bluuebunny/crossref_metadata_2025_split huggingface dataset:
73-LB: Tirzepatide 5, 10, and 15 mg vs Injectable Semaglutide 0.5 mg for the Treatment of Type 2 Diabetes—An Indirect Treatment Comparison
Authors: PANTALONE KEVIN M. , TOFE SANTIAGO , FAN LUDI , PAIK JIM S. , RANTA KARI T. , SAPIN HELENE , OSUMILI BEATRICE 
Published: June 2023

Semaglutide (sema) 0.5 mg is part of type 2 diabetes (T2D) standard of care as initial maintenance dose. While there has been a study conducted on TZP and sema 1.0 mg, showing TZP superiority, currently there is no head-to-head study comparing TZP and sema 0.5 mg. Therefore, the objective of this analysis was to evaluate the efficacy and safety of TZP and sema 0.5 mg using adjusted indirect comparisons.
Adjusted indirect comparisons were performed using the Bucher method to compare the relative efficacy and safety of TZP 5, 10, 15 mg and sema 0.5 mg via a common comparator (sema 1.0 mg) based on trial results from SURPASS-2 (TZP vs sema 1.0 mg) and SUSTAIN 7 (sema 0.5 and 1.0 mg vs dulaglutide 0.75 and 1.5 mg).
All TZP doses showed statistically significant greater reductions in HbA1c, weight and BMI from baseline to week 40 compared to sema 0.5 mg (Figure).
TZP demonstrated a comparative safety profile for adverse events (AEs) but patients had statistically significant greater odds of treatment discontinuations due to AEs for TZP 10 and 15 mg. All TZP doses demonstrated no statistically significant differences vs sema 0.5 mg in the odds or likelihood of gastrointestinal AEs.
In these adjusted indirect comparisons the extent of differences between TZP and sema 0.5 mg regarding HbA1c and weight reductions provide insights on their comparative effectiveness in the absence of a head-to-head study.

Disclosure
K. M. Pantalone: Consultant; AstraZeneca, Bayer Inc., Corcept Therapeutics, Diasome, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi, Research Support; Bayer Inc., Merck & Co., Inc., Novo Nordisk, Twin Health, Speaker's Bureau; AstraZeneca, Corcept Therapeutics, Merck & Co., Inc., Novo Nordisk. S. Tofe: Advisory Panel; Lilly, Novo Nordisk, Research Support; Lilly, Novo Nordisk, Speaker's Bureau; Lilly, Novo Nordisk. L. Fan: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. J. S. Paik: None. K. T. Ranta: Employee; Eli Lilly and Company. H. Sapin: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. B. Osumili: Employee; Eli Lilly and Company.

Funding
Eli Lilly and Company
731-P: The Effect of Abatacept upon Glucose and C-Peptide Endpoints at One Year of Treatment and on Follow-up
Authors: SIMS EMILY K. , RUSSELL WILLIAM E. , HEROLD KEVAN C. , SOSENKO JAY 
Published: June 2023

The TrialNet abatacept randomized-controlled trial tested for the ability to delay the progression of T1D in Stage 1 [multiple autoantibody (Ab) positive and normal glucose on OGTT] individuals aged 6-45. No drug effect was detected on the primary endpoint of either dysglycemia or T1D (whichever came first). Based on evidence that C-peptide-based metabolic measures are more specific for T1D and detect an early impact of disease-modifying therapy, we performed post-hoc analyses using these variables and stratified on baseline metabolic profiles. In participants with lower baseline metabolic risk (Index60 &lt;0.00) we assessed if changes in metabolic measures would differ between treatment groups. A favorable effect was evident for the combined glucose and C-peptide endpoints within 1 year of treatment (Table). Next we compared individuals with Index60&lt;0.00 at baseline for exceeding an Index60 threshold of 1.00 on follow-up. 5-year risks were 38.9% for the placebo and 21.1% for the abatacept groups (p=0.016). In summary, for Stage 1 individuals with low baseline metabolic risk, combined glucose and C-peptide endpoints can detect a favorable abatacept effect at 1 year and, more conventionally, a decreased T1D progression risk on follow-up. Future trials of abatacept or other agents in Stage 1 T1D should include combined glucose and C-peptide measures as pre-specified endpoints.

