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.

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.

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