bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glucagon-Receptor Signaling Regulates Mitochondrial Bioenergetics via Hepatic Farnesol X Receptor
Authors: KIM TEAYOUN , NASON SHELLY , ANTIPENKO JESSICA P. , VESTRI CATHERINA S. , SMITH-JOHNSTON KELLEY , PEPIN MARK E. , WENDE ADAM R. , FINAN BRIAN , DIMARCHI RICHARD , PEREZ-TILVE DIEGO , MOELLERING DOUGLAS R. , HABEGGER KIRK M. 
Published: June 2018

Glucagon, an essential regulator of glucose and lipid metabolism, also promotes weight loss. We have identified that the hepatic Farnesol X Receptor (FXR) plays an important role in an anti-obesogenic effect of glucagon receptor (GcgR) agonism. Chronic administration of IUB288, a potent GcgR agonist, significantly reduced diet-induced obesity (DIO) in wild type (WT, 17%) mice compared to (FXR∆liver, 6%) liver-specific FXR knock-out mice. Weight loss was associated with increased energy expenditure (p&lt;0.05) and fat oxidation (reduced RQ, p&lt;0.05). We hypothesized that GcgR agonism alters mitochondrial bioenergetics, at least in part, through hepatic FXR signaling. IUB288 treatment increased body temperature (p&lt;0.05) and [14C]-palmitate oxidation capacity of liver homogenate (p&lt;0.05) to a greater extent in DIO WT mice than in FXR∆liver mice. RNA-Seq analysis of DIO liver samples revealed that the mitochondrial oxidative phosphorylation pathway, fatty acid metabolism, and bile acid metabolism were enriched in WT treated with IUB288, but not in FXR∆liver mice. Liver slices isolated from WT mice treated with IUB288 for two days significantly increased state 3 respiration rates compared to FXR∆liver mice using high resolution respirometry. Respiration was increased utilizing both carbohydrate (pyruvate, malate, glutamate, and succinate) and lipid substrates (palmitoyl-carnitine), suggesting GcgR-agonism modulates hepatic mitochondrial respiration via FXR. Our study elucidates a molecular mechanism of the anti-obesogenic effect of GcgR signaling. This heretofore-unappreciated aspect of glucagon biology has implications for the use of GcgR agonism in therapeutic strategies for multiple components of the metabolic syndrome.

Disclosure
T. Kim: None. S. Nason: None. J.P. Antipenko: None. C.S. Vestri: None. K. Smith-Johnston: None. M.E. Pepin: None. A.R. Wende: None. B. Finan: Employee; Self; Novo Nordisk Inc. R. DiMarchi: Employee; Self; Novo Nordisk Inc. D. Perez-Tilve: Research Support; Self; Novo Nordisk A/S, Cohbar. D.R. Moellering: None. K.M. Habegger: Consultant; Self; Glyscend, Inc.. Research Support; Self; Glyscend, Inc.. Consultant; Self; Intarcia Therapeutics, Inc..
Vitamin D3 Alleviates High-Fat Diet–Induced Endoplasmic Reticulum Stress and Insulin Resistance in Mice
Authors: LIU LU , LI XIAOHUA 
Published: June 2018

Endoplasmic reticulum stress (ERs) may be a key mechanism for the connection of obesity, chronic inflammation, and insulin resistance (IR). As we know, vitamin D3 deficiency is prevalent in obese patients, and it may be an independent risk factor for obesity-induced IR and type 2 diabetes mellitus (T2DM). However, the effects of vitamin D3 on ERs, inflammatory response, and IR were still unknown. This study investigate the effects of vitamin D3 on ERs, inflammatory response, and IR in high-fat-diet (HFD) induced obese mice. Eighty male C57BL/6 mice were randomly divided into four group, including control group (n = 20), HFD group, HFD + low dose (50 IU/kg) of vitamin D3 group (VitD-L), HFD + high dose (250 IU/kg) of vitamin D3 group (VitD-H). The control group was fed with common feed, and the other groups were fed with HFD. After the establishment of the obesity model, the mice in experimental group was fed with different dose of vitamin D3 for 1 week. Then western blot was used to detect the protein expression level of Bip, IRE1, PERK and NF-κB in adipose tissue; serum levels of TNF-α, IL-6, serum 25-hydroxyvitamin D3, fasting blood glucose, glycosylated hemoglobin, triacylglyceride and fasting insulin were measured and the insulin resistance index was calculated. The results indicated that vitamin D3 in both low and high dose could significantly down-regulate the expression level of Bip, IRE1 and PERK, and decrease the expression levels of NF-κB, TNF-α, and IL-6 (p &lt; 0.05). It could also significantly decrease the levels of fasting blood glucose, glycosylated hemoglobin, triacylglyceride and fasting insulin in obese mice (p &lt; 0.05), and significantly alleviate the insulin resistance phenomenon in obese mice. The results indicated that vitamin D3 supplementation could reduce the synthesis and release of inflammatory factors, alleviate endoplasmic reticulum stress and insulin resistance.

