Harnessing Macrophage Lysosomal Lipid Metabolism in Obesity (ATM)

Harnessing Macrophage Lysosomal Lipid Metabolism in Obesity-Associated Diseases

The goal of this study is to evaluate the role of transcription factor EB (TFEB) in adipose (fat) tissue macrophages (ATM) in regulating adipose tissue and systemic metabolic function in obesity. The investigators will assess the differences in ATM lipid metabolism in people with metabolically abnormal obesity and lean individuals.

Both groups will have:

• screening visit
• imaging (body composition testing - dual-energy x-ray absorptiometry (DEXA) scans, magnetic resonance imaging [MRI] and magnetic resonance spectroscopy [MRS] scans)
• Overnight visit with intravenous infusion (IV), muscle, and fat tissue biopsies Participants with obesity will complete meetings with study team members for a weight loss intervention to achieve a 10% body weight loss.

Study Overview

• Status: Not yet recruiting
• Conditions: Healthy; Obesity; Diabetes Type 2; Nonalcoholic Fatty Liver
• Intervention / Treatment: Other: Dietary consultation weight loss intervention

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Heather McHatton; Phone Number: (573) 882-7619; Email: heathermchatton@health.missouri.edu
• Study Contact Backup: Name: Aman Pritish Aher; Email: amanpritishaher@umsystem.edu

Study Locations

• United States
  • Missouri
    • Columbia, Missouri, United States, 65212
      • University of Missouri School of Medicine
      • Contact: Bettina Mittendorfer; Phone Number: 573-822-9377; Email: b.mittendorfer@missouri.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria :

• age: ≥18 but ≤70 years
• not pregnant or breastfeeding
• weight stable and sedentary before enrollment
• no use tobacco products, excessive amounts of alcohol, or dietary supplements, or medications known to or suspected to affect glucose and lipid metabolism (aside from certain medications used to treat diabetes in the metabolically abnormal obesity [MAO]-Type 2 Diabetes group)
• no evidence of significant organ system dysfunction or disease (e.g. chronic severe kidney disease, cancer)
• participants must fulfil all of the following group-specific inclusion criteria below:

Lean group:

• Body mass index (BMI) ≥18.5 but <25.0 kg/m2
• Intrahepatic triglyceride (IHTG) content <5%
• fasting blood glucose concentration: <100 mg/dl
• blood glucose concentration 2 h after a 75 g oral glucose challenge: <140 mg/dl
• Hemoglobin A1C (HbA1c) <5.7 %

Metabolically normal obesity (MNO) group:

• BMI ≥30.0 but <45.0 kg/m2
• IHTG content <5%
• fasting blood glucose concentration: <100 mg/dl
• blood glucose concentration 2 h after a 75 g oral glucose challenge: <140 mg/dl
• HbA1c <5.7 %

Metabolically abnormal obesity (MAO)-insulin resistance and non-alcoholic fatty liver disease (NAFLD) group:

• BMI ≥30.0 but <45.0 kg/m2
• IHTG content >7.5%
• fasting blood glucose concentration: ≥100 but <126 mg/dl
• blood glucose concentration 2 h after a 75 g oral glucose challenge: ≥140 but <200 mg/dl
• HbA1c: ≥5.7 but <6.4 %

MAO-type 2 diabetes group:

• BMI ≥30.0 but <45.0 kg/m2
• clinical diagnosis of type 2 diabetes or fasting blood glucose concentration >126 mg/dl or blood glucose concentration 2 h after a 75 g oral glucose challenge>200 mg/dl or HbA1c >6.4 % without medication if not diagnosed and medically treated for diabetes

Exclusion Criteria:

- Individuals that do not meet all inclusion Criterion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Lean Individuals; No intervention will be administered.
Experimental: Metabolically abnormal obese Individuals (obesity with normoglycemia and abnormal liver fat content); Participants will undergo a dietary weight loss intervention to achieve 10% weight loss over about 6 months.	Other: Dietary consultation weight loss intervention; Participants will meet with a member of the study team biweekly for about 6 months.
Experimental: Metabolically normal obese Individuals (obesity with normoglycemia and normal liver fat content); Participants will undergo a dietary weight loss intervention to achieve 10% weight loss over about 6 months.	Other: Dietary consultation weight loss intervention; Participants will meet with a member of the study team biweekly for about 6 months.
Experimental: Individuals with Type 2 Diabetes Mellitus; Participants will undergo a dietary weight loss intervention to achieve 10% weight loss over about 6 months.	Other: Dietary consultation weight loss intervention; Participants will meet with a member of the study team biweekly for about 6 months.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin sensitivity assessed as insulin-mediated glucose disposal during a hyperinsulinemic-euglycemic clamp procedure.		up to 6 months after the intervention
24-hour plasma glucose concentration		up to 6 months after the intervention
Macrophage isolation in adipose tissue biopsy	macrophage gene expression using RNA sequencing and fluorescent activated cell sorting (FACS)	up to 6 months after the intervention
Macrophage isolation in skeletal muscle tissue	macrophage gene expression using RNA sequencing and fluorescent activated cell sorting (FACS)	up to 6 months after the intervention

Collaborators and Investigators

• Sponsor: Bettina Mittendorfer
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Bettina Mittendorfer, University of Missouri-Columbia

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2024
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: March 14, 2024
• First Submitted That Met QC Criteria: March 21, 2024
• First Posted (Actual): March 28, 2024

Study Record Updates

• Last Update Posted (Actual): March 28, 2024
• Last Update Submitted That Met QC Criteria: March 21, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Liver Diseases; Overnutrition; Nutrition Disorders; Overweight; Body Weight; Diabetes Mellitus, Type 2; Obesity; Fatty Liver; Non-alcoholic Fatty Liver Disease
• Other Study ID Numbers: 2098077; R01DK131188 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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