bluuebunny/crossref_metadata_2025_split huggingface dataset:
302-LB: Mild Mitochondrial Stress in POMC Neurons Promotes Thermogenesis in Inguinal White Adipose Tissues and Prevents Diet-Induced Obesity
Authors: KIM SEONG JUN , MIN SE HEE , KANG GIL MYOUNG , KIM JI YE , CHOI JONG HAN , KIM MIN-SEON 
Published: June 2019

Mild mitochondrial stress in POMC neurons promotes thermogenesis in inguinal white adipose tissues and prevents diet-induced obesity.
Normal mitochondrial dynamics and functions in hypothalamic neurons are pivotal in the maintenance of systemic energy homeostasis. CRIF1 has been identified as a mito-ribosomal protein which critically mediates incorporation of mitochondrial DNA (mtDNA)-encoded oxidative phosphorylation (OXPHOS) polypeptides into the inner mitochondrial membrane. Complete loss of CRIF1 in neurons causes severe OXPHOS dysfunction and leads to a neuronal death. To study the impact of mitochondrial stress in hypothalamic proopiomelanocortin (POMC) neurons, we generated a mice model lacking CRIF1 expression specifically in the POMC neurons using cre-lox system. Both male and female POMC-cre; CRIF1f/f mice developed obesity since the 10-15 weeks of age due to a gradual loss of POMC neurons. Unexpectedly, energy expenditure and thermogenesis were enhanced in POMC-cre; CRIF1+/f mice compared to their wild littermates. Moreover, they were resistance to diet-induced obesity when exposed to a high fat diet (HFD) before the 10 weeks of age. For the mechanism of enhanced thermogenesis, we found increased UCP1 expression and brown adipocyte-like cells in the inguinal subcutaneous white adipose tissue (ingWAT), so called "browning of subcutaneous fat depot." More strikingly, the expression of mitochondrial unfolded protein response (UPRmt) markers was significantly increased in the ingWAT of POMC-cre; CRIF1+/f mice. These findings strongly suggest that mild mitochondrial stress in POMC neurons causes mitochondrial stress response in the remote organ (ingWAT) via unidentified cell-non-autonomous mechanisms, leading to increased thermogenic activity in this fat depot.

Disclosure
S. Kim: None. S. Min: None. G. Kang: None. J. Kim: None. J. Choi: None. M. Kim: None.

Funding
National Research Foundation of Korea (NRF-2013M3C7A1056024)
307-OR: Interaction of Diabetes Genetic Risk and Successful Lifestyle Modification in the Diabetes Prevention Program
Authors: RAGHAVAN SRIDHARAN , JABLONSKI KATHLEEN A. , DELAHANTY LINDA M. , MARUTHUR NISA , LEONG AARON , FRANKS PAUL W. , KNOWLER WILLIAM C. , FLOREZ JOSE C. , DABELEA DANA ,   DPP RESEARCH GROUP
Published: June 2019

Intensive lifestyle intervention (ILS) targeting diet, physical activity (PA), and weight loss is efficacious for diabetes mellitus (DM) prevention, but not all high-risk individuals benefit. We tested whether DM genetic risk helps identify persons for whom ILS had a greater influence on DM risk. We studied 823 individuals in the ILS arm of the Diabetes Prevention Program with genetic and lifestyle data who were free of DM at one year after study enrollment. We estimated the associations of a DM genetic risk score (GRS) based on 67 loci from a recent genome-wide association study and achievement of three ILS goals at one year (7% weight loss, 150 minutes/week of self-reported moderate to strenuous leisure-time PA, and a goal for self-reported daily total fat intake) with incident DM using multivariable proportional hazards regression, including multiplicative interaction terms (i.e., on rate ratios) between GRS and each ILS goal. We used multivariable Poisson regression to estimate absolute risk reduction (ARR) in DM from ILS goal achievement across tertiles of the GRS, including tests for additive interaction (i.e., on rate differences) between GRS and each ILS goal. The GRS, and achieving each ILS goal and achieving all three ILS goals were associated with incident DM (all p&lt;0.05; mean follow-up 3.0 years). There were no significant multiplicative interactions between GRS and achievement of any or all ILS goals. There were significant additive interactions between GRS and achievement of the weight loss (p&lt;0.001), PA (p=0.03), and all three ILS goals (p&lt;0.001). The ARR in incident DM associated with achievement of all three ILS goals increased across GRS tertiles: 1.8 [0.3, 3.4], 3.1 [1.5, 4.7], 3.9 [1.6, 6.2] fewer DM cases/100-person-years from the 1st to 3rd tertile. Genetic risk may identify high-risk subgroups for whom successful lifestyle modification is associated with greater absolute risk reduction of DM and a lower number needed to treat with lifestyle interventions.