Disclosure
L. Liu: None. X. Li: None.
Mortality Risk in Adults With and Without Type 2 Diabetes after 18 Years of Follow-up in Northern Spain—The Asturias Study
Authors: ARES JESSICA , VALDES SERGIO , BOTAS PATRICIA , SÁNCHEZ-RAGNARSSON CECILIA , MENÉNDEZ-TORRE EDELMIRO , DELGADO ELIAS 
Published: June 2018

Objective: People who develop type 2 diabetes (T2D) have higher mortality risk. Regarding Asturias Study, after 18 years of follow-up, we have estimated all-cause, cardiovascular and cancer mortality-risks according to categories of impaired glucose metabolism.
Research Design and Methods: Asturias study (launched in 1998) included a mortality follow-up of 18 years of its regionwide sample representative of population aged 30-75 years. Age and sex- stratified hazard ratios (HR) were calculated for 48 participants with diagnosed T2D (self reported diagnosis or antidiabetic medication), 83 with undiagnosed T2D (no diagnosed T2D, glycated hemoglobin A1c ≥6,5%, fasting glycemia≥126 mg/dL or glycemia after 75g glucose load ≥200 mg/dL), 296 with prediabetes (glycated hemoglobin A1c 5,7-6,4%, fasting glycemia 100-125 mg/dL or glycemia after 75g glucose load 140-199 mg/dL) and 607 with normoglycemia.
Results: Over 18,612 person-years, 204 people died (32 with undiagnosed T2D, 30 with diagnosed T2D, 62 with prediabetes and 80 with normoglycemia). HR for all cause mortality, adjusted by previous cardiovascular disease, history of high blood pressure, LDL cholesterol level, age, sex, BMI and estimate glomerular filtration rate, was 2.22 (1.42-3.48) for diagnosed T2D, 1.57 (1.03-2.39) for undiagnosed diabetes. Adjusted hazard ratio for cardiovascular mortality was 3.12 (1.55-6.29) for diagnosed T2D and, for cancer mortality, was 1.83 (0.79-4.22) vs. normoglycemia. Women with T2D have higher age-standarized cardiovascular-mortality risk than men with T2D (7.36 (2,84-19.09) vs. 1.58 (1.45-5.56)). People with prediabetes have similar mortality risks as people with normoglycemia.
Conclusions: In Asturias, age and sex-standardized all-cause mortality is more than two times higher for adults with T2D than for adults without T2D. HR for cardiovascular mortality is highly increased in women with T2D comparing with men with the same condition.

Disclosure
J. Ares: Research Support; Self; Sanofi. S. Valdes: None. P. Botas: None. C. Sánchez-Ragnarsson: None. E. Menéndez-Torre: Speaker's Bureau; Self; Sanofi, AstraZeneca, Novo Nordisk A/S. E. Delgado: Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca, Novo Nordisk A/S. Advisory Panel; Self; Sanofi-Aventis. Speaker's Bureau; Self; Sanofi-Aventis. Research Support; Self; Sanofi-Aventis. Speaker's Bureau; Self; Esteve, Boehringer Ingelheim Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Abbott. Speaker's Bureau; Self; Lilly. Research Support; Self; Menarini Group.
Bofutsushosan Improves Gut Barrier Function with a Bloom of Akkermansia Muciniphila and Improves Glucose Metabolism in Diet-Induced Obese Mice
Authors: FUJISAKA SHIHO , USUI ISAO , NAWAZ ALLAH , IGARASHI YOSHIKO , KADO TOMONOBU , OKABE KEISUKE , YAGI KUNIMASA , NAKAGAWA TAKASHI , TOBE KAZUYUKI 
Published: June 2018

