bluuebunny/crossref_metadata_2025_split huggingface dataset:
Siah2 in Adipocytes Promotes M2-Like Macrophage Activation in Adipose Tissue
Authors: KILROY GAIL E. , TAYLOR JESSICA L. , DANG THANH , YU YONGMEI , FLOYD ELIZABETH 
Published: June 2018

Obesity is associated with chronic, low-grade adipose tissue inflammation that is linked to glucose intolerance and insulin resistance. Although enzymes of the ubiquitin-proteasome system are known to regulate signaling in classical inflammation, involvement of the ubiquitin-proteasome system in obesity-induced metabolic inflammation is relatively unexplored. We previously found that the ubiquitin ligase mammalian homolog of seven-in-absentia (Siah2) alters peroxisome proliferator-activated receptor γ (PPARγ) protein levels and selectively regulates PPARγ activity. Using a mouse model of global Siah2 deletion (Siah2KO), we observed that Siah2KO mice become obese on a high fat diet (HFD), but remain glucose tolerant and insulin sensitive. This corresponds to reduced expression of pro-inflammatory markers, substantially fewer crown-like structures and less fibrosis in adipose tissue although the adipocytes are enlarged. To determine if Siah2 expression in adipocytes accounts for the Siah2KO phenotype, we created an adipocyte-specific Siah2KO model (Siah2AdKO). Although HFD-induced obesity is attenuated in Siah2AdKO mice, the mice become glucose intolerant and insulin resistant. The visceral adipose tissue is infiltrated by M1-like macrophages, corresponding to increased crown-like structures and fibrosis while M2-like macrophages are reduced. PPARγ activity is selectively regulated, but PPARγ protein levels are unchanged in the Siah2AdKO mice. The levels of pro-inflammatory markers such as IL-6 are increased, but as in the global Siah2KO model, TNFα, SAA3 and PAI-1 expression is decreased. Thus, our data indicates Siah2 in adipocytes influences polarization of macrophages in adipose tissue independent of regulating PPARγ protein levels. Moreover, Siah2 in adipocytes mediates expression of a subset of pro-inflammatory adipokines, but surprisingly, these factors do not appear to drive adipose tissue inflammation in this model of obesity.

Disclosure
G.E. Kilroy: None. J.L. Taylor: None. T. Dang: None. Y. Yu: None. E. Floyd: None.
Liver-Specific Reactivation of MC3R Partially Reverses the Obesity of MC3R Deficiency
Authors: LEVI NOAH J. , JUN JOO YUN , PATEL TUSHAR P. , UHLMAN ANDREW J. , ROBERSON ROBIN , YANOVSKI JACK A. 
Published: June 2018

The Melanocortin 3 Receptor (MC3R) regulates appetite, food intake, and energy expenditure in humans and mice. MC3R is primarily expressed in the hypothalamus and other CNS regions but is also present in peripheral tissues including the liver. Total body knockouts of MC3R have a distinct obese phenotype of increased fat mass with decreased lean mass. However, when MC3R is reactivated only in the brain of mice that are globally MC3R deficient, the obese phenotype is not completely recovered compared to wild type mice, suggesting peripheral MC3R may also regulate energy homeostasis. To begin to examine the role of peripheral MC3R in energy balance, we investigated the extent to which liver specific reactivation of MC3R reversed the obese phenotype seen in the global knockout. We generated a liver specific MC3R recovery model by crossing a floxed-transcription blocker MC3R (MC3R-/-) mouse line with mice expressing albumin-Cre recombinase (Alb-Cre+/+); both strains were in a C57BL/6J (BL/6) background. We measured the body weight and body composition (using dual energy X-ray absorptiometry) of 10-12-week-old MC3R-/-, MC3R-/- + Alb-Cre +/-, and MC3R-/- + Alb-Cre +/+ and BL/6 mice. We found amongst female mice that expression of Alb-Cre (reactivating only hepatic MC3R) was sufficient to partially reverse the increased percentage fat mass of MC3R-/- (MC3R-/-: n=15, 22.15 ± 4.78%; MC3R-/- + Alb-Cre +/- : n=5, 21.22 ± 3.13%; MC3R-/- + Alb-Cre +/+ : n=3, 17.83 ± 4.04%; BL/6: n=17, 15.72 ± 3.18%; p &lt; 0.0001). A similar pattern of partial recovery was also observed for fat grams (p=0.0009), % lean mass (p=0.0003), and lean grams (p=0.002), with no differences in body weight amongst genotypes (p=0.612). Data for male mice were insufficient to perform analyses at this time. We conclude hepatic MC3R is an important regulator of energy homeostasis and body composition. The potential roles for MC3R in other tissues where it is expressed remain to be determined.