Disclosure
S. Raghavan: None. K.A. Jablonski: None. L.M. Delahanty: Advisory Panel; Self; Jana Care Inc., Omada Health, Inc., Weight Watchers International, Inc. N. Maruthur: Other Relationship; Self; Johns Hopkins HealthCare Solutions. A. Leong: None. P.W. Franks: Board Member; Self; Zoe Ltd. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Novo Nordisk A/S, Novo Nordisk Foundation, Sanofi, Servier. W.C. Knowler: None. J.C. Florez: None. D. Dabelea: None. DPP Research Group: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases
31-OR: Skeletal Muscle Drp1 Maintains Metabolic Homeostasis through Preserving Mitochondrial Complex II Function
Authors: ZHOU ZHENQI , HEVENER ANDREA L. 
Published: June 2019

Dynamin-related protein 1 (Drp1) is a primary mediator of mitochondrial fission, the process of dividing an individual mitochondrion into two organelles. We have previously shown that Drp1 expression is reduced in muscle of dysglycemic men compared to healthy normoglycemic men at rest and during exercise. Moreover, our laboratory has observed mitochondrial fission incompetence in several mouse models of skeletal muscle insulin resistance. To determine whether mitochondrial fission incompetence alters muscle metabolism and insulin action, we generated two mouse models with muscle-selective conventional and inducible deletion alleles of Drp1 (mDrp1KO and miDrp1KO respectively). Muscle deletion of Drp1 reduced fatty acid oxidation, promoted the accumulation of myocellular lipids, elevated the respiratory exchange ratio (RER) assessed by indirect calorimetry, and impaired insulin action. Examination of mitochondria from mDrp1KOmuscle using transmission electron microscopy revealed a notably elongated morphology compared to Controlf/f. Moreover, real time respirometry revealed an impairment in mitochondrial complex II activity that was a likely consequence of defective SDH assembly. Complex II assembly factor SDHAF2, required for flavination of the SDHA subunit and complex II activity, was markedly reduced in both Drp1 deletion mouse models and in Drp1 knockdown (KD) myotubes. Using immunoprecipitation approaches in mouse muscle and murine myotubes, we determined that SDHAF2 associates with Drp1, and that this relationship is critical for the translocation of SDHAF2 protein into mitochondria during fission. Pharmacological inhibition of complex II recapitulated the impairment in lipid oxidation and insulin action seen in mDrp1KO and Drp1KD cells. Our findings indicate that Drp1 is critical for fatty acid oxidation and the maintenance of insulin action by controlling the assembly and function of mitochondrial complex II.

Disclosure
Z. Zhou: None. A.L. Hevener: None.

Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK109724)
310-LB: Intracellular Protein Therapy with Truncated SOCS3 Suppresses Obesity
Authors: LEE KUYSOOK 
Published: June 2019

Aim: Therapeutic molecule systemic delivery technology (TSDT), a platform for the discovery/development of new medicinal drugs, is enabled with a new generation of hydrophobic cell-penetrating peptides (CPPs), namely advanced macromolecule transduction domains (aMTDs). Leptin is an adipocyte-derived hormone that suppresses food intake and stimulates energy expenditure, leading to a reduction in stored body fat. However, patients with obesity have high levels of leptin, resulting in expression of suppressor of cytokine signaling (SOCS) 3 which is a negative feedback regulator of janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling initiated by the leptin receptor (ObR). Leptin resistance arises in part from the inhibition of leptin-initiated JAK/STAT signaling by SOCS3 binding to the phosphorylated Tyr-985 of ObR. We developed a cell-permeable, trans-dominant SOCS3 protein (CP-?SOCS3) to antagonize endogenous SOCS3 binding at P-Tyr-985 of ObR for use as an anti-obesity agent.
Method: We have developed CP-?SOCS3 by fusing the SOCS3 SH2-domain (46∼177 AA) to an aMTD sequence and tested the protein for the ability to enhance leptin induced ObR signaling, prolong leptin sensitivity and suppress weight gain in murine obesity models.
Result: CP-?SOCS3 interacted with ObR and enhanced leptin signaling (activation of STAT3) in mouse hypothalamus cells (mHypoA2/21 cells). In addition, CP-?SOCS3 showed 14.9% body weight loss in 14 days (15 mg/kg, daily, IV) in high fat diet-induced obese (DIO) mice. Food intake (33.6%), epididymal fat mass (34.1%) and serum leptin (59.5%) also decreased as compared to the mice treated with diluent. Furthermore, CP-?SOCS3 positively regulated leptin-initiated JAK/STAT signaling in DIO mice.
Conclusion: These results provide further validation of TSDT as a platform to develop protein-based biotherapeutics and suggest that CP-?SOCS3 has potential as a protein-based anti-obesity agent.

