Metabolic Flux Analysis in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD)

Metabolic Flux Analysis in MASLD

This prospective, single-center pilot study will evaluate metabolic flux dysregulation in adults with obesity and suspected or confirmed metabolic dysfunction-associated steatotic liver disease (MASLD) who are scheduled for protocol-eligible bariatric surgery at Vanderbilt University Medical Center. Participants will undergo research assessments before surgery, during the planned bariatric surgery encounter, and approximately 6 months after surgery. The study uses non-radioactive stable isotope tracer infusions, serial blood sampling, abdominal MRI/MRE, and research tissue specimens collected only during clinically planned bariatric surgery to quantify hepatic and extrahepatic metabolic fluxes. The primary objective is to determine how hepatic citric acid cycle flux and related metabolic pathways change after bariatric surgery and how these metabolic measures relate to liver fat, liver stiffness, and biopsy-graded MASLD/MASH severity.

Study Overview

• Status: Not yet recruiting
• Conditions: Obesity; Bariatric Surgery; Metabolic Dysfunction-Associated Steatohepatitis; Metabolic Dysfunction-Associated Steatotic Liver Disease
• Intervention / Treatment: Procedure: Bariatric surgery; Other: Stable isotope tracer infusion; Diagnostic test: MRI/MRE; Procedure: Research tissue collection during planned bariatric surgery

Detailed Description

MASLD and its progressive form MASH are associated with obesity, insulin resistance, altered hepatic substrate delivery, and changes in mitochondrial metabolism. However, the direction and significance of hepatic citric acid cycle flux changes in human MASLD remain unresolved. This study will apply in vivo metabolic flux analysis using non-radioactive stable isotope tracers to quantify hepatic and extrahepatic metabolic pathway activity in bariatric surgery participants before and after surgery.

Participants will complete three study timepoints. Approximately one week before surgery, participants will undergo fasting physical measurements, questionnaires, research blood collection, and abdominal MRI/MRE to quantify liver fat and stiffness. On the day of surgery, participants will receive intravenous infusions of [¹³C₃]lactate, [6,6-²H₂]-D-glucose, and [9,9-²H₂]palmitate for approximately 120 minutes with serial blood collection. During the clinically planned bariatric surgery, research tissue specimens may be collected from liver, omentum, subcutaneous adipose tissue, and skeletal muscle only if the surgeon determines collection can be performed safely without interfering with clinical care. Approximately 6 months after surgery, participants will repeat fasting physical measurements, questionnaires, MRI/MRE, stable isotope tracer infusion, and blood collection; no follow-up tissue biopsies will be collected.

Isotope enrichment patterns in plasma metabolites and tissue metabolites will be analyzed by mass spectrometry and modeled using metabolic flux analysis software to estimate hepatic citric acid cycle flux, gluconeogenesis, glucose turnover, free fatty acid turnover, lactate turnover, and selected extrahepatic metabolic fluxes. Liver fat and stiffness will be assessed by MRI/MRE, and intraoperative liver tissue will be scored for MASLD/MASH features using established histologic criteria.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Charles R Flynn, PhD; Phone Number: 615-343-8329; Email: MASLD.research@vumc.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Scheduled and clinically cleared for protocol-eligible bariatric surgery at Vanderbilt University Medical Center.
• BMI ≥40 kg/m², or BMI >35 kg/m² with at least one obesity-associated comorbidity, such as type 2 diabetes, cardiovascular disease, hypertension, hyperlipidemia, obstructive sleep apnea, MASLD, osteoarthritis, or polycystic ovarian syndrome.
• Able and willing to complete study procedures, including informed consent, questionnaires, blood draws, MRI/MRE imaging, stable isotope tracer infusion, and research tissue collection during planned bariatric surgery.
• Able to provide informed consent in English.

Exclusion Criteria:

• Contraindication to MRI/MRE, including implanted cardiac defibrillator, pacemaker, or other MRI-incompatible implanted device.
• Prior gastric or intestinal surgery, pancreatic surgery, or other prior surgery that, in the judgment of the study team or bariatric surgeon, would interfere with study procedures or outcome interpretation.
• Active cancer or ongoing cancer treatment.
• Presence or history of HIV infection.
• Alcohol use above study-defined limits: more than 14 alcoholic drinks per week for men or more than 7 alcoholic drinks per week for women, or illicit drug use that would interfere with safe participation or interpretation of study results.
• Anemia or other hematologic condition that would increase risk from study blood collection.
• Abnormal ECG or clinically significant cardiovascular finding that would increase risk from study procedures.
• Impaired renal function or other clinically significant condition that would increase risk from study participation.
• Known Wilson's disease, alpha-1 antitrypsin deficiency, hemochromatosis, or other non-MASLD chronic liver disease that would confound interpretation of study outcomes.
• Any medical, surgical, or safety condition that, in the judgment of the PI, clinical co-investigator, CRC staff, anesthesia team, or bariatric surgeon, would make participation unsafe or interfere with completion of study procedures.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Bariatric Surgery Participants Undergoing Metabolic Flux Assessment; Adults scheduled and clinically cleared for protocol-eligible bariatric surgery at VUMC will undergo research MRI/MRE, blood collection, non-radioactive stable isotope tracer infusions, and intraoperative research tissue collection during planned bariatric surgery, followed by repeat noninvasive metabolic assessment approximately 6 months after surgery.