Disclosure
N.J. Levi: None. J. Jun: None. T.P. Patel: None. A.J. Uhlman: None. R. Roberson: None. J.A. Yanovski: Research Support; Self; Rhythm Pharmaceuticals Inc., Zafgen.
Mice Lacking Both Cannabinoid-1 and Cannabinoid-2 Receptors Are Resistant to Diet-Induced Obesity
Authors: ALSHAARAWY OMAYMA , KURJAN EMILY , TRUONG NGUYEN , OLSON LAWRENCE K. 
Published: June 2018

Exogenous cannabinoids are a group of related compounds derived from the Cannabis plant, commonly known as marijuana. The discovery of cannabinoid receptors (CB1R and CB2R) has provided a platform for investigating the health effects of cannabinoids. The CB1R is predominantly expressed in the central nervous system, whereas CB2R is primarily expressed in the immune system. Mounting evidence has shown that activation of CB1 is associated with increased food intake and obesity, whereas activation of CB2 is associated with decreased levels of cytokines associated with insulin resistance and type 2 diabetes (T2D). Epidemiological studies, however, have shown a decreased prevalence of obesity and T2D among cannabis users. Here we use high-fat diet (HFD, 45% of calories from fat vs. control LFD with 10% of calories from fat) to study the metabolic changes in male mice lacking receptors of the cannabinoid system (CB-DKO) when compared to wild type (WT) C57BL/6 mice. Eight-weeks old CB-DKO mice displayed lower body fat percent and higher percent of lean mass tissue when compared to WT mice. After 12 weeks, WT mice gained an average of 22 grams on HFD compared to 9 grams on LFD. CB-DKO mice did not respond to HFD, gaining an average of 5 grams on both HFD and LFD. This corresponded to a 5% increase in body fat in CB-DKO mice compared to 18% increase in WT mice. Glucose tolerance test indicated increased insulin sensitivity in CB-DKO mice. Automated measurements revealed no significant differences in food intake or locomotion between CB-DKO and WT mice, whereas CB-DKO mice displayed higher indirect calorimetry parameters including VO2, respiratory exchange ratio, and energy expenditure. Gene expression analysis confirmed an upregulation of thermogenic genes (UCP1, CIDEA, and COX8B) suggesting browning of white adipose tissue in CB-DKO mice. These findings highlight the role of the cannabinoid system in metabolic control of adipose tissues and their potential role for insulin resistance and T2D risk.

Disclosure
O. Alshaarawy: None. E. Kurjan: None. N. Truong: None. L.K. Olson: None.
Characterization of AJ5012 as a Novel Peripheral Cannabinoid 1 Receptor Antagonist in Mouse Models of Obesity
Authors: KIM JUNGEUN , YOON JUHWAN , KIM EUNHA , YOON SUNG-HWA , KIM WOOK 
Published: June 2018