Disclosure
K. Lee: None.
313-LB: Weighting Approaches for a Genetic Risk Score and an Oxidative Stress Score for Predicting the Incidence of Obesity in a Korean Population
Authors: KIM MINJOO , JIN YOO HYE , HAN YOUNGMIN , HO LEE JONG 
Published: June 2019

Background/Objectives: We aimed to predict the incidence of obesity in a Korean population using a genetic risk score (GRS) constructed with obesity-related single nucleotide polymorphisms (SNPs) along with an oxidative stress score (OSS).
Subjects/Methods: A total of 9,460 Korean subjects and 356,974 SNPs were included. The GRS was constructed using three significant obesity-related SNP loci, and the OSS was calculated with three reliable oxidative stress biomarkers.
Results: In an association study, the top three SNPs, rs2846412, rs58424360, and rs591120, showed profound associations with obesity in a Korean population (all FDR &lt; 0.1). The GRS showed a more significant association with increased obesity (OR = 2.879, 95% CI = 2.283-3.630) than individual SNPs did after adjusting for age and sex. Three oxidative stress biomarkers, including malondialdehyde (MDA), oxidized low-density lipoprotein (ox-LDL), and 8-epi-prostaglandin F2α (8-epi-PGF2α), showed significantly high levels in the obese group. Moreover, the OSS, which was the sum of each oxidative stress biomarker score, showed a markedly high association with the incidence of obesity, with an OR of 3.213 (p = 3.57E-18). Based on the results from the regression tests and a receiver-operating characteristic (ROC) curve analysis, we found that HOMA-IR, hs-CRP, the GRS, and the OSS were the most relevant factors for the incremental risk of obesity and were significantly associated with the incidence of obesity. The area under the ROC curve (AUROC) was improved when the GRS was added to the model with the OSS and two obesity-related parameters (from 74.2% to 75.1%).
Conclusions: We first identified that subjects with an obesity GRS and a high OSS may have a higher risk of obesity. Our findings and weighting approaches were effective in predicting the incidence of obesity; furthermore, the GRS is a relevant factor that significantly predicts the risk of obesity.

Disclosure
M. Kim: None. H. Yoo: None. Y. Han: None. J. Lee: None.

Funding
Korean Ministry of Health and Welfare (HI13C0715); Korean National Research Foundation (NRF-2017R1C1B2007195, NRF-2012M3A9C4048762)
313-OR: PACAP from the Ventromedial Hypothalamic Nucleus Controls Both Energy Balance and Glucose Homeostasis
Authors: BOZADJIEVA NADEJDA , ROSS RACHEL A. , LOWELL BRADFORD , FLAK JONATHAN N. 
Published: June 2019

Obesity results from energy imbalance, due, at least in part, to suppressed energy expenditure. While the brain tunes energy expenditure, the neurocircuits, and essential components within these circuits, that can accelerate and decelerate energy consumption have not yet been revealed in great detail. The ventromedial hypothalamic nucleus (VMN) is a critical site for the control of sympathetic tone, which controls a range of physiologic indices including energy expenditure. While the VMN contains, almost exclusively, glutamatergic neurons, neuropeptides are also expressed within the nucleus. Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) is the most abundant neuropeptide in the VMN. Since previous studies have implicated PACAPVMN in responses to energy status, we hypothesized that PACAPVMN is necessary for energy balance by promoting energy expenditure. We acquired a PACAPflox mice that, in the presence of cre, results in a truncated protein, preventing communication downstream by PACAP. Because PACAP is expressed in the periphery, we administered a VMN injection of AAVcre in PACAPflox mice. Bilateral AAVcre administration ablated dmVMN PACAP expression. We found that, in both male and female mice, loss of PACAPVMN results in massive obesity, adiposity, and hyperglycemia. Surprisingly, food intake only increased once body weight had almost doubled. In support of this notion, PACAPVMNKO suppressed VO2 and not activity, despite massive obesity. In addition to energy imbalance, PACAPVMNKO induced hyperinsulinemia and suppressed glucose clearance to brown adipose tissue, heart, and muscle during hyperinsulinemic/euglycemic clamp. Our data demonstrate that PACAP is an essential component for the promotion of energy expenditure and glucose clearance by the VMN. Future studies will reveal both the VMN cells that use PACAP for these functions, as well as the downstream cells that control energy balance and glucose homeostasis.