Bofutsushosan (BFT), an oriental herbal medicine, has been clinically used for obese patients. To explore the impact of BFT on glucose metabolism, male C57BL6 mice were fed on high-fat diet (HFD) for 12 weeks and administered either BFT (25 mg /day) or saline for the last 8 weeks. Oral glucose tolerance test and insulin tolerance test revealed improved glucose metabolism with improved insulin sensitivity in BFT treated mice, which was associated with decreased inflammatory gene expressions and improved insulin signaling in the adipose tissue. Whereas the weight of liver and adipose tissue was not changed, cecum weight was significantly increased by BFT. 16S rRNA sequence analysis of fecal samples showed that microbial composition was markedly changed. BFT reduced the relative abundance of Bacteroidetes from 52% to 34%, whereas it increased Verrucomicrobia from 3.4% to 24%. An increase in Verrucomicrobia was mainly associated with Akkermansia mucuniphila (Akk). The bloom of Akk was observed at one week of BFT treatment. Consistent with the previous reports that Akk improves gut barrier function and prevents from metabolic endotoxemia in obese subjects, BFT decreased the gut permeability as assessed by FITC-dextran gavage assay, which was associated with increased claudin-1 protein in the colon. Furthermore, plasma endotoxin level and hepatic lipopolysaccharide binding protein expression were significantly decreased in BFT group. Antibiotic treatment canceled the metabolic effect of BFT. Moreover, when the gut microbiota of BFT-treated mice were transferred to HFD-fed mice, glucose metabolism was significantly improved with decreased diet -induced inflammation with AKK bloom. These data demonstrate that BFT increases Akk in the gut, which may contribute to improving gut barrier function and preventing metabolic endotoxemia, leading to improved diet-induced inflammation, thereby controlling glucose metabolism.

Disclosure
S. Fujisaka: Research Support; Self; Mochida Pharmaceutical Co., Ltd., Eli Lilly and Company, MSD K.K., Toyama First Bank. I. Usui: None. A. Nawaz: Research Support; Spouse/Partner; Kobayashi Foundation, Kobayashi Foundation, Kobayashi Foundation. Y. Igarashi: None. T. Kado: None. K. Okabe: None. K. Yagi: None. T. Nakagawa: None. K. Tobe: Research Support; Self; Bristol-Myers Squibb Company, Takeda Pharmaceutical Company, Teijin Pharma Limited, Japan Diabetes Society, Eli Lilly and Company, MSD K.K., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Inc., Astellas Parma Inc, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Company, Limited, Novo Nordisk Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Tsumura & Co., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Sumitomo Dainippon Pharma Co.
Over 22 kg/m2 of BMI at Young Age Is a Risk Factor for Future Diabetes in Japanese Men
Authors: SOMEYA YUKI , TAMURA YOSHIFUMI , KOHMURA YOSHIMITSU , AOKI KAZUHIRO , SUZUKI KOYA , KAWAI SACHIO , DAIDA HIROYUKI 
Published: June 2018