Obesity-induced adipose tissue inflammation, in which the NLRP3 inflammasome is a pivotal mediator, is implicated in the development of insulin resistance. Cannabinoid 1 receptor (CB1R) antagonists have been shown to improve insulin resistance and the associated metabolic abnormalities, but their therapeutic development was discontinued due to neuropsychiatric side effects. Although growing evidence suggests the role of CB1Rs in proinflammatory signaling, their direct effects on adipose tissue inflammation have not yet been evaluated. Here we report that the peripherally restricted CB1R antagonist AJ5012, which exhibits beneficial metabolic effects comparable with its brain-penetrant parent compound rimonabant, suppresses macrophage infiltration into white adipose tissue, activation of the NLRP3 inflammasome, and production of proinflammatory cytokines in diet-induced obese mice. Moreover, we identified the downstream signaling pathways by which CB1R regulates proinflammatory gene expression. These results suggest that peripheral CB1R blockade improves obesity-induced insulin resistance by suppressing adipose tissue inflammation via the NLRP3 inflammasome.

Disclosure
J. Kim: None. J. Yoon: None. E. Kim: None. S. Yoon: None. W. Kim: None.
Adaptation Process of the Transposed Ileum during Early Postoperative Period after Ileal Transposition
Authors: AHN CHANG HO , OH TAE JUNG , MOON SUN JOON , KWAK SOO HEON , PARK KYONG SOO , CHO YOUNG MIN 
Published: June 2018

The intestine undergoes diverse changes to adapt the altered environment after bariatric surgery, which have various implications in the molecular mechanisms of bariatric surgery. Ileal transposition (IT) is an experimental surgery to investigate the role of the distal ileum in bariatric surgeries. To systematically investigate the gut adaptation process in IT, we performed a gene expression profiling of the transposed ileum compared to the ileum in situ at different postoperative time points. Sprague-Dawley rats fed a chow diet underwent IT or sham surgery. In IT, 10 cm of the distal ileal segment was transposed distal to the Treitz ligament. In sham surgery, the intestine was resected at the same anatomical location and anastomosed in situ. Either 1 or 4 weeks after surgery, total RNA was extracted from the ileal tissue and used for microarray analysis. Principal component analysis showed that the difference between 1 and 4 weeks was the largest. The difference between IT and sham groups were larger at 4 weeks than 1 week. A total of 1792 differentially expressed genes (DEGs) were identified including 659 and 1133 DEGs at 1 and 4 weeks, respectively. Interestingly, only 45 and 24 DEGs were commonly up- or down-regulated at the two time points, remaining 96.1% of DEGs were uniquely regulated at either time points. The network analysis showed that the affected biologic processes were related to structural (cell adhesion and immune responses) and functional (glucose and fatty acid metabolism) adaptations. Up-regulated extracellular proteins and their interacting integrins at 1 week, and cytokines, chemokines and their receptors at 4 weeks were interlinked. In glucose metabolism, up-regulation of GLUT2, HK3 and down-regulation of G6PC suggested enhanced glucose uptake and glycolysis. Collectively, our results suggest that the adaptation process of the transposed ileum dynamically evolve during early postoperative period incorporating structural and functional changes.

Disclosure
C. Ahn: None. T. Oh: None. S. Moon: None. S. Kwak: None. K. Park: None. Y. Cho: None.
Genetic Nicotinamide N-Methyltransferase Deficiency Improves Insulin Sensitivity in DIO Mice
Authors: BRACHS SEBASTIAN , POLACK JAMES , BRACHS MARIA , JAHN-HOFMANN KERSTIN , ELVERT RALF , PFENNINGER ANJA , BÄRENZ FELIX , MARGERIE DANIEL , MAI KNUT , KANNT AIMO , SPRANGER JOACHIM 
Published: June 2018

