Non-alcoholic Fatty Liver Disease in Low Birth Weight Individuals

Increased Risk of Non-alcoholic Fatty Liver Disease in Low Birth Weight Individuals - Reversibility and Mechanistic Studies.

The investigators will conduct a proof-of-principle 4-weeks low-calorie diet (LCD) intervention study in low birth weight (LBW) subjects and normal birth weight (NBW) controls with documented (MR scan) liver fat content equal to or above 5%. The investigators will provide extended in-depth mechanistic insight into the role of impaired subcutaneous adipose tissue (SAT) expandability in ectopic fat deposition before and after LCD.

Study Overview

• Status: Recruiting
• Conditions: NAFLD
• Intervention / Treatment: Other: No intervention; Behavioral: Caloric restriction intervention

Detailed Description

An adverse fetal environment characterized by low birth weight (LBW) plays a key role in the development of type 2 diabetes (T2D). The investigators recently demonstrated a 3-fold increase in liver fat in 26 early middle-aged LBW compared to 22 normal birth weight (NBW) men, and 20% of the LBW - but none of the normal birth weight (NBW) - men had previously unknown non-alcoholic fatty liver disease (NAFLD). The investigators hypothesize that ectopic fat deposition and NAFLD is among the earliest disease manifestations and on the critical path to the development of more severe cardiometabolic disease in LBW. The investigators furthermore hypothesize, that LBW individuals exhibit ectopic liver fat due to reduced capacity to store fat in the subcutaneous adipose tissue (SAT) depot, and that early detection and subsequent intensive caloric restriction, in middle-aged LBW individuals with overt NAFLD, may represent a targeted and highly efficient way forward to prevent more severe cardiometabolic disease manifestations in LBW subjects.

To further explore the recent findings, the investigators aim to perform an extended nested case-control screening study for NAFLD (now MASLD) in 250 early middle-aged non-obese LBW men and women, and subsequently to conduct a proof-of-principle 4 week low-calorie diet (LCD) intervention study in the subjects with hepatic fat content of or above 5% (MR scan). Individuals identified with MALSD in the screening study will be invited to participate in the reversibility study. The reversibility study includes measures of hepatic fat content (primary outcome) MR, fibroscan, DEXA scan, clinical biochemistry and collection of SAT adipose tissue biopsies and progenitor cells for further studies before and after the LCD intervention. The investigators will provide extended in-depth mechanistic insight into transcriptional, epigenetic as well as functional SAT and preadipocyte perturbations underlying impaired SAT expandability in individuals with and without MASLD studied before and after different dietary interventions including LCD and high carbohydrate overfeeding.

• Study Type: Interventional
• Enrollment (Estimated): 8
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Charlotte Brøns, Phd; Phone Number: +4526129093; Email: charlotte.broens.01@regionh.dk

Study Locations

• Denmark
  • Aarhus, Denmark
    • Recruiting
    • Steno Diabetes Center Aarhus
    • Contact: Julie Julie Bondgaard Løhde, MD; Email: juliebm@biomed.au.dk
  • Herlev, Denmark
    • Recruiting
    • Steno Diabetes Center Copenhagen
    • Contact: Charlotte Brøns Brøns, PhD; Phone Number: +45 26129093; Email: charlotte.broens.01@regionh.dk
    • Contact: Allan Vaag Vaag, MD, PhD; Email: allan.arthur.vaag@regionh.dk

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• subjects with NAFLD (liver fat content ≥5% liver fat content verified on MRS in the screening NAFLD study)

Exclusion Criteria:

• BMI<18.5 and BMI>30 kg/m2
• Family history of diabetes (siblings, parent, and grandparents)
• Disease/medication known to affect primary outcome
• Self-reported high physical activity level
• Alcohol intake above general recommendations.
• Metabolic/liver disease
• Weight gain/loss of >3 kg within the past 6 months

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• 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: individuals with MASLD	Other: No intervention; No intervention; Behavioral: Caloric restriction intervention; The intervention consist of 4-weeks low calories diet (LCD) using total meal replacement from NUPO. A dietician will guide the participants an ensure well-being during the intervention.; Other Names: No intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Liver fat content	Liver elastography (FibroScan)	Change from baseline in liver fat content at 4 weeks
Liver fat content	Validation by Magnetic resonance spectroscopy (MRS)	Change from baseline in liver fat content at 4 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body composition	DEXA scan	Baseline and after 4 weeks
Liver stiffness	Liver elastography (FibroScan)	Baseline and after 4 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adipocyte size	Adipose tissue immunohistochemistry	Baseline and after 4 weeks
Collagen content	Adipose tissue immunohistochemistry	Baseline and after 4 weeks
Transcriptomics	RNAseq of bulk subcutaneous adipose tissue	Baseline and after 4 weeks
Transcriptomics	RNAseq of ex vivo cultured preadipocytes	Baseline and after 4 weeks
Epigenetics	Genome-wide DNA methylation of subcutaneous adipose tissue	Baseline and after 4 weeks
Epigenetics	Genome-wide DNA methylation of ex vivo cultured preadipocytes	Baseline and after 4 weeks
Metabolism of ex vivo differentiated preadipocytes	Functional characterization of lipid metabolism	Baseline and after 4 weeks
Metabolism of ex vivo differentiated preadipocytes	Functional characterization of glucose metabolism	Baseline and after 4 weeks

Collaborators and Investigators

• Sponsor: Steno Diabetes Center Copenhagen
• Collaborators: Lund University; Aarhus University Hospital
• Investigators: Principal Investigator: Charlotte Brøns, PhD, Steno Diabetes Center Copenhagen

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2026
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: April 11, 2023
• First Submitted That Met QC Criteria: April 24, 2023
• First Posted (Actual): May 6, 2023

Study Record Updates

• Last Update Posted (Actual): May 4, 2026
• Last Update Submitted That Met QC Criteria: April 28, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Energy expenditure; Insulin resistance; Caloric restriction; Insulin secretion; Adipose tissue biology
• Additional Relevant MeSH Terms: Metabolic Diseases; Digestive System Diseases; Glucose Metabolism Disorders; Liver Diseases; Hyperinsulinism; Fatty Liver; Nutritional and Metabolic Diseases; Non-alcoholic Fatty Liver Disease; Insulin Resistance
• Other Study ID Numbers: NAFLD reversibility

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: not allowed to share according to GDPR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No