Type 2 diabetes (T2DM) is easily developed in Asian adults with normal body mass index (BMI), compared with other ethnicities with similar BMI. For example, it has been shown that slightly increased BMI level (&gt;23 kg/m2) in middle age (around 50 years old) is a risk for development of T2DM in Asians. However, it is still unclear whether slightly elevated BMI at young age within normal BMI range (&lt;25 kg/m2) also increases the risk of T2DM later in life. To clarify this, we investigate the impacts of BMI at young age on development of T2DM later in life by historical cohort study. The study subjects are male alumni who were graduated physical education school in Japan from 1971 to 1991. From 2007 to 2017, a self-administered follow-up questionnaire was sent by mail to the subjects to ask their previous medical diagnosis of diabetes. This study analyzed 657 male alumni and covered 32-year follow-up period (interquartile range: IQR: 27-36) which included 20,607 person-years of observation. Subjects were 22 (22-22) years old at graduated college and 54 (50-59) years old at final follow-up investigation. Median BMI was 22.0 (21.1-23.0) kg/m2 at college age and 23.9 (22.3-25.6) kg/m2 at first follow-up investigation. During the period, 57 men developed diabetes. Then, the participants were categorized into four categories: BMI at college age of &lt;21.0 kg/m2 (n=155), 21.0-22.0kg/m2 (n=172), 22.0-23.0kg/m2 (n=170), and ≥23.0kg/m2 (n=160), and the incidence of diabetes was compared. The prevalence rates of diabetes for lowest to highest BMI categories were 4.5%, 7.6%, 11.2%, and 11.3%, respectively (p=0.10), and their hazard ratios were 1.00 (reference), 1.65 (95% CI: 0.66-4.14), 2.45 (1.02-5.87), and 2.51 (1.05-6.03), respectively (p=0.02 for trend). This trend was similar after adjustment for age, year of graduation, smoking and participation in college sports club. These data suggested that over 22.0kg/m2 of BMI at young age might be a risk factor for future T2DM in Japanese men.

Disclosure
Y. Someya: None. Y. Tamura: None. Y. Kohmura: None. K. Aoki: None. K. Suzuki: None. S. Kawai: None. H. Daida: None.
Zinc Alpha2 Glycoprotein Promotes Browning in Adipocytes
Authors: XIAO XIN-HUA , QI XIAO-YAN , WANG YA-DI , XU CAN-XIN , LIU JIANG-HUA 
Published: June 2018

Recent studies have highlighted recruiting and activating brite adipocytes in WAT (so-called “browning”) would be an attractive anti-obesity strategy. Zinc alpha2 glycoprotein (ZAG) as an important fat-adipokine, is reported to ameliorate glycolipid metabolism and lose body weight in obese mice. However whether the body reducing effect mediated by browning programme remains unclear. Here, we show that overexpression of ZAG in 3T3-L1 adipocytes enhanced expression of brown fat-specific markers (UCP-1, PRDM16 and CIDEA), mitochondrial biogenesis genes (PGC-1α, NRF-1/2 and mtTFA) and the key lipid metabolism lipases (ATGL, HSL, CPT1-A and p-acyl-CoA carboxylase). Additionally, those effects were dramaticlly abolished by H89/SB203580, revealing ZAG-induced browning depend on PKA and p38 MAPK signaling. Overall, our findings suggest that ZAG is a candidate therapeutic agent against obesity via induction of brown fat-like phenotype in white adipocytes.

Disclosure
X. Xiao: None. X. Qi: None. Y. Wang: None. C. Xu: None. J. Liu: None.
LRP1 Regulates Adiposity by Controlling Energy Balance in MC4R Neurons
Authors: KANG MIN-CHEOL , SEO JI A. , CHO HYUNSOO , LEE HYUNNA , KIM YOUNG-BUM 
Published: June 2018

Hypothalamic low-density lipoprotein receptor-related protein 1 (LRP1), a member of LDL receptor family, plays a pivotal role in the regulation of food intake and body-weight homeostasis. However, the role of LRP1 in MC4R-expressing neurons remains unknown. This study was to determine whether deleting LRP1 from MC4R-expressing neurons affects adiposity and energy balance in mice. Here we show that MC4R neuron-specific LRP1 deletion results in decreased body weight in mice fed a normal chow diet (control 30.4±0.8g vs. MC4R-LRP1 deficient mice 27.2±0.5g, p&lt;0.05). Consistent with this, MRI analysis indicated that fat mass in MC4R-LRP1 deficient mice significantly decreased by ∼64% without changes in lean mass, compared with control mice. This occurred despite the fact that MC4R-LRP1 deficient mice are hyperphagic (control 3.99±0.17g vs. MC4R-LRP1 deficient mice 4.71±0.18g, p&lt;0.05). In addition, MTII’s ability to suppress food intake was impaired in MC4R-LRP1 deficient mice. These effects are mainly due to increased energy metabolism, as evidenced by the fact that oxygen consumption for 24 hours increased in MC4R-LRP1 deficient mice compared with control mice (control mice 6002±287 ml/kg/hour vs. MC4R-LRP1 deficient mice 7121±1947 ml/kg/hour, p&lt;0.01), along with exhibiting insulin sensitivity and glucose tolerance. However, locomotor activity was normal in these mice. The current data demonstrate that LRP1 signaling in MC4R neurons is required for the homeostatic regulation of energy expenditure and adiposity. Thus, LRP1 is a key player of energy balance in MC4R-expressing neurons.

