAT, actually exhibit a reduction in inflammatory marker expression. This ability to reduce adipose inflammation while enhancing lipid storage capacity allows the CREB3L3 KO mice to gain more weight on HFD, yet maintain a healthy metabolic profile.

Disclosure
M.A. McCann: None. G. Qiang: None. V. Gil: None. H. Whang Kong: None. K. Zhang: None. C. LIew: None.
Androgens Activate Myeloid Cells during High-Fat Diet Exposure Promoting Sex Differences in Metabolic Disease
Authors: GRIFFIN CAMERON A. , ABRISHAMI SIMIN , VARGHESE MITA , SINGER KANAKADURGA 
Published: June 2018

Men have a higher risk of metabolic and cardiovascular disease than pre-menopausal women, but the mechanisms of these differences are elusive. Chronic myeloid inflammation during obesity contributes to metabolic disease risk and is significantly more robust in males. Given the paucity of data on male sex hormones contributing to macrophage responses in obesity, our objective was to understand the role of androgens in promoting obesity-induced myeloid inflammation. Male and female C57Bl/6J mice were fed a 60% high fat diet for 24 weeks. Glucose tolerance and insulin sensitivity were measured. Monocyte transfer experiments assessed sex differences in bone marrow myeloid responses to obesity independent of host sex. Gonadectomy, mice deficient of androgen receptor signaling (ARtfm) and monocyte specific androgen receptor (AR) knockout mice (LysMAR-/y) were used to model androgen deficiency. Compared to males, females had dampened inflammatory responses with reduced CD11c+ ATMs and cytokines, even with increased adiposity. RNASeq demonstrated sex differences in gene pathways of both metabolic and inflammatory activation in ATMs. Male monocytes transferred into females remained primed for pro-inflammatory response and induced an increase in adiposity. Castrated males exposed to high fat diet had impaired glucose tolerance and increased insulin sensitivity with increased adiposity and lower numbers of CD11c+ ATMs. These same findings were seen in ARtfm mice. Testosterone enhanced palmitate-stimulated myeloid colony production, and this response was dampened in castrated, ARtfm, and LysMAR-/y mice. These studies demonstrate that androgens play a critical role in enhanced metabolic dysfunction and enhanced myeloid inflammation in response to obesogenic cues. Androgen driven myeloid inflammation leads to metabolic dysfunction in a cell-autonomous manner driving sex-differences in obesity induced meta-inflammation.

Disclosure
C.A. Griffin: None. S. Abrishami: None. M. Varghese: None. K. Singer: None.
Endothelial/Nitric Oxide Regulation of Brown Adipose Tissue Activating Lipokine, 12, 13-diHOME and Its Antiatherogenic Actions
Authors: PARK KYOUNGMIN , LI QIAN , LYNES MATT , YOKOMIZO HISASHI , SHINJO TAKANORI , ST-LOUIS RONALD , FU JIALIN , RASK-MADSEN CHRISTIAN , TSENG YU-HUA , KING GEORGE L. 
Published: June 2018

Activation of brown adipose tissue (BAT) has been shown to decrease atherosclerosis due to its systemic actions to improve insulin sensitivity and facilitate weight loss. However, the direct effect of BAT cytokines on vascular arterial function and atherosclerosis has not been studied. We have reported that enhancing insulin’s action on the endothelial cells (EC) by overexpressing IRS1 to the EC on ApoE-/- background (ECIRS1/ApoE-/- mice) greatly increased insulin induced NO production and decreased atherosclerosis. ECIRS1 mice exhibited significant increases in BAT mass and activation when exposed to cold temperature (5°C), in parallel with elevation of BAT lipokine, 12,13-diHOME levels at basal, regular chow (RD) or high fat diet (HFD) compared to wild type mice (WT) by 188±33% and 187±39%, respectively, (P&lt;0.01). Recently, 12,13 diHOME has been reported to activate BAT (Nat. Med, 2017. Elevation of 12, 13 diHOME induced by cold temperature was inhibited by L-NAME, an inhibitor of NO. In EC, the addition of 12,13-diHOME increase pAkt from 1-100nM, but without affecting peNOS and pErk. However, oxLDL-induced pErk activity and VCAM-1 expression were reduced in 12,13-diHOME (1nM) treated EC. Further, 12,13-diHOME also increased intracellular calcium concentration with parallel elevation in NO production in EC. Functionally, 12,13-diHOME(1nM-10nM) increased vascular relaxation in myography experiments significantly by 7.5%-24%. Using antibody arrays for assessing the effects of 12,13-diHOME on NO production in EC, signaling studies showed 12,13-diHOME activated mTOR, CREB and HSP27 (by 50, 2.5, and 4 fold, respectively) and down-regulated tyrosine-protein kinase (HCK) and GSK3α/β (by 30% and 26%, p&lt;0.05) in EC. These studies for the first time showed that insulin’s action in EC can regulate BAT lipokine 12,13-diHOME expression in a positive feedback loop to increase NO and increase vasodilation with associated decrease in atherosclerosis.

