Increased Liver Fat Is Associated with Severe Metabolic Perturbations in Men Born with a Low Birth Weight

Background: Ectopic fat deposition resulting from impaired subcutaneous adipose tissue expandability may take center stage in the pathophysiological events linking low birth weight (LBW) with increased risk of developing Type 2 diabetes (T2D) . However, the extent to which adult LBW subjects exhibit increased hepatic fat accumulation is controversial.

Methods and Results: Using 1H MR spectroscopy, we found a significantly increased hepatic fat content (P=0.014) in 26 early middle-aged and non-obese LBW males compared with 21 BMI- and age-matched normal birth weight (NBW) controls. Interestingly, 5 LBW (20%) versus no NBW subjects, had previously unrecognized overt nonalcoholic fatty liver disease (NAFLD) with a median hepatic fat content of 9.45%. The LBW w/NAFLD displayed widespread metabolic changes compared with both NBW and LBW w/o NAFLD subjects including hepatic insulin resistance (P=0.02) , increased fasting plasma triglycerides (TGs) (P=0.03) , cholesterol (P=0.05) , leptin, C-peptide and GLP-1 levels, as well as decreased adiponectin levels (P-range: 0.02-0.007) . Among 65 distinct metabolites and 279 lipids identified by untargeted serum metabolomic and lipidomic analyses, the levels of 7 metabolites including ornithine and citrulline, were different (P<0.05) between LBW w/NAFLD and NBW subjects, pointing towards increased urea cycling in the LBW w/NAFLD subjects. Moreover, the LBW w/NAFLD subjects displayed disproportionately increased levels of phosphatidylcholines and TGs (P<0.05) , with both lipid species qualitatively changed in the LBW w/NAFLD subjects consisting of an increased amount of long chain fatty acids as well as fewer double bonds. These structural lipid characteristics are known to be associated with T2D.

Conclusion: The data support a role for ectopic fat deposition in the pathophysiological events and trajectories linking LBW with increased risk of developing T2D and associated cardiometabolic traits including dyslipidemia.