Disclosure
M. Kang: None. J.A. Seo: None. H. Cho: None. H. Lee: None. Y. Kim: None.
Hypothalamic Glucose Concentrations Are Higher in Subjects with Type 1 Diabetes (T1D) and Impaired Awareness of Glycemia (IAH) than in T1D without IAH
Authors: MOHEET AMIR , DEELCHAND DINESH , KUMAR ANJALI , OZ GULIN , SEAQUIST ELIZABETH R. 
Published: June 2018

IAH occurs commonly in patients with T1D but its pathogenesis remains uncertain. Previous investigation has suggested that recurrent hypoglycemia leads to an upregulation of brain glucose transport thereby assuring that the brain will have better fuel delivery during subsequent episodes of hypoglycemia. If so, subjects with T1D and IAH should have higher hypothalamic brain glucose concentrations than subjects with T1D without IHA when studied at the same level of glycemia. Here we used 1H-magnetic resonance spectroscopy at 7 T to measure (Glucose+Taurine)/ total Creatine in a 13x12x10 mm3 hypothalamic voxel in such patient groups while they were maintained at euglycemia and then hypoglycemia using a glucose clamp. Since taurine and creatine do not change with glycemia, this is a valid measure of brain glucose concentrations. IAH was defined using the Clarke questionnaire with subjects found indeterminate further classified using the Gold questionnaire. We found that hypothalamic (Glucose+Taurine)/ total Creatine was significantly higher in T1D with IAH at both euglycemia and hypoglycemia when compared to T1D without IAH. These data support the hypothesis that a change in glucose transport may contribute to the pathogenesis of IAH.
T1D with IAH (n=9)T1D without IAH (n=9)Age (years)47.6 ± 1729.2 ± 8Hemoglobin A1c (%)7.3 ± 0.97.3 ± 0.7Glycemia at euglycemia (mg/dl)98 ± 495 ± 7Glycemia during hypoglycemia (mg/dl)48 ± 348 ± 5Epinephrine during hypoglycemia (pg/ml)250 ± 155711±442*Symptom score during hypoglycemia8 ± 936 ± 14**Hypothalamic glucose at euglycemia (Glucose+Taurine)/ total Creatine (mM)0.43 ± 0.110.27 ± 0.08**Hypothalamic glucose at hypoglycemia (Glucose+Taurine)/ total Creatine (mM)0.23 ± 0.040.15 ± 0.02***p=0.03, **p &lt; 0.001.

Disclosure
A. Moheet: None. D. Deelchand: None. A. Kumar: None. G. Oz: Research Support; Self; Takeda Pharmaceuticals U.S.A., Inc. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company, Sanofi, Zucera, InfoMed, 360 consulting. Other Relationship; Self; Novo Nordisk Inc..
Compound C Protects Mice from Diet-Induced Obesity and Hepatosteatosis
Authors: WANG FANG , YANG WENJUN , XIANG RONG , YUAN JINGJING , LIU YUXING , CHEN KEZHU , MO ZHAOHUI 
Published: June 2018

