Background & Aims There have been few studies of the role of de novo lipogenesis in the development of nonalcoholic fatty liver disease (NAFLD). We used isotope analyses to compare de novo lipogenesis and fatty acid flux between subjects with NAFLD and those without, matched for metabolic factors (controls). Methods We studied subjects with metabolic syndrome and/or levels of alanine aminotransferase and aspartate aminotransferase >30 mU/L, using magnetic resonance spectroscopy to identify those with high levels (HighLF, n = 13) or low levels (LowLF, n = 11) of liver fat. Clinical and demographic information was collected from all participants, and insulin sensitivity was measured using the insulin-modified intravenous glucose tolerance test. Stable isotopes were administered and gas chromatography with mass spectrometry was used to analyze free (nonesterified) fatty acid (FFA) and triacylglycerol flux and lipogenesis. Results Subjects with HighLF (18.4% ± 3.6%) had higher plasma levels of FFAs during the nighttime and higher concentrations of insulin than subjects with LowLF (3.1% ± 2.7%; P = .04 and P < .001, respectively). No differences were observed between groups in adipose flux of FFAs (414 ± 195 μmol/min for HighLF vs 358 ± 105 μmol/min for LowLF; P = .41) or production of very-low-density lipoprotein triacylglycerol from FFAs (4.06 ± 2.57 μmol/min vs 4.34 ± 1.82 μmol/min; P = .77). In contrast, subjects with HighLF had more than 3-fold higher rates of de novo fatty acid synthesis than subjects with LowLF (2.57 ± 1.53 μmol/min vs 0.78 ± 0.42 μmol/min; P = .001). As a percentage of triacylglycerol palmitate, de novo lipogenesis was 2-fold higher in subjects with HighLF (23.2% ± 7.9% vs 10.1% ± 6.7%; P < .001); this level was independently associated with the level of intrahepatic triacylglycerol (r = 0.53; P = .007). Conclusions By administering isotopes to subjects with NAFLD and control subjects, we confirmed that those with NAFLD have increased synthesis of fatty acids. Subjects with NAFLD also had higher nocturnal plasma levels of FFAs and did not suppress the contribution from de novo lipogenesis on fasting. These findings indicate that lipogenesis might be a therapeutic target for NAFLD.

Pregnancy and puerperium are periods of intense hormonal changes. Maternal metabolism adapts to spare the mother from harm on behalf of her developing offspring and major alterations maintain normal glucose tolerance. Insulin secretion increases during a normal pregnancy to compensate for pregnancy-induced insulin resistance and maintain euglycemia. Women at risk for gestational diabetes have insulin resistance before conception. Gestational diabetes develops when a woman at risk is unable to meet the insulin secretory demands imposed by the additional insulin resistance characteristic of pregnancy. The lactogens, human placental lactogen and prolactin, are major stimuli for the adaptation of the endocrine pancreas during gestation. This review discusses the role of lactogens on glucose homeostasis during pregnancy and proposes a mechanism by which the hormonal control of lactation, led by prolactin, may regulate adipocyte biology, glucose and lipid metabolism, and guard postpartum women against type 2 diabetes.

BACKGROUND: Lipogenesis contributes substantially to the pathological accumulation of intrahepatic triacylglycerol (IHTG) in metabolic dysfunction–associated steatotic liver disease (MASLD). Since hepatic lipogenesis is highly sensitive to energy intake, we hypothesized that mechanisms of MASLD regression induced by weight loss would be driven by a marked reduction in the lipogenic pathway. METHODS: Overweight adults with high liver fat (HighLF; n = 9; IHTG ≥ 5.6% measured by ¹ H-magnetic resonance spectroscopy) or low (normal) liver fat (LowLF; n = 6; IHTG < 5.6%) received dietary counseling for 6 months and underwent comprehensive metabolic phenotyping during inpatient studies that captured fasting and fed states. Multiple stable isotopes were used to assess the contribution of lipogenesis, free fatty acids (FFAs), and dietary fat to IHTG. RESULTS: Body weight loss (–10% ± 2%) reduced IHTG in individuals with MASLD (19.4% ± 3.6% to 4.5% ± 2.1%, P < 0.001). Insulin sensitivity improved significantly (46%, P < 0.01), while fasting FFA flux from adipose tissue was not different. VLDL-triacylglycerol (VLDL-TG) concentrations fell by 38% ( P = 0.02) because of a 67% reduction in contribution from lipogenesis ( P = 0.02), whereas the absolute contributions from FFAs and dietary fat to VLDL-TG were not different. Reduced lipogenesis was significantly associated with loss of IHTG. CONCLUSION: These data underscore the primary role of lipogenesis in MASLD pathology and highlight the importance of controlling this pathway through treatment strategies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01371396). FUNDING: National Institutes of Health (NIH) grant RL1DK081187; Task Force for Obesity Research at Southwestern (TORS) NIH UL1DE019584; and Clinical and Translational Science Award NIH/National Center for Advancing Translational Sciences UL1-RR024982.

Milk production may involve a transient development of insulin resistance in nonmammary tissues to support redistribution of maternal macronutrients to match the requirements of the lactating mammary gland. In the current study, adipose and liver metabolic responses were measured in the fasting state and during a two-step (10 and 20 mU/m²/min) hyperinsulinemic-euglycemic clamp with stable isotopes, in 6-week postpartum women who were lactating (n = 12) or formula-feeding (n = 6) their infants and who were closely matched for baseline characteristics (e.g., parity, body composition, and intrahepatic lipid). When controlling for the low insulin concentrations of both groups, the lactating women exhibited a fasting rate of endogenous glucose production (EGP) that was 2.6-fold greater and a lipolysis rate that was 2.3-fold greater than the formula-feeding group. During the clamp, the groups exhibited similar suppression rates of EGP and lipolysis. In the lactating women only, higher prolactin concentrations were associated with greater suppression rates of lipolysis and lower intrahepatic lipid and plasma triacylglycerol concentrations. These data suggest that whole-body alterations in glucose transport may be organ specific and facilitate nutrient partitioning during lactation. Recapitulating a shift toward noninsulin-mediated glucose uptake could be an early postpartum strategy to enhance lactation success in women at risk for delayed onset of milk production.

In mothers who are nursing their infants, increased clearance of plasma metabolites into the mammary gland may reduce ectopic lipid in the liver. No study to date has investigated the role of lactation on liver lipid synthesis in humans, and we hypothesized that lactation would modify fatty acid and glucose handling to support liver metabolism in a manner synchronized with the demands of milk production. Lactating (n = 18) and formula-feeding women (n = 10) underwent metabolic testing at 6-week postpartum to determine whether lactation modified intrahepatic triacylglycerols (IHTGs), measured by proton magnetic resonance spectroscopy. Subjects ingested oral deuterated water to measure fractional de novo lipogenesis (DNL) in VLDL-TG during fasting and during an isotope-labeled clamp at an insulin infusion rate of 10 mU/m²/min. Compared with formula-feeding women, we found that lactating women exhibited lower plasma VLDL-TG concentrations, similar IHTG content and similar contribution of DNL to total VLDL-TG production. These findings suggest that lactation lowers plasma VLDL-TG concentrations for reasons that are unrelated to IHTG and DNL. Surprisingly, we determined that the rate of appearance of nonesterified fatty acids was not related to IHTG in either group, and the expected positive association between DNL and IHTG was only significant in formula-feeding women. Further, in lactating women only, the higher the prolactin concentration, the lower the IHTG, while greater DNL strongly associated with elevations in VLDL-TG. In conclusion, we suggest that future studies should investigate the role of lactation and prolactin in liver lipid secretion and metabolism.