Nicotinamide N-methyltransferase (NNMT) is expressed in most tissues including muscle, adipose tissue, liver and digestive organs. Recent research suggests the involvement of NNMT in the pathogenesis of obesity, insulin resistance and related metabolic disease. Antisense oligonucleotide (ASO) knockdown in high-fat diet (HFD)-fed mice led to reduced weight gain, relative fat mass, plasma insulin levels and improved glucose tolerance. We tested the hypothesis, that genetic NNMT deletion protects mice on HFD and Western diet (WD) against obesity and explored the metabolic effects of NNMT. Using NNMT ASO treatment and a NNMT knockout mouse (NNMT-/-), we investigate the effects of NNMT deletion on energy metabolism, glucose homeostasis and the development of obesity. We also examined data from a human study concerning NNMT expression and 1-methylnicotinamide (MNA) levels regarding weight reduction. In WD-fed mice, NNMT ASO treatment improved acute glucose tolerance, reduced weight gain and fat mass increase and, consequently, lowered plasma insulin levels. NNMT-/- mice exhibited virtually no MNA but threefold higher nicotinamide levels. Whereas NNMT-/- male and female mice on normal chow revealed no metabolic phenotype, NNMT-/- males on HFD showed improved glucose infusion rates, nearly complete insulin-mediated suppression of endogenous glucose production and an enhanced glucose uptake during a hyperinsulinemic-euglycemic clamp. Furthermore, NNMT-/- females on WD showed reduced weight gain, less fat mass and lower plasma insulin levels compared to controls. While NNMT gene expression in human fat biopsies increased over weight loss, corresponding plasma MNA levels significantly declined after weight reduction, suggesting that other mechanisms rather than adipose NNMT expression modulate circulating MNA levels during weight reduction.
In conclusion, we observed an improvement of basal metabolic parameters and insulin sensitivity in NNMT-deficient mouse models.

Disclosure
S. Brachs: Research Support; Self; Sanofi-Aventis Deutschland GmbH. J. Polack: None. M. Brachs: Research Support; Spouse/Partner; Sanofi. K. Jahn-Hofmann: None. R. Elvert: Employee; Self; Sanofi. A. Pfenninger: None. F. Bärenz: None. D. Margerie: Employee; Self; Sanofi-Aventis Deutschland GmbH. K. Mai: None. A. Kannt: Employee; Self; Sanofi. Stock/Shareholder; Self; Sanofi. J. Spranger: Research Support; Self; Sanofi R&D.
STAT1 Ablation in CD11c+ Cells Protects Mice from Obesity-Induced Insulin Resistance
Authors: ANTONY ANTU KALATHOOKUNNEL , PERRARD XIAOYUAN D. , LIAN ZEQIN , PERRARD JERRY , HENNIGHAUSEN LOTHAR , SMITH CLIFTON W. , BALLANTYNE CHRISTIE M. , WU HUAIZHU 
Published: June 2018

Background: Obesity is a global epidemic and major risk factor for insulin resistance and type 2 diabetes. Obesity is associated with low grade chronic inflammation of adipose tissue (AT). F4/80+CD11c+ macrophages/dendritic cells are increased and polarized into M1-like phenotypes in AT and may contribute to insulin resistance in mouse models of obesity. STAT1 is a transcription factor that play key roles in macrophage polarization into M1-like phenotypes. Hence, we investigated the role of CD11c+ macrophage/dendritic cell STAT1 in obesity-induced AT inflammation and insulin resistance.
Methods: Mice with specific knockout of STAT1 in CD11c+ cells were generated by crossbreeding STAT1 fl/fl and CD11c-Cre mice. CD11c/STAT1 KO and littermate controls were fed either high fat diet (HFD, for 16 weeks) to induce obesity or normal diet (ND) as lean controls. We evaluated body composition, insulin sensitivity, gene expression of inflammatory markers, various immune cells and brown/beige adipogenesis markers in AT.
Results: Perigonadal white AT (PWAT) and body weight were not significantly different between KO and control groups but liver weight and liver-to-body weight ratio were significantly reduced in obese KO mice (p&lt;0.05). STAT1 KO mice on HFD exhibited improved insulin sensitivity examined by insulin tolerance test (p&lt;0.05) and reduced expression of inflammatory markers TNFα, IFNγ, IL-12 and MCP1 in PWAT and subcutaneous AT (SAT) compared to littermate controls (p&lt;0.05). AT immune cell analysis revealed that STAT1 ablation caused a decrease in M1-like proinflammatory polarization and increase in M2-like polarization of F4/80+ macrophages, reduced number of total CD3+ T cells and CD8+T cells in PWAT. In addition, brown/beige adipogenesis markers UCP1, CIDEA and Prdm16 also upregulated (p&lt;0.05) in SAT of obese KO mice.
Conclusion: Our results show the critical role of macrophage/dendritic cell STAT1 in obesity-induced AT inflammation and insulin resistance.