Disclosure
N. Bozadjieva: None. R.A. Ross: None. B. Lowell: None. J.N. Flak: Research Support; Self; Novo Nordisk Inc.

Funding
American Diabetes Association/Pathway to Stop Diabetes (1-17-INI-15 to J.N.F.)
314-LB: Dapagliflozin Induced Weight Loss and Metabolic Effects in Conjunction with a Low Carbohydrate Diet
Authors: HANSON PETRA , RANDEVA HARPAL , BARBER THOMAS M. , OHARE JOSEPH P. 
Published: June 2019

Type 2 diabetes mellitus (T2DM) is closely associated with obesity. Lifestyle modification, including dietary modification, leads to weight loss, a crucial part of management of patients with T2DM. Evidence shows that treatment with Dapagliflozin leads to weight loss. However, there is a lack of in-depth studies exploring the body composition changes induced by Dapagliflozin in patients following low carbohydrate diet. Our aim was to undertake a detailed assessment of the appetitive and metabolic effects of Dapagliflozin in patients with T2DM. Participants had detailed metabolic studies, including indirect calorimetry (energy expenditure measurements), appetite assessment and quantification of body fat using BodPod in the Human Metabolism Research Unit; University Hospitals of Coventry and Warwickshire (UHCW), UK. The study duration is for 12 months; interestingly, preliminary data from 10 participants who completed 6 months follow-up showed statistically significant weight loss of 5.7 kg at month 6 (Figure 1). There was significant decrease in fat mass observed at month 3 (6.3kg) with no difference in muscle mass. There was no difference in energy expenditure before and after 12 months treatment with dapagliflozin. There was no change in self-reported appetite. These results indicate that low carbohydrate diet improves Dapagliflozin's potential for weight loss, with fat loss in particular.

Disclosure
P. Hanson: Other Relationship; Self; AstraZeneca, AstraZeneca. H. Randeva: None. T.M. Barber: None. J.P. OHare: None.

Funding
AstraZeneca; University Hospital of Coventry and Warwickshire
315-OR: Two Brown Adipocyte Subpopulations with Distinct Thermogenic Activity Coexist and Undergo Dynamic Interconversions upon Changes in Environmental Temperature
Authors: SONG ANYING , JANG MIN JEE , WU XIWEI , JIANG LEI , SCHERER PHILIPP E. , WANG QIONG 
Published: June 2019

Brown adipose tissue (BAT) exerts beneficial metabolic effects on obesity and insulin resistance. Unmasking the complex physiology of BAT thermogenesis is essential to improve our ability to identify effective therapeutic approaches for metabolic disorders. Utilizing the AdipoChaser mouse, we discovered that there are two subpopulations of “classical” brown adipocytes, adiponectin “low expressers” and “high expressers,” co-existing within the BAT. Single-cell sequencing confirms that there are two brown adipocyte subpopulations that differ by adiponectin expression. Low adiponectin expressers also have lower UCP1 expression. We refer to the adiponectin low expresser as low thermogenic brown adipocyte (BA-L), and adiponectin high expresser as high thermogenic brown adipocyte (BA-H). The BA-L has larger lipid droplets, lower mitochondrial content, and higher mitochondrial membrane potential, reflecting reduced thermogenic activity. The BA-H subpopulation is enriched of genes involved in lipolysis, fatty acid oxidation, glycolysis, and oxidative phosphorylation; while the BA-L subpopulation is enriched of genes involved in fatty acid uptake and cell-to-cell trafficking. Upon changes in environmental temperature, the two brown adipocyte subpopulations undergo dynamic inter-conversions. Cold exposure converts BA-L into BA-H, while a thermoneutral environment does the opposite. Developmentally, brown adipocytes initiate differentiation between embryonic day 10 and 16 and they uniformly develop into BA-H. The BA-L subpopulation emerges postnatally. Importantly, the conversion of BA-L into BA-H upon cold exposure is impaired by age, but not by high fat diet feeding. Our results reveal the functional heterogeneity of brown adipocytes. Rather than being uniformly regulated, the thermogenic activity of BAT is controlled by the number of brown adipocytes recruitable into the BA-H pool.

Disclosure
A. Song: None. M. Jang: None. X. Wu: None. L. Jiang: None. P.E. Scherer: None. Q. Wang: None.