Introduction and Aims: Obesity and its resulting metabolic disturbances are major health threats and are the main cause of nonalcoholic fatty liver disease (NAFLD). Comound C has been demonstrated to be not only an inhibitor of AMPK, but also has some actions independent of AMPK inhibition. In our previous studies, we unexpectedly found compound C is an anti-inflammatory and anti-NLRP3 inflammasome agent in vitro. The aim of this study was to investigate the effects of compound C on a mouse model of high-fat diet (HFD) (60 kcal% fat)-induced obesity and hepatosteatosis in vivo.
Methods: C57BL/6 mice were fed with either a standard or a HFD for 14 weeks. These mice were divided in three groups [Normal chow, HFD + Vehicle, and HFD + compound C (6 mg/kg i.p., once a day)] and treated for an additional 4 weeks. All animals were weighed weekly and food intakes measured twice weekly. Liver histology as well as pro-inflammatory gene expression in liver and white adipose tissue (WAT) were examined.
Results: There was a significant reduction in body-weight gain and daily food intake in compound C-treated group compared with HFD group (P &lt; 0.05). Glucose tolerance test and insulin tolerance test showed that compound C increased glucose metabolism and alleviated insulin resistance compared with the HFD group. Histology analysis showed a significant reduction of hepatic steatosis and ballooning by compound C. To further characterize the activity of compound C, quantitative RT-PCR analysis of pro-inflammatory markers were performed, demonstrating that compound C significantly reduced IL-1β, IL-18, IL-6 and TNF-a gene expression in the liver as well as in the WAT (P &lt; 0.01). Moreover, NLRP3 inflammasome which plays an important role in obesity and NAFLD was significantly decreased by compound C using western blot assay.
Conclusions: Taken together, these results suggest that compound C offers the potential as a novel therapy for obesity and NAFLD, probably by impairing NLRP3 inflammasome activation and the related inflammasion.

Disclosure
F. Wang: None. W. Yang: None. R. Xiang: None. J. Yuan: None. Y. Liu: None. K. Chen: None. Z. Mo: None.
The Ldb1 Transcriptional Coregulator Is Required for Brown Adipose Development and Function
Authors: KEPPLE JESSICA , LIU YANPING , KIM TEAYOUN , ROWE GLENN C. , HABEGGER KIRK M. , HUNTER CHAD S. 
Published: June 2018

Brown adipose tissue (BAT) is critical for thermogenesis and glucose homeostasis. BAT utilizes fatty acids and glucose for heat production via mitochondrial uncoupling, and is thus an attractive therapeutic target for combatting obesity. Exploiting the energy uncoupling capacity of this tissue requires a greater understanding of underlying BAT transcriptional mechanisms. We recently reported on a transcriptional co-regulator, LIM domain binding protein 1 (Ldb1), which appears to have novel roles in BAT biology. Ldb1 acts as a dimerized scaffold allowing for the assembly of transcriptional complexes and is important for the development and function of many tissues, including the brain and pancreatic islets. However, direct roles for BAT-expressed Ldb1 have not been elucidated. We set out to test the hypothesis that Ldb1 directly impacts BAT development and function. We developed a mouse model in which Ldb1 was deleted in thermogenic adipocytes using an Uncoupling protein 1 (Ucp1)-driven Cre recombinase, termed Ldb1δBAT. These knockout mice had reductions in BAT-selective mRNAs, including Ucp1 and Elovl3, a result similarly observed in X9 beige cell lines lacking Ldb1. Ldb1δBAT mice were unable to defend body temperature during a cold challenge, suggesting thermogenic defects. We also observed glucose intolerance in Ldb1δBAT mice via intraperitoneal glucose challenge. Ldb1 deletion in preadipocytes resulted in reduced Ucp1 expression upon induction to mature adipocytes. These data suggest a direct role for Ldb1 in maintaining thermogenic and metabolic function in BAT, as well as a developmental role in preadipocytes. Additional metabolic and transcriptional profiling of the Ldb1δBAT model will interrogate the mechanisms underlying Ldb1 control of BAT function, potentially leading to novel obesity and diabetes therapeutic targets.

Disclosure
J. Kepple: None. Y. Liu: None. T. Kim: None. G.C. Rowe: None. K.M. Habegger: Consultant; Self; Glyscend, Inc.. Research Support; Self; Glyscend, Inc.. Consultant; Self; Intarcia Therapeutics, Inc.. C.S. Hunter: None.