Dietary fat and carbohydrates differentially alter insulin sensitivity during caloric restriction

BACKGROUND AND AIMS: We determined the effects of acute and chronic calorie restriction with either a low-fat, high-carbohydrate diet or a low-carbohydrate diet on hepatic and skeletal muscle insulin sensitivity. METHODS: Twenty-two obese subjects (body-mass index, 36.5±0.8kg/m(2)) were randomized to a high-carbohydrate (>180g/d) or low-carbohydrate (<60g/d) energy-deficit diet. A euglycemic–hyperinsulinemic clamp, muscle biopsies, and magnetic resonance spectroscopy were used to determine insulin action, cellular insulin signaling and intrahepatic triglyceride content before, after 48 h, and after ~11 wks (7% weight loss) of diet therapy. RESULTS: At 48 h, intrahepatic triglyceride content decreased more in the low-carbohydrate than the high-carbohydrate diet group (29.6±4.8% vs. 8.9±1.4%; P<0.05), but was similar in both groups after 7% weight loss (low-carbohydrate diet, 38.0±4.5% vs. high-carbohydrate diet, 44.5±13.5%). Basal glucose production rate decreased more in the low-carbohydrate than the high-carbohydrate diet group at 48 h (23.4±2.2% vs. 7.2±1.4%, P<0.05) and after 7% weight loss (20.0±2.4% vs. 7.9±1.2%, P<0.05). Insulin-mediated glucose uptake did not change at 48 h, but increased similarly in both groups after 7% weight loss (48.4±14.3%, P<0.05). In both groups, insulin-stimulated phosphorylation of Jun N-terminal kinase decreased by 29±13% and phosphorylation of Akt and insulin receptor substrate -1 increased by 35±9% and 36±9%, respectively, after 7% weight loss (all p<0.05). CONCLUSION: Moderate calorie restriction causes temporal changes in liver and skeletal muscle metabolism; 48 h of calorie restriction affects the liver (intrahepatic triglyceride content, hepatic insulin sensitivity, and glucose production), whereas moderate weight loss affects muscle (insulin-mediated glucose uptake and insulin signaling)

Dynamic shifts in the composition of resident and recruited macrophages influence tissue remodeling in NASH

Macrophage-mediated inflammation is critical in the pathogenesis of non-alcoholic steatohepatitis (NASH). Here, we describe that, with high-fat, high-sucrose-diet feeding, mature TIM

Silencing alanine transaminase 2 in diabetic liver attenuates hyperglycemia by reducing gluconeogenesis from amino acids

Hepatic gluconeogenesis from amino acids contributes significantly to diabetic hyperglycemia, but the molecular mechanisms involved are incompletely understood. Alanine transaminases (ALT1 and ALT2) catalyze the interconversion of alanine and pyruvate, which is required for gluconeogenesis from alanine. We find that ALT2 is overexpressed in the liver of diet-induced obese and db/db mice and that the expression of the gene encoding ALT2 (GPT2) is downregulated following bariatric surgery in people with obesity. The increased hepatic expression of Gpt2 in db/db liver is mediated by activating transcription factor 4, an endoplasmic reticulum stress-activated transcription factor. Hepatocyte-specific knockout of Gpt2 attenuates incorporation o

Steatosis drives monocyte-derived macrophage accumulation in human metabolic dysfunction-associated fatty liver disease

BACKGROUND & AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common complication of obesity with a hallmark feature of hepatic steatosis. Recent data from animal models of MAFLD have demonstrated substantial changes in macrophage composition in the fatty liver. In humans, the relationship between liver macrophage heterogeneity and liver steatosis is less clear. METHODS: Liver tissue from 21 participants was collected at time of bariatric surgery and analysed using flow cytometry, immunofluorescence, and H&E microscopy. Single-cell RNA sequencing was also conducted on a subset of samples (n = 3). Intrahepatic triglyceride content was assessed via MRI and tissue histology. Mouse models of hepatic steatosis were used to investigate observations made from human liver tissue. RESULTS: We observed variable degrees of liver steatosis with minimal fibrosis in our participants. Single-cell RNA sequencing revealed four macrophage clusters that exist in the human fatty liver encompassing Kupffer cells and monocyte-derived macrophages (MdMs). The genes expressed in these macrophage subsets were similar to those observed in mouse models of MAFLD. Hepatic CD14 CONCLUSIONS: The human liver in MAFLD contains macrophage subsets that align well with those that appear in mouse models of fatty liver disease. Recruited myeloid cells correlate well with the degree of liver steatosis in humans. MdMs appear to participate in lipid uptake during early stages of MALFD. IMPACT AND IMPLICATIONS: Metabolic dysfunction associated fatty liver disease (MAFLD) is extremely common; however, the early inflammatory responses that occur in human disease are not well understood. In this study, we investigated macrophage heterogeneity in human livers during early MAFLD and demonstrated that similar shifts in macrophage subsets occur in human disease that are similar to those seen in preclinical models. These findings are important as they establish a translational link between mouse and human models of disease, which is important for the development and testing of new therapeutic approaches for MAFLD

Many Labs 2: Investigating Variation in Replicability Across Samples and Settings