Disclosure
E.K.Sims: Speaker's Bureau; Medscape, American Diabetes Association. W.E.Russell: None. K.C.Herold: Board Member; NexImmune, Consultant; Provention Bio, Inc. J.Sosenko: None.
733-P: Diabetes Remission Outcomes Protocol (DROP)—Early Observation
Authors: KIBAA KARIM , DHAVER SHILTON E. , JOHNSON COLLEEN , VOTTA JENNIE L. , SHAHAR JACQUELINE I. , MITCHELL CHRISTINE , BEATON JOAN M. , SALAH TAREQ , AL-BADRI MARWA , KHATER ABDELRAHMAN , MCCARRAGHER RYAN , HAMDY OSAMA 
Published: June 2023

A 12-week multidisciplinary intensive lifestyle intervention (ILI) was shown to induce diabetes remission (A1C &lt;6.5%, on no medications for ≥3 months), particularly among participants with short diabetes duration. Diabetes remission was also achieved with very low-calorie diet (VLCD) or bariatric surgery. Diabetes Remission Outcomes Protocol (DROP) at Joslin Diabetes Center is an ILI designed to induce diabetes remission in patients with type 2 diabetes who meet 3 criteria: 1- duration of diabetes &lt;5 years, 2- A1C &lt;8%, 3- On up to 2 antihyperglycemic medications, but no insulin. It involves two phases: an intervention phase for 12 weeks and a maintenance phase for 9 months. During intervention phase, participants follow a time-restricted fasting for 16 hours and VLCD (800-1000 Kcal/day). Participants also receive cognitive behavioral support and perform exercises designed to maintain lean muscle mass (LMM). They stop all diabetes medications at the beginning of the program and are monitored by CGM. Reintroduction of medications is suggested if glucose time in range (70-180 mg/dL) (TIR) drops to &lt;70%. During maintenance phase, participants return to 1500-1800 calorie diet with the aim of maintaining weight loss and diabetes remission. We tested feasibility of DROP in a pilot of 5 participants with mean age of 52.8±11.4 years, diabetes duration of 13.2±11.8 months, and A1C of 6.44±0.3% on 2 medications. By the end 12-weeks, average weight loss was 19.9 lbs (8.1%). A1C decreased to 6.14±0.48% (p=0.02) on no medications and TIR was 98%. LMM /total body weight significantly increased by 0.03±0.02 (p=0.03). Patient-reported quality of life measures showed significant improvements in the World Health Organization-5 Well-Being Index (p=0.03), Diabetes Distress Scale-17 (p=0.05) and 36-Item Short Form Survey (p=0.04) submodules. DROP is promising approach to induce diabetes remission and improve patients’ quality of life in selected patients with type 2 diabetes. Larger cohorts should be evaluated for longer duration.

Disclosure
K.Kibaa: None. A.Khater: None. R.Mccarragher: None. O.Hamdy: Advisory Panel; Abbott Nutrition, Nemaura Medical, L-Nutra Inc., Twin Health, Consultant; Sanofi, Research Support; Novo Nordisk, Eli Lilly and Company, Gilead Sciences, Inc., Stock/Shareholder; Healthimation. S.E.Dhaver: None. C.Johnson: None. J.L.Votta: None. J.I.Shahar: None. C.Mitchell: None. J.M.Beaton: None. T.Salah: None. M.Al-badri: None.
742-P: Diabetes Prevention Effect of Practically Applicable Intervention in Clinical Settings Based on the Korean Diabetes Prevention Study (KDPS)
Authors: CHON SUK , JIN YUN SOO , WOO JEONG-TAEK ,   THE KOREAN DIABETES PREVENTION STUDY INVESTIGATORS
Published: June 2023

