Increased liver fat associates with severe metabolic perturbations in low birth weight men

Abstract

Objective: Ectopic liver fat deposition, resulting from impaired subcutaneous adipose tissue expandability, may represent an age-dependent key feature linking low birth weight (LBW) with increased risk of Type 2 diabetes (T2D). We examined whether presumably healthy early middle-aged, non-obese LBW subjects exhibit increased liver fat content, whether increased liver fat in LBW associates with severity of dysmetabolic traits, and finally whether such associations may be confounded by genetic factors. Methods: Using 1H magnetic resonance spectroscopy, we measured hepatic fat content in 26 early middle-aged, non-obese LBW and 22 BMI-matched normal birth weight (NBW) males. Endogenous glucose production was measured by stable isotopes, and a range of plasma adipokine and gut hormone analytes were measured by multiplex ELISA. Genetic risk scores were calculated from GWAS data for birth weight, height, T2D, plasma cholesterol and risk genotypes for non-alcoholic fatty liver disease (NAFLD). Results: The LBW subjects had significantly increased hepatic fat content compared with NBW controls (P=0.014), and 20% of LBW versus no controls, had overt NAFLD. LBW subjects with NAFLD displayed widespread metabolic changes compared with NBW and LBW individuals without NAFLD, including hepatic insulin resistance, plasma adipokine and gut hormone perturbations as well as dyslipidemia. As an exception, plasma adiponectin levels were lower in LBW subjects both with and without NAFLD. Genetic risk for selected differential traits did not differ between groups. Conclusion: Increased liver fat content including overt NAFLD may be on the critical path linking LBW with increased risk of developing T2D in a non-genetic manner.

The PPARα/CYP4A14 bile acid pathway is associated with lipid metabolism disorders caused by low birth weight with high-fat diet

“…After 17 weeks of HFD, the body weight was not significantly different between the two groups (Figure 1C). Several clinic studies suggested that LBW individuals on HFD showed an increased trend toward serum TC and liver fat compared to NBW on HFD (18)(19)(20). Animal studies also showed that LBW is a risk factor for increased hepatic cholesterol (21).…”

Circulating Metabolomic and Lipidomic Signatures Identify a Type 2 Diabetes Risk Profile in Low-Birth-Weight Men with Non-Alcoholic Fatty Liver Disease

“…The study included 48 healthy Caucasian males born at gestational weeks 39–41 between 1979 and 1980 and recruited from the Birth Registry at the Danish Health Data Authority, as described previously [ 3 ]. In total, 26 individuals were born with a birth weight < 10th percentile (LBW) and 22 individuals were age- and BMI-matched controls born with a birth weight between the 50th and 90th percentile (NBW).…”

“…Low-birth-weight (LBW) is a marker of an adverse fetal environment and is associated with an increased risk of developing type 2 diabetes (T2D) [ 1 , 2 ]. We recently reported that 20% of non-obese (BMI < 30 kg/m 2 ) LBW individuals with a mean age of 38 years exhibit previously unrecognized non-alcoholic fatty liver disease (NAFLD), supporting the hypothesis of ectopic fat deposition as a key pathophysiological feature underlying development of T2D in individuals born with a LBW [ 3 , 4 , 5 , 6 ]. The LBW individuals with NAFLD were characterized by elevated hepatic insulin resistance, fasting levels of insulin, C -peptide, and triglycerides (TG), as well as elevated plasma levels of leptin and GLP-1, compared with both LBW and normal-birth-weight (NBW) individuals without NAFLD [ 3 ].…”

“…The LBW individuals with NAFLD were characterized by elevated hepatic insulin resistance, fasting levels of insulin, C -peptide, and triglycerides (TG), as well as elevated plasma levels of leptin and GLP-1, compared with both LBW and normal-birth-weight (NBW) individuals without NAFLD [ 3 ]. As an exception, plasma adiponectin levels were decreased to the same extent in LBW individuals with and without NAFLD compared with NBW individuals [ 3 ]. Nevertheless, the results collectively suggested that increased liver fat and NAFLD may be on the critical path to T2D development in LBW subjects.…”

Understanding heterogeneity of responses to, and optimizing clinical efficacy of, exercise training in older adults: NIH NIA Workshop summary

“…Both early and late life stimuli are capable of creating a metabolic environment that leads to epigenomic programming or “memory” in tissues. One recent example of this is the observation that low birthweight infants have higher liver fat and earlier onset of prediabetes compared to normal birth weight counterparts [ 65 ]. These findings suggest that differences in metabolic health across various stages of life have residual effects.…”