Disclosure
A. Kalathookunnel Antony: None. X.D. Perrard: None. Z. Lian: None. J. Perrard: None. L. Hennighausen: None. C.W. Smith: None. C.M. Ballantyne: Research Support; Self; Abbott, Amarin Corporation, Amgen Inc., Esperion Therapeutics, Ionis Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Regeneron Pharmaceuticals, Inc., Roche Diagnostics Corporation, Sanofi. Consultant; Self; Abbott, Amarin Corporation, Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Esperion Therapeutics, Ionis Pharmaceuticals, Inc., Matinas BioPharma, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Regeneron Pharmaceuticals, Inc., Roche Diagnostics Corporation, Sanofi. H. Wu: None.
Challenging the Adipocyte Color Barrier—TR Activation Elicits White to Beige Transdifferentiation Independent of Beta-Adrenergic Signaling
Authors: XIA YAN , LIANG XIAOFEI , LEE MARK E. , PHILLIPS KEVIN 
Published: June 2018

Induction of beige adipocytes, or brown-like adipocytes, in white adipose tissues (WAT) has become an alluring possibility to combat diabetes and metabolic diseases. Beige adipocytes express abundant UCP1 protein and exert energy dissipating and thermogenic functions similar to brown adipocytes. In this study, we compared the beiging effects of a synthetic thyroid hormone receptor (TR) agonist, GC1, with the beta-adrenergic receptor (β-AR) agonist CL316243, which is generally accepted as the most efficacious beiging agent, and explored mechanistic similarities and distinctions between the two compounds in a variety of in vitro cell models.
Here we show that GC1 induces beiging, in cultured adipocytes derived from inguinal WAT, to a much greater extent than CL316243; in addition, TR activation by GC1 is sufficient to induce beiging in a variety of viscerally derived white adipocytes, as well as 3T3-L1 cells, actions which CL316243 is incapable of. Both GC1 and CL316243 increased expression of ATGL and p-HSL, two key lipases known to be necessary for the activation of UCP1-mediated uncoupling and thermogenesis, although GC1 increased these proteins to a higher extent. Enzymes involved in lipid beta-oxidation, such as ACC/p-ACC and LCAD, are also much more markedly enhanced in GC1-treated cells than those treated with CL316243. Interestingly, the loss of all β-ARs, does not affect the ability of TR activation to elicit beiging, demonstrating that TR agonism induces beiging by novel mechanisms that are independent of beta-adrenergic signaling. Thus, select TR agonists appear to be sufficient to elicit beiging in a fashion that appears to be mechanistically distinct from perhaps all other known beiging agents (nearly all of which require β-AR signaling), making them important tools in assessing the therapeutic potential of beige fat activation to treat diabetes and metabolic disease.

Disclosure
Y. Xia: None. X. Liang: None. M.E. Lee: None. K. Phillips: None.
Resistin Is Associated with Blood-Brain Barrier Disruption in Mice Resistant to Diet-Induced Obesity and Treated with Topiramate
Authors: SALAMEH THERESE S. , MORTELL WILLIAM , BANKS WILLIAM A. 
Published: June 2018

