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 deep phenotyping 4-weeks caloric restriction intervention study in low birth weight (LBW) subjects with NAFLD and normal birth weight (NBW) controls. Furthermore, the investigators will provide extended in-depth mechanistic insight into the role of impaired subcutaneous adipose tissue (SAT) expandability in ectopic fat deposition in LBW subjects in LBW individuals with and without NAFLD.

Study Overview

• Status: Not yet 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 in 250 early middle-aged non-obese LBW men and women, and subsequently to conduct a deep-phenotyping, proof-of-principle 4 week time-restricted eating (TRE) intervention study in 12 LBW subjects with NAFLD including measures of hepatic fat content, glucose, insulin and lipid metabolism, as well as 24h metabolic profiles using respiratory chambers. Finally, 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 LBW individuals with and without NAFLD and NBW controls studied before and after different dietary interventions including TRE and high carbohydrate overfeeding.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Not Applicable

Contacts and Locations

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

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• LBW subjects with NAFLD (liver fat content ≥5% liver fat content verified on MRS)
• Gender- and body mass index-matched NBW controls without NAFLD
• Born at term (weeks 39-41)

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: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LBW individuals with NAFLD	Behavioral: Caloric restriction intervention; The intervention consist of 4-weeks limiting daily food intake to a window of 8 hours (8am to 4pm) and water-fasting for the remaining hours of the day. Participants (LBW NAFLD individuals only) will be instructed to eat a balanced diet according to the current dietary guidelines reduced by 20% calories to ensure energy deficit.; Other Names: No intervention
Placebo Comparator: NBW controls without NAFLD; Age-, gender- and body mass index-matched NBW controls without NAFLD	Other: No intervention; 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
Liver fibrosis	Liver elastography (FibroScan)	Baseline and after 4 weeks
Whole-body insulin sensitivity	Stepwise hyperinsulinemic-euglycemic clamp	Baseline and after 4 weeks
Beta-cell function	Intravenous glucose tolerance test	Baseline and after 4 weeks
Glucose turnover rate	Stable isotope dilution technique	Baseline and after 4 weeks
Fat turnover rate	Stable isotope dilution techniques	Baseline and after 4 weeks
Urea turnover rate	Stable isotope dilution techniques	Baseline and after 4 weeks
24-hour energy metabolism	Indirect calorimetry in respiratory chamber	Baseline and after 4 weeks
Body composition	DEXA scan	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 (Estimated): August 1, 2024
• Primary Completion (Estimated): August 1, 2025
• Study Completion (Estimated): August 1, 2025

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): April 19, 2024
• Last Update Submitted That Met QC Criteria: April 18, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Energy expenditure; Insulin resistance; Caloric restriction; Insulin secretion; Adipose tissue biology
• Additional Relevant MeSH Terms: Digestive System Diseases; Body Weight; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Birth Weight
• Other Study ID Numbers: NAFLD reversibility

Drug and device information, study documents

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