Background: The Korean Diabetes Prevention Study (KDPS, NCT02981121), a national clinical study to prevent T2DM, started in 2016 and is currently ongoing. This study was to evaluate the preventive effect of KDPS intervention for up to 1 year.
Methods: The enrollment criteria are adults aged 30-70 with a BMI ≥ 23 kg/m2 at high risk of T2DM. Three Intervention methods are hospital-based lifestyle modification (hLSM) developed by Korean Diabetes Association, metformin (MET, 250mg~1000mg) and control standard management (STM) including a visit to the doctor every 6 months. LSM consists of 4 times individual diet interventions and lifestyle modification to keep 10 healthy habits with 7 times on-site and 8 times on phone-call contact. We assessed FPG and A1c every 6 months and OGTT every 12 months to check DM progression.
Results: A total of 1611 subjects at 15 university hospitals performed screening with 75g OGTT (KDPS 1: 2016.11 ~ 2018.12, KDPS 2: 2020.9 ~ 2022.4). Eight hundred forty-four patients (male 44.2%) were randomized. The mean age was 56.1 years, BMI 26.6 kg/m2, WC 91.2 cm, FPG 103.2 mg/dL, PP2G 154.9 mg/dL, A1c 5.9%, and there was no significant difference between the three groups. KDPS 2 had a short follow-up period, thus DM prevention effect of up to 1 year was analyzed in 485 subjects of KDPS 1. Up to 1 year, the cumulative incidence of DM was 12/100 person-years (PY) in the LSM, 18/100 PY in MET, and 27/100 PY in STM (P=0.1440). Compared to STM, HR for T2DM in LSM was 0.51 (P=0.0508), and the HR in the MET was 0.82 (P=0.5205).
Conclusion: The KDPS was intended to evaluate the DM prevention efficacy of the intervention methods practically applicable in clinical settings in Korea. The hLSM tended to have a 49% DM prevention effect compared to the STM. However, in the case of the MET, there was no significant difference from the control group. Further full analysis of KDPS results is needed for long term effect.

Disclosure
S.Chon: None. S.Yun: None. J.Woo: None. The korean diabetes prevention study investigators: n/a.

Funding
Korean Disease Control and Prevention Agency (2020-ER6402-00)
746-P: Semaglutide Increases the Proportion of People with T2D Achieving a Metabolic Composite Endpoint
Authors: JI LINONG , AHMANN ANDREW , AHRÉN BO , CAPEHORN MATTHEW , HU PING , LINGVAY ILDIKO , LIU WENYAN , RODBARD HELENA W. , SHEN ZEWEI , SORLI CHRISTOPHER H. 
Published: June 2023

Hyperglycemia, high BP and dyslipidemia are common risk factors for CVD. The aim of this study was to assess the proportion of participants treated with once-weekly (OW) semaglutide, or a comparator, achieving a metabolic composite target endpoint in the SUSTAIN trials. Participants from SUSTAIN 1-5, 7-10 and SUSTAIN China with uncontrolled T2D treated with OW semaglutide vs comparators (incl. placebo) were pooled, and the proportion achieving the endpoint (HbA1c &lt;7%, BP &lt;140/90 mmHg and non-HDL cholesterol &lt;130 mg/dL) was assessed. Endpoints were analyzed using on treatment without rescue medication data for each trial, using a binomial logistic regression model with treatment, region/country, and stratification factor as fixed effects and baseline value (HbA1c/BP/Non-HDL) as covariate. Pooled analysis was conducted using logistic regression with treatment and trial as fixed effects and baseline value as covariate. Treatment with 0.5 and 1 mg OW semaglutide was associated with higher odds (OR range 1.4-24.4) of achieving the endpoint vs comparators (Figure). The proportion of participants reaching the composite endpoint across all trials was 24% and 32% for 0.5 mg and 1.0 mg semaglutide, respectively, vs 11% for comparators (p&lt;0.0001). The results indicate that OW semaglutide may assist with the co-management of T2D and cardiometabolic risk factors, which could reduce the risk of CVD in people with T2D.

