Transcriptional Changes in Isolated Human Adipocytes During Obesity

Human Adipocytes - Transcriptional Network Changes Associated With Obesity

Adipocytes play an important role in our body through their function as metabolic energy stores in the form of fat deposits, which are stored when metabolic energy is in excess and released when energy levels are low. In severe obesity, adipose tissue grows through the production of more adipocytes from stem cells (hyperplasia) and the increase in the size of existing adipocytes (hypertrophy). This ability of adipocytes, to maintain their functionality during tissue expansion, is critical in determining the development of obesity-related comorbidities. However, not all adipocytes are the same as adipocyte function differs greatly depending on the depot in which they are found. To elucidate the mechanisms underlying adipocyte adaptability, it is necessary to obtain a deep systems biology understanding of how signaling in different types of adipocytes regulates metabolism and function. Currently, this research group is conducting a systems biology analysis of adipocyte plasticity in obesity in mouse models, but adipose tissue biopsies from different depots in humans are lacking and needed to investigate the regulation of adipocyte function and plasticity in humans. Such studies of adipocytes are crucial for the understanding how obesity affects adipose tissue function and leads to comorbidities.

Study Overview

• Status: Enrolling by invitation
• Conditions: Adiposity; Obesity, Abdominal

Detailed Description

The development of overweight and obesity is associated with major changes in adipose tissue, including structural changes in cell type composition as well as gene expression in individual adipose tissue cell types. The molecular mechanisms underlying these changes are not yet known. The investigators therefore hypothesized that overweight and obesity cause changes in the transcriptional program of adipocytes and this leads to impaired function of adipocytes. This study will use advanced genomic technologies available that can measure the dynamic changes in the transcriptome and genomic landscape of isolated adipocytes from patient biopsies, to better understand which changes in the adipocytes in particular underlie the severe comorbidities that occur with the development of obesity. It is expected that the described project will contribute important knowledge about adipocyte-specific transcriptional programs that play a crucial role in obesity. This and thus may contribute to the knowledge required to develop adapted- and personalized medicines, or new therapeutic approaches to treat obesity and its associated diseases.

Recruitment of 100 subjects will be from patients referred for surgical cholecystectomies, herniotomies or similar operations at Bispebjerg Hospital. The control group will consist of study participants with a BMI ≥ 19 kg/m2 and < 25 kg/m2, and the "case" group will consist of study participants with a BMI ≥ 25 kg/m2. When including subjects, emphasis will be placed on achieving a control group of approximately 25 subjects and a "case" group of approximately 75 subjects with varying degrees of elevated BMI.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2400
    • Bispebjerg Hospital

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Probability Sample

Study Population

Recruitment of subjects will be from patients referred for surgical cholecystectomies, herniotomies or similar operations, at Bispebjerg Hospital.

Description

Inclusion Criteria:

• Age > 18 years old
• BMI> 19 kg/m2
• Can receive oral and written information and give appropriate consent

Exclusion Criteria:

• Active viral hepatitis, HIV positive
• Autoimmune diseases (i.e. lupus)
• Chronic use of corticosteroids (cortisone)
• Unable to give appropriate consent
• Contraindications for biopsy: bleeding tendency.
• Cancer or other comorbidity with an expected survival time of less than 12 months

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Male and female participants with various BMI; Both male and female participants will be included, with the goal of creating a cohort in which all levels of BMI are equally present. Adipocytes of the abdominal subcutaneous and visceral adipose tissue depots will be isolated and sequenced to perform linear regression analysis of transcriptional networks across BMI.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adipocytes specific signaling	RNA sequencing of isolated adipocytes	June 2024 - Sept 2025
Gene regulatory networks	ATAC sequencing of isolated adipocytes to determine the accessible chromatin regions.	June 2024 - Sept 2025

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adipocyte cell size	Determining the average adipocyte cell size and cell size distribution in both tissue depots.	Sept 2024 - Dec 2024
Standard blood tests	Analysis of standard blood tests by research diagnostics department of the hospital; including nutritional status (haemoglobin, magnesium, zinc, phosphate, ferritin, iron, albumin. Vitamin D, urea), coagulation (INR, APTT, platelets), blood lipids (total cholesterol, LDL, HDL, triglycerides) and insulin resistance (HOMA-IR, HbA1c, C-peptide, glucose).	Jan 2025 - Sept 2025
Adipokine secretion	Storage of extra serum and plasma for additional analysis of adipokines such as Adiponectin and Leptin.	Jan 2025 - Sept 2025

Collaborators and Investigators

• Sponsor: University of Southern Denmark
• Collaborators: Bispebjerg Hospital
• Investigators: Principal Investigator: Susanne Mandrup, PhD, s.mandrup@bmb.sdu.dk

Publications and helpful links

Helpful Links

• Website of main investigating party

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2023
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): September 1, 2025

Study Registration Dates

• First Submitted: December 16, 2024
• First Submitted That Met QC Criteria: March 31, 2025
• First Posted (Actual): April 2, 2025

Study Record Updates

• Last Update Posted (Actual): April 2, 2025
• Last Update Submitted That Met QC Criteria: March 31, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Keywords: Obesity; Human primary adipocytes; Systems-wide biology; Gene regulatory networks
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Overweight; Obesity; Obesity, Abdominal
• Other Study ID Numbers: S-20200123

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