Funding
American Diabetes Association (1-19-JDF-023 to Q.W.); National Institutes of Health (K01DK107788R03, HD095414); City of Hope
318-OR: Targeting PPARγ Phosphorylation Prevents Obesity by Inducing a Brown-Like Healthy Remodeling of Adipose Tissue
Authors: RABHI NABIL , FARMER STEPHEN R. 
Published: June 2019

The prevalence of obesity—and thus the incidence of metabolic diseases, including type 2 diabetes and cardiovascular disease—is dramatically increasing worldwide. Despite the critical role of adipose tissues in nutrient metabolism, there are surprisingly few clinically-approved medications targeting adipose tissue. Thiazolidinediones (TZDs), PPARγ agonists are exceptions that act in adipose tissue, but they are associated with adverse effects such as weight gain, and heart failure. An exciting series of studies demonstrate that posttranslational modifications can selectively enhance the insulin sensitizing activity of PPARγ. Our laboratory previously showed that roscovitine (RS), a CDK inhibitor, prevents diet-induced obesity by blocking PPARγ S273 phosphorylation, which promotes formation of UCP1+ (brite) adipocytes in WAT. RNA profiling reveals that brite adipocytes are distinct from beige adipocytes, which arise through catecholamine signaling suggesting that brown-like adipocytes in WAT may arise from multiple origins. Using adipocytes and progenitor’s lineage tracing mice, we demonstrate that brite adipocytes originate from mature white adipocytes through trans-differentiation. Inhibition of S273 phosphorylation of PPARγ in obese mice prevents weight gain, restores insulin and glucose sensitivity and a normal pancreatic β-cells response to glucose as well as prevents liver steatosis and adipocytes formation in bone. Moreover, mass spectrometry analysis of extracellular matrix proteins showed a reduced adipose tissues fibrosis following RS treatment. Mechanistically, inhibition of PPARγ phosphorylation shifts its interaction with cofactors favoring a brown-like healthy remodeling of adipose tissue, which includes suppression of genes associated with inflammation and fibrosis. Overall, we demonstrate targeting PPARγ phosphorylation using RS can constitute a new therapy for obesity and its metabolic complications.

Disclosure
N. Rabhi: None. S.R. Farmer: None.

Funding
American Heart Association (17POST33660875); Francophone Society of Diabetes (R01DK102199-01)
323-LB: Activation of the GLP-1 Receptor Signaling Prevents Beta-Cell Dedifferentiation in a Mouse Model of Wolfram Syndrome through Modulating TXNIP Expression
Authors: TANABE KATSUYA , AMO-SHIINOKI KIKUKO , HATANAKA MASAYUKI , TANIZAWA YUKIO 
Published: June 2019

Loss of functional β cells results in a gradual progression of insulin insufficiency in Wolfram syndrome caused by recessive WFS1 mutations. Currently, there are no specific treatment recommendations for the disease. We have so far evidenced that, in the Wfs1-/- mice, β cells become dedifferentiated and revert to endocrine progenitor-like cells expressing Ngn3, and a subset of β cells takes α cell fate. Such β cell plasticity appears after nursing, independently of hyperglycaemia, and becomes more apparent along with diabetes progression accompanied with no significant increase in apoptosis. In this study, we examined the potential effects of a GLP-1 receptor agonist on β cell plasticity and glucose homeostasis in young Wfs1−/− mice without noticeable hyperglycaemia.
Results: Four weeks administration of Ex-4 resulted in an off-drug amelioration of glucose excursions after glucose loading in Wfs1−/− mice, with insulin secretory dynamics that were indistinguishable from those in WT mice, despite no alteration in beta cell mass. In association with the functional improvements, Ex-4 alleviated β cell dedifferentiation evidenced by a decrease of MafA and a Ngn3 emergence. At the same time, Ex-4 reversed a robust increase in thioredoxin interacting protein (TXNIP) in Wfs1-/- β cells. Mechanistically, Ex-4 suppressed it at both transcriptional and post-translational levels. Furthermore, we have found that genetic ablation of Txnip in Wfs1-/- mice inhibited β cell dedifferentiation, resulting in prevention of diabetes progression with preservation of β cell mass. Our finding implies that activation of the GLP-1 receptor signaling may prevent β cells from becoming dedifferentiated by modulating Txnip and may slow diabetes progression in Wolfram syndrome.

Disclosure
K. Tanabe: None. K. Amo-Shiinoki: None. M. Hatanaka: None. Y. Tanizawa: None.

Funding
Japan Society for the Promotion of Science (16K09752, 15K21198, 15K09390); Japan Diabetes Society; Japan Association for Diabetes Education and Care