Resistin has been linked to diabetes, obesity, insulin resistance, atherosclerosis, and the development of cardiovascular disease. However, the effects and the molecular mechanisms of resistin on endothelial permeability, a key event in the development of atherosclerosis, inflammation, and vascular disease, have not been fully elucidated. Diabetes is associated with changes in the brain microvasculature leading to dysfunction and disruption of the blood-brain barrier (BBB), a specialized system of microvascular endothelial cells protecting the brain from toxic substances in circulation, while permitting CNS entry of nutrients and endocrine signals using active transport mechanisms and passive diffusion. As diabetes is associated with cognitive impairment, understanding the molecular mechanisms of endothelial permeability in the brain is important in developing appropriate therapeutic agents. Topiramate (TPM), a mitochondrial carbonic anhydrase inhibitor, prevents BBB disruption in mouse models of type I and II diabetes. Mice resistant to the development of diet-induced obesity, when treated with TPM, had increased serum levels of resistin and increased BBB permeability to all brain regions except the hippocampus and hypothalamus, brain regions paradoxically disrupted in models of type II diabetes. In vitro treatment of brain endothelial cells with resistin demonstrated a decrease in endothelial nitric oxide synthase (eNOS) along with increased permeability and decreased TEER, a measure of electrical resistance across a cell monolayer. This increase in permeability occurs because diet-resistant mice treated with TPM are unable to attenuate the effects of hyperglycemia-induced oxidative stress and inflammation. Topiramate, which is protective of the BBB in types I and II diabetes, seems paradoxically toxic to the BBB in mice resistant to diet-induced obesity and this toxicity is associated with increases in serum resistin.

Disclosure
T.S. Salameh: None. W. Mortell: None. W.A. Banks: None.
Insulin Resistance and In Vivo Lipolytic Rate Are Positively Associated with Body Iron Stores in Obese Women
Authors: RYAN BENJAMIN J. , VAN PELT DOUGLAS W. , GUTH LISA M. , LUDZKI ALISON , GIOSCIA-RYAN RACHEL A. , AHN CHIWOON , HOROWITZ JEFFREY F. 
Published: June 2018

High body iron stores are positively related to insulin resistance in humans, but the underlying mechanisms remain unresolved. Iron stimulates lipolysis in murine adipocytes in vitro, but the influence of iron stores on lipolytic rate in vivo is unknown. Our aim was to determine if body iron stores are associated with lipolytic rate and whole-body insulin sensitivity in obese, pre-menopausal women. We studied 20 subjects with clinically-normal (20-200 ng/mL) plasma [ferritin], an index of body iron stores. Fatty acid rate of appearance into systemic circulation (FA Ra) was assessed by 13C-palmitate isotope dilution, insulin resistance was assessed by hyperinsulinemic-euglycemic clamp, and abdominal subcutaneous adipose tissue protein expression was assessed via immunoblot. [Ferritin] was significantly (p &lt; 0.01), positively correlated with FA Ra (r2 = 0.42), adipose hormone sensitive lipaseser660 phosphorylation (p-HSLser660, a marker of lipolytic activation in adipose tissue; r2 = 0.41), and whole-body insulin resistance (r2 = 0.33). Importantly, [ferritin] remained a significant, independent predictor for these parameters in multiple regression models including body mass index, plasma [adiponectin], and plasma [CRP] as covariates. We stratified subjects into tertiles based on [ferritin] to compare high-normal and low-normal [ferritin] groups (138 ± 30 vs. 40 ± 15 ng/mL). Compared with the low-normal [ferritin] group, the high-normal [ferritin] group had significantly (p &lt; 0.02) higher FA Ra (15.6 ± 5.5 vs. 8.8 ± 2.4 µmol/kg fat mass/min), adipose p-HSLser660 (1.3 ± 0.4 vs. 0.6 ± 0.2 AU) and whole-body insulin resistance (glucose infusion rate 9.2 ± 2.3 vs. 14.3 ± 3.5 mg/kg fat free mass/min). There were no between-group differences in anthropometric characteristics, plasma [adiponectin], or plasma [CRP]. Our findings suggest that iron-mediated activation of adipose lipolysis may be a mechanism linking body iron stores and insulin resistance in obese humans.

Disclosure
B.J. Ryan: None. D.W. Van Pelt: None. L.M. Guth: None. A. Ludzki: None. R.A. Gioscia-Ryan: None. C. Ahn: None. J.F. Horowitz: None.