Disclosure
L.Ji: Other Relationship; Eli Lilly and Company, Novo Nordisk, Merck & Co., Inc., Bayer Inc., Sanofi-Aventis U.S., Roche Pharmaceuticals, MSD Life Science Foundation, AstraZeneca, Boehringer Ingelheim Inc., Abbott, Metronics. C.H.Sorli: Employee; Acerus Pharmaceuticals. A.Ahmann: Advisory Panel; Medtronic. B.Ahrén: Speaker's Bureau; Novo Nordisk, Nestlé Health Science, Stock/Shareholder; Novo Nordisk, AstraZeneca, Eli Lilly and Company. M.Capehorn: Advisory Panel; Novo Nordisk, Lilly Diabetes, Boehringer Ingelheim Pharmaceuticals Inc., Research Support; Boehringer Ingelheim Inc., Novo Nordisk, Lilly, Speaker's Bureau; Novo Nordisk, Lilly, Boehringer Ingelheim Inc. P.Hu: Employee; Novo Nordisk (China). I.Lingvay: Advisory Panel; Novo Nordisk A/S, Lilly Diabetes, Boehringer-Ingelheim, Sanofi, Consultant; Carmot Therapeutics, Inc., Merck Sharp & Dohme Corp., Janssen Scientific Affairs, LLC, Pfizer Inc., Intercept, Intarcia, Valeritas, TargetRWE, Shionogi, Zealand Pharma, Structure, Bayer, Research Support; Novo Nordisk A/S, Boehringer-Ingelheim. W.Liu: Employee; Novo Nordisk (China). H.W.Rodbard: Advisory Panel; Merck Sharp & Dohme Corp., Pacira BioSciences, Inc., Research Support; Eli Lilly and Company, Medtronic, Sanofi, Novo Nordisk. Z.Shen: Employee; Novo Nordisk (China).
759-P: Changes in Liver Fat in Patients with Type 2 Diabetes by Presence of Genetic Hepatic Steatosis in the SURPASS-3 MRI Substudy
Authors: CUSI KENNETH , GASTALDELLI AMALIA , FERNANDEZ LANDO LAURA , LIU MINZHI , TORCELLO-GOMEZ AMELIA , RODRÍGUEZ ÁNGEL 
Published: June 2023

Patatin-like phospholipase 3 (PNPLA3) I148 genetic variant is highly associated with nonalcoholic fatty liver disease. Tirzepatide (TZP), a novel GIP/GLP-1 receptor agonist, significantly reduced liver fat content (LFC) vs insulin degludec (IDeg) in a subpopulation of patients in the SURPASS-3 phase 3 trial. This post-hoc analysis evaluated changes from baseline to Week 52 in LFC and cardiometabolic parameters by presence of PNPLA3 I148 allele (yes [genotype CG/GG] or no [genotype CC]).
Insulin-naïve patients with type 2 diabetes inadequately controlled on metformin with/without SGLT-2i and fatty liver index ≥60 at baseline had an MRI scan performed prior to randomization (1:1:1:1) to once-weekly TZP (5, 10, 15 mg) or IDeg. LFC was assessed with MRI.
Patients (mean baseline age, 56.2 years; diabetes duration, 8.3 years; HbA1c, 8.2%; weight, 94.4 kg; BMI, 33.5 kg/m2; 30% on SGLT-2i) experienced greater reductions in LFC, weight, HbA1c, and overall greater improvement in lipids profile and liver enzymes with all doses of TZP than with IDeg regardless of the presence of PNPLA3 I148 allele (Table). Findings with TZP were consistent in both subgroups.
In summary, TZP led to clinically meaningful improvements in several cardiometabolic parameters in patients with type 2 diabetes regardless of the presence of PNPLA3 I148 allele.

Disclosure
K. Cusi: Research Support; Echosens, Inventiva. Consultant; Poxel SA. Research Support; LabCorp, Zydus. Consultant; Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, 89bio, Inc., Bristol-Myers Squibb Company, Lilly, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Medscape, Myovant, Novo Nordisk, ProSciento, Quest Diagnostics, Sagimet, Sonic Incytes, Terns. A. Gastaldelli: Consultant; Boehringer Ingelheim International GmbH, Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Advisory Panel; Pfizer Inc. Consultant; Fractyl Health, Inc. Advisory Panel; Novo Nordisk, Merck Sharp & Dohme Corp., Boehringer Ingelheim International GmbH. Other Relationship; Pfizer Inc. Consultant; Merck Sharp & Dohme Corp. L. Fernandez Lando: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M. Liu: Consultant; Eli Lilly and Company. A. Torcello-Gomez: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Á. Rodríguez: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company.

Funding
Eli Lilly and Company
760-P: Discovery of GSBR-1290, a Highly Potent, Orally Available, Novel Small Molecule GLP-1 Receptor Agonist
Authors: MAO TING , MENG QINGHUA , ZHANG HAIZHEN , ZHANG JINQIANG J. , SHI SONGTING , GUAN ZHIBO , JIANG XINGLONG , ZHANG FANG , LEI HUI , LIN XICHEN 
Published: June 2023

