BACKGROUND & AIMS: There have been few studies on 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 individuals 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 of intrahepatic triacylglycerol (LowLF, n=11). 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 (non-esterified) fatty acid (FFA) and triacylglycerol flux and lipogenesis. RESULTS: Individuals with HighLF (18.4%±3.6%) had higher plasma levels of FFA during the nighttime and 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 FFA (414±195 μmol/min for HighLF vs 358±105 μmol/min for LowLF; P=.41) or production of very low-density lipoprotein triacylglycerols from FFA (4.06±2.57 μmol/min vs 4.34±1.82 μmol/min; P=.77). By 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 individuals with NAFLD and control subjects, we confirmed that those with NAFLD increase synthesis of fatty acids. Subjects with NAFLD also had higher nocturnal plasma levels of FFA and did not suppress the contribution from de novo lipogenesis upon fasting. These findings indicate that lipogenesis might be a therapeutic target for NAFLD.

The current data provide support for the use of the VLDL-triacylglycerol 16:1n-7 molar percentage as a biomarker for elevated liver fat when isotope use is not feasible; however, larger-scale confirmatory studies are needed.

Objective This study determined whether reductions in postprandial plasma FFA flux would lead to reductions in plasma acylcarnitine (AC) concentrations. Materials/Methods Plasma AC were measured by LC-MS/MS in the fasting state and over 6h after a high-fat (50% energy) meal was fed to 16 overweight and obese subjects with a wide range of insulin sensitivities. Body composition was measured by DEXA, insulin sensitivity by FSIVGTT, substrate oxidation by indirect calorimetry, blood metabolite and hormone concentrations biochemically, and fatty acid flux by using stable isotope tracers. Results Lean body mass (LBM) and fasting fat oxidation correlated positively (r > 0.522, P<0.05), while glucose oxidation correlated negatively (r < −0.551, P <0.04) with fasting AC. Postprandially, plasma glucose, insulin, and TG concentrations increased, and FFA concentrations decreased significantly. The responses of plasma AC species depended on chain length and saturation, with C14:0, C16:0, and C18:0 remaining unchanged, and unsaturated species (e.g., C14:1, C14:2) falling significantly (21–46%, P < 0.03). Post-meal nadir AC concentrations were positively associated with LBM, postprandial fatty acid flux and FFA concentrations (r > 0.515, P < 0.05). By contrast, nadir AC correlated negatively with insulin sensitivity and spillover of meal-derived fatty acids (r < −0.528, P < 0.04). Conclusions Conditions that impact fatty acid flux contribute to the control of postprandial plasma AC concentrations. These data underscore the need for a better understanding of postprandial fatty acid oxidation and dietary fat delivery in the setting of adipose insulin resistance to determine how postprandial lipemia contributes to chronic disease risk.

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.

Introduction Although cardiovascular diseases (CVD) are the leading cause of death among Americans, significant disparities persist in CVD prevalence, morbidity, and mortality based on race and ethnicity. However, few studies have examined risk factor reduction among the poor and ethnic minorities. Methods Community-based participatory research (CBPR) study using a cluster randomized design — African-American church congregations are the units of randomization and individuals within the congregations are the units of analysis. Outcome variables include dietary change (Diet History Questionnaire), level of physical activity (7-Day Physical Activity Recall), lipoprotein levels, blood pressure, fasting glucose, and hemoglobin A1c. Results Eighteen (18) church congregations were randomized to either a health maintenance intervention or a control condition. Complete data were obtained on 392 African-American individuals, 18 to 70 years of age, predominantly employed women with more than a high school diploma. Treatment and intervention groups were similar at baseline on saturated fat intake, metabolic equivalent of tasks (METS) per day, and other risk factors for CVD. Conclusions The GoodNEWS trial successfully recruited and evaluated CVD-related risk among African-American participants using a CBPR approach. Several logistical challenges resulted in extending the recruitment, preliminary training, and measurement periods. The challenges were overcome with the assistance of a local community consultant and a professional event planner. Our experience supports the need for incorporating non-traditional community-based staff into the design and operational plan of CBPR trials.

Adiponectin overexpression in mice increases insulin sensitivity independent of adiposity. Here, we combined stable isotope infusion and in vivo measurements of lipid flux with transcriptomic analysis to characterize fatty acid metabolism in transgenic mice that overexpress adiponectin via the aP2-promoter (ADNTg). Compared with controls, fasted ADNTg mice demonstrated a 31% reduction in plasma free fatty acid concentrations (P = 0.008), a doubling of ketones (P = 0.028), and a 68% increase in free fatty acid turnover in plasma (15.1 ± 1.5 vs. 25.3 ± 6.8 mg/kg · min, P = 0.011). ADNTg mice had 2-fold more brown adipose tissue mass, and triglyceride synthesis and turnover were 5-fold greater in this organ (P = 0.046). Epididymal white adipose tissue was slightly reduced, possibly due to the approximately 1.5-fold increase in the expression of genes involved in oxidation (peroxisome proliferator-activated receptor α, peroxisome proliferator-activated receptor-γ coactivator 1α, and uncoupling protein 3). In ADNTg liver, lipogenic gene expression was reduced, but there was an unexpected increase in the expression of retinoid pathway genes (hepatic retinol binding protein 1 and retinoic acid receptor beta and adipose Cyp26A1) and liver retinyl ester content (64% higher, P < 0.02). Combined, these data support a physiological link between adiponectin signaling and increased efficiency of triglyceride synthesis and hydrolysis, a process that can be controlled by retinoids. Interactions between adiponectin and retinoids may underlie adiponectin's effects on intermediary metabolism.

Objectives Insulin control of fatty acid metabolism has long been deemed dominated by suppression of adipose lipolysis. This study’s goal was to test the hypothesis that this single role of insulin is insufficient to explain observed fatty acid dynamics. Methods and Results Fatty acid kinetics were measured during a meal-tolerance test and insulin sensitivity assessed by IVGTT in overweight human subjects (n=15, BMI 35.8 ± 7.1 kg/m2). Non-steady state tracer kinetic models were formulated and tested using ProcessDB© software. Suppression of adipose release alone could not account for NEFA concentration changes postprandially, but when combined with insulin activation of fatty acid uptake was consistent with the NEFA data. The observed insulin Km for NEFA uptake was inversely correlated with both insulin sensitivity of glucose uptake (IVGTT Si) (r=−0.626, P=0.01), and whole body fat oxidation after the meal (r=−0.538, P=0.05). Conclusions These results support insulin regulation of fatty acid turnover by both release and uptake mechanisms. Activation of fatty acid uptake is consistent with the human data, has mechanistic precedent in cell culture, and highlights a new potential target for therapies aimed at improving the control of fatty acid metabolism in insulin-resistant disease states.

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.