Procedure: Bariatric surgery; Clinically indicated bariatric surgery, such as Roux-en-Y gastric bypass or sleeve gastrectomy, performed as part of standard clinical care.; Other Names: Roux-en-Y-gastric byass; sleeve gastrectomey; Other: Stable isotope tracer infusion; Intravenous non-radioactive stable isotope tracers administered for research measurement of metabolic flux: [¹³C₃]lactate, [6,6-²H₂]-D-glucose, and [9,9-²H₂]palmitate.; Diagnostic test: MRI/MRE; Abdominal MRI proton density fat fraction and magnetic resonance elastography to assess hepatic fat and stiffness before surgery and approximately 6 months after surgery.; Other Names: magnetic resonance imaging; magnetic resonance elastography; Procedure: Research tissue collection during planned bariatric surgery; Liver, omentum, subcutaneous adipose tissue, and skeletal muscle specimens collected only during clinically planned bariatric surgery and only if safe in the surgeon's judgment.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in hepatic citric acid cycle flux after bariatric surgery	Change in hepatic citric acid cycle flux estimated from stable isotope enrichment patterns, including [¹³C₃]lactate-based measurements, before bariatric surgery and approximately 6 months after surgery.	Baseline/day of surgery to approximately 6 months post-surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in hepatic gluconeogenic flux	Estimated from plasma glucose isotope enrichment and metabolic flux modeling	Baseline/day of surgery to ~6 months
Change in endogenous glucose production	Estimated using [6,6-²H₂]-D-glucose tracer dilution	Baseline/day of surgery to ~6 months
Change in free fatty acid turnover	Estimated using [9,9-²H₂]palmitate tracer dilution	Baseline/day of surgery to ~6 months
Change in lactate turnover / lactate-related flux	Estimated using stable isotope enrichment patterns	Baseline/day of surgery to ~6 months
Liver fat by MRI-PDFF	Hepatic fat fraction quantified by MRI-PDFF	Baseline to ~6 months
Liver stiffness by MRE	Liver stiffness quantified by magnetic resonance elastography	Baseline to ~6 months
Histologic MASLD/MASH severity	Liver biopsy scored for steatosis, inflammation, ballooning, fibrosis, and MASLD activity score	Intraoperative baseline only
Extrahepatic metabolic fluxes	Metabolic fluxes in skeletal muscle, omentum, and subcutaneous adipose tissue estimated from intraoperative tissue specimens	Intraoperative baseline only
Serum inflammatory markers	Research measurement of inflammatory markers including CRP, cytokines, adhesion molecules, and related biomarkers	Baseline/day of surgery; possibly ~6 months if collected
Metabolic hormone profile	Insulin, leptin, C-peptide, GLP-1, GIP, PYY, ghrelin	Baseline/day of surgery; possibly ~6 months if collected
Bile acid profile	Bile acids measured by LC-IM-MS	Baseline/day of surgery; possibly ~6 months if collected

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Investigators: Principal Investigator: Charles R Flynn, PhD, Vanderbilt University Medical Center

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2026
• Primary Completion (Estimated): September 30, 2029
• Study Completion (Estimated): January 1, 2060

Study Registration Dates

• First Submitted: August 7, 2026
• First Submitted That Met QC Criteria: August 7, 2026
• First Posted (Actual): August 12, 2026

Study Record Updates

• Last Update Posted (Actual): August 12, 2026
• Last Update Submitted That Met QC Criteria: August 7, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• Keywords: bariatric surgery; liver fat; sleeve gastrectomy; Roux-en-Y gastric bypass; gluconeogenesis; citric acid cycle; magnetic resonance elastography; MASLD; MASH; stable isotope tracer; metabolic flux analysis; free fatty acid turnover
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Digestive System Diseases; Liver Diseases; Overweight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Fatty Liver; Therapeutics; Diagnostic Techniques and Procedures; Diagnosis; Surgical Procedures, Operative; Tomography; Diagnostic Imaging; Ultrasonography; Bariatrics; Obesity Management; Magnetic Resonance Imaging; Bariatric Surgery; Elasticity Imaging Techniques
• Other Study ID Numbers: 260832

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified or coded individual-level data and biospecimens may be shared for future research only as permitted by the informed consent document, IRB approval, institutional policy, data-use agreements, and applicable privacy protections. No direct identifiers will be included in publications, presentations, reports, or shared datasets.
• IPD Sharing Time Frame: Data will be available within one year after study end.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No