Peptidic glucagon-like peptide 1 receptor agonists (GLP-1RAs) are established treatments for patients with Type 2 Diabetes Mellitus (T2DM) and obesity. However, the need for injection and cold chain storage may limit the utility of most peptidic GLP-1RAs. An oral small molecule GLP-1RA that offers enhanced bioavailability and stability could be more convenient and accessible to patients. Here we report the discovery of GSBR-1290, a highly potent, orally available, novel small molecule GLP-1RA and the characterization of its in vitro and in vivo pharmacology profiles. GSBR-1290 is a small molecule GLP-1RA with high binding affinity to human GLP-1R. GSBR-1290 strongly activated GLP-1R Gαs cAMP pathway without inducing measurable β-arrestin recruitment signaling, which indicates it is a fully biased agonist. The insulin secretion stimulation effect of GSBR-1290 was evaluated in a functional human pancreatic beta cell line, in which GSBR-1290 showed dose dependent induction of insulin secretion. The in vivo efficacy of GSBR-1290 on insulin secretion, glucose control and food intake were evaluated in nonhuman primates (NHPs). In an acute intravenous glucose tolerance test (ivGTT), a single dose of GSBR-1290 strongly induced insulin secretion and glucose clearance. In a repeated dosing study, GSBR-1290 administered orally once daily for 7-day demonstrated robust increase in insulin secretion and glucose clearance in ivGTT and a dose dependent reduction of food intake and body weight. Overall, GSBR-1290 demonstrated potent in vivo efficacy in stimulating insulin secretion, improving glucose tolerance, and reducing food intake and body weight. In conclusion, GSBR-1290 is a highly potent, orally available, fully biased GLP-1RA. Human clinical trials are underway to further evaluate GSBR-1290 as a potential therapy for T2DM and obesity.

Disclosure
T.Mao: Employee; Structuretx. X.Lin: Employee; Structure Therapeutics. Q.Meng: Employee; Beijing Stonewise Technology, Structure Therapeutics Inc. H.Zhang: Employee; Structuretx. J.J.Zhang: Employee; Structure Therapeutics Inc. S.Shi: Employee; Structure Therapeutics Inc. Z.Guan: Employee; Structure Therapeutics. X.Jiang: Employee; Structure Therapeutics. F.Zhang: Employee; Structure Therapeutics, Eternity BioSciences, Stock/Shareholder; Novo Nordisk. H.Lei: Employee; Structure Therapeutics.
763-P: Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of a Dual GLP-1/GIP Receptor Agonist (HRS9531) in Healthy Subjects—A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose (SAD and MAD) Study
Authors: HE KUN , WEI FANG , CHEN HONG , ZHANG YANYAN , SHENG ZHEN , WEN QING 
Published: June 2023

Background: Accumulating evidences suggest that dual GLP-1/GIP receptor agonist can achieve prominent glycemic control and body weight loss. Here we report the results of a phase 1 SAD and MAD study of HRS9531 in healthy subjects (NCT05152277).
Methods: In the SAD, healthy subjects were randomized (4:1) to receive subcutaneous injection of HRS9531 (0.1, 0.3, 0.9, 2.7, 5.4, and 8.1 mg) or placebo. In the MAD, healthy subjects were randomized (4:1) to receive HRS9531 (0.9, 2.7, and 5.4 mg [2.7/2.7/4.0/5.4 mg titration]) or placebo once a week for 4 wks. The primary endpoints for both parts were safety and tolerability.
Results: Sixty and 30 subjects were recruited into SAD and MAD respectively. The most common adverse events were abdominal distension and nausea in SAD, and urine ketone body present and nausea in MAD; all considered mild to moderate in severity (mostly mild). No severe hypoglycemia or serious events occurred. Drug exposure were proportional to dose from 0.9-8.1 mg. The median Tmax and mean t1/2 were 48-72 h and 156-182 h in SAD, and 48-72 h and 169-192 h after the fourth dosing in MAD, respectively. Fasting plasma glucose (FPG) levels decreased dose-dependently after single and multiple dosing. The 0 to 2 h glucose AUC during oral glucose tolerance test (OGTT) on D23 decreased dose-dependently relative to placebo in MAD. In SAD, body weight loss was dose-dependent and the maximal mean loss on D8 was 3.8 kg (4.9%) in 8.1 mg group. In MAD, the mean weight loss on D29 (after 4 wks treatment) ranged 4.3-7.7 kg (6.7%-9.3%) across 0.9-5.4 mg groups, and maximal loss (8.0 kg, 10.0%) occurred on D36 in 5.4 mg group.
Conclusions: HRS9531 was well tolerated, had favorable PK, and led to evident glucose decrease and body weight loss. These data support further clinical development of HRS9531 for metabolism-related disorders such as T2DM and obesity.

