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.

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.

Adipose tissue biology, Caloric restriction, Insulin resistance, Energy expenditure, Insulin secretion

Participants will be recruited from a nested case-control (NAFLD) screening study. Participants will be examined on two separate days at baseline (both groups) and after 4-weeks caloric restriction (LBW with NAFLD only). The caloric restriction intervention will start immediately after completion of baseline examinations. Participants will adhere to a caloric restriction protocol for 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 will be instructed to eat a balanced diet according to the current dietary guidelines reduced by 20% calories to ensure energy deficit. A weighed food diary and accelerometers will be used for 3-days to estimate baseline dietary intake and physical activity and to monitor intervention adherence after 2 and 4 weeks.

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.

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