Disclosure
K. Park: None. Q. Li: None. M. Lynes: None. H. Yokomizo: None. T. Shinjo: None. R. St-Louis: None. J. Fu: None. C. Rask-Madsen: Research Support; Self; Novo Nordisk A/S. Y. Tseng: Other Relationship; Self; Chugai Pharmaceutical Co., Ltd.. Research Support; Self; MedImmune. G.L. King: Research Support; Self; Sanofi-Aventis.
Fructose Consumption Induces Strain-Specific Transcriptomic Response Perturbing Different Pathways in Genetically Diverse Mouse Strains
Authors: ZHANG GUANGLIN , BYUN HYAE RAN , YING ZHE , ZHAO YUQI , GOMEZ-PINILLA FERNANDO , YANG XIA 
Published: June 2018

Metabolic syndrome (MetS) predisposes individuals to type 2 diabetes mellitus and cardiovascular diseases. Epidemiological and clinical studies support fructose intake as an environmental risk for MetS and the associated metabolic diseases. To explore the role of genomic variability in determining metabolic responses to fructose, we fed three strains of mice, namely C57/B6 (B6), DBA and FVB, with 8% fructose for 12 weeks. Fructose-fed DBA mice gained a significantly higher amount of body weight and glucose intolerance from the 4th to the 12th week, while B6 and FVB showed no differences in these phenotypes over 12 weeks. In addition, elevated insulin levels were found in fructose-fed DBA and FVB mice, and cholesterol levels were uniquely elevated in B6 mice. To explore the molecular underpinnings, we applied RNA sequencing to investigate the effect of fructose on the transcriptional profiles of liver, adipose and hypothalamus tissues. Different strains showed distinct patterns of transcriptional and pathway perturbations in a tissue-specific manner. Among pathways altered in the liver tissue, fatty acid and cholesterol metabolic pathways were prominent in B6 mice, while DBA mice showed unique over-representation of pathways related to PPAR signaling pathway. In adipose tissue, pathways are more related to fatty acid metabolism and oxidation in B6 mice, whereas no metabolic pathways were found to be enriched for differential genes in DBA and FVB mice. In hypothalamus tissue, only B6 showed significant enrichment for pathways involved in protein folding, pancreatic secretion and fatty acid beta-oxidation. Using network modeling, we predicted potential key regulators of fructose response such as FGF-21 and Sqle in the liver, Cav1 and DPP-4 in adipose tissue and Fmod in the hypothalamus. Our findings provide molecular insights into the mechanisms by which fructose contributes to the development of MetS and metabolic diseases.

Disclosure
G. Zhang: None. H. Byun: None. Z. Ying: None. Y. Zhao: None. F. Gomez-Pinilla: None. X. Yang: None.
Iron-Overload Evaluation by Noninvasive Methods in Patients with Nonalcoholic Fatty Liver Disease, Overweight, and Hyperferritinemia
Authors: BRANISSO PAULA P.F. , OLIVEIRA CLAUDIA P. , LEÃO FILHO HILTON M. , SANTOS ARITANIA , LIMA FABIANA R. , MANCINI MARCIO , CARRILHO FLAIR JOSÉ , ROCHA MANOEL , CERCATO CINTIA 
Published: June 2018

Introduction: Hyperferritinemia (HF) may reflect the inflammatory status of patients with NAFLD and obesity, but about 33% reflects a real hepatic iron overload. The dysmetabolic iron overload syndrome (DIOS) definition is HF, normal transferrin saturation, and mild hepatic iron overload in a patient with metabolic disorders. The gold standard for diagnosis of iron overload is the liver biopsy. As it is an invasive method, new methods are necessary. Among them, magnetic resonance imaging (MRI) is the most available one.
Methods: This study evaluated patients with HF, overweight and NAFLD. All patients were submitted to liver biopsy. MRI relaxometry (Fat/Iron analysis - 3T machine), measurement of inflammatory markers (TNF α and IL-6), analysis of the expression of ferritin light and heavy chain subunits (FTL and FTH) and serum hepcidin were held. Data were correlated with liver biopsy.
Results: 152 biopsy-proven NAFLD patients were screened but only 67 were included in this study. DIOS frequency was 37%. The cut off of ferritin levels were correlated with iron overload in liver biopsy was 284,3 ng/ml (sensibility of 74% and specificity of 84%). Hepcidin levels were higher in DIOS patients, correlating with hepatic siderosis. IL-6 and TNF α were similar among the groups. The expression of FTH and FTL were similar in role sample, although there was a tendency of FTL in iron overload group. In the other hand, FTL correlates with metabolic syndrome and abdominal circumference, while FTH correlates with in higher fat scores. The MRI was able to identify mild iron overload. The R2 * cut off level was 58,9 s -1.
Conclusions: HF may reflect iron overload when above 284,3 ng/ml; MRI using relaxometry method is accurate to evaluate mild iron overload in DIOS patients; Hepcidin correlates with iron and serum ferritin in NAFLD patients; FTL correlates with metabolic syndrome and abdominal circumference while FTH correlates with in higher fat scores.

Disclosure
P.P.F. Branisso: None. C.P. Oliveira: None. H.M. Leão Filho: None. A. Santos: None. F.R. Lima: None. M. Mancini: None. F. Carrilho: None. M. Rocha: None. C. Cercato: None.