Disclosure
K.He: None. F.Wei: None. H.Chen: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Y.Zhang: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Z.Sheng: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Q.Wen: None.

Funding
Jiangsu Hengrui Pharmaceuticals Co., Ltd.
770-P: Efficacy and Safety of Once-Weekly PB-119 Monotherapy vs. Placebo in Chinese Patients with Type 2 Diabetes in a Randomized Controlled Trial
Authors:   PEGBIO STUDY GROUP, XU MIN , LIANG RUIFANG 
Published: June 2023

Background: PB-119 is a novel once-weekly polyethylene glycolated exenatide developed in China for T2DM treatment. Favorable efficacy and safety profile had been demonstrated in two phase 2 studies respectively completed in US and China.
Methods: In this multicenter, double-blind, placebo-controlled, 52-week phase 3 study, 273 drug-naïve Chinese patients with type 2 diabetes were randomized (1:1) to receive subcutaneous PB-119 150ug once weekly or volume-matched placebo once weekly for 24 weeks, followed by 28-week extension during which all the patients were treated with PB-119 150ug once weekly. The primary endpoint was the HbA1c change from baseline to week 24. ClinicalTrials.gov, NCT04504370
Results: At week 24, HbA1c showed a significantly decrease with PB-119 (-1.35%) than placebo (-0.51%, p&lt;0.001). Significant more patients reached the target of HbA1c less than 7.0% in the PB-119 group versus the placebo group (50.4% vs 14.2%; p&lt;0.001). Significant greater reduction in FPG (-1.26mmol/L vs. -0.52mmol/L) and PPG (-2.52 vs. -0.85mmol/L) were achieved (P&lt;0.001). The remarkable glycemic lowering effect sustained till the end of week 52. Meanwhile, Insulin, C-peptide and HOMA-ß were significantly increased with PB-119 versus placebo. HOMA-IR was significantly reduced with PB-119 compared with placebo. Significant improvement of blood pressure and blood lipid profile were demonstrated with PB-119 treatment early from week 8 (TC -0.2mmol/L, LDL-C -0.19mmol/L, DBP -1.8mmHg at week 52, p&lt;0.05 compared to the baseline). Most adverse events were mild and transient. Incidence of nausea (8%) and vomit (5.1%) were low. No Grade 2 or above hypoglycemia (&lt; 3.0mmol/L) occurred.
Conclusion: PB-119 significantly and sustainably improves glycemic control, lipid profile, blood pressure, beta-cell function and insulin resistance, and well tolerated. Dose titration is not needed.

Disclosure
Pegbio study group: n/a. M.Xu: None. R.Liang: None.
79-OR: Targeted Erasure of DNA Methylation by TET3 with C/EBPδ Rewires Adipogenic Execution for Energy Metabolism
Authors: PARK JEU , BUM KIM JAE 
Published: June 2023

DNA methylation is one of the key epigenetic modifications in the establishment of cell-type-specific characteristics. However, how DNA methylation is selectively regulated at adipocyte-specific loci during adipogenesis remains unclear. We have demonstrated that the transcription factor, C/EBPδ, and the DNA methylation eraser, TET3, cooperatively control adipocyte differentiation. We performed whole-genome bisulfite sequencing to explore the DNA methylation in adipocyte differentiation. Intriguingly, DNA methylation selectively decreases at adipocyte-specific loci carrying the C/EBP binding motif, which correlates with the activity of adipogenic promoters and enhancers. Mechanistically, we find that C/EBPδ recruits a DNA methylation eraser, TET3, to catalyze DNA demethylation and stimulate the expression of key adipogenic genes. Ectopic expression of TET3 potentiates in vitro and in vivo adipocyte differentiation and restores insulin sensitivity and decreased adipogenic potential, which is observed in aged mice and humans. Together, our study highlights how targeted reprogramming of DNA methylation through cooperative action of the transcription factor C/EBPδ, and the DNA methylation eraser TET3, controls adipocyte differentiation for whole body energy metabolism.

Disclosure
J.Park: None. J.Kim: None.

Funding
National Research Foundation of Korea (2018R1A5A1024340 to J.B.K. and J.P), (2020R1A3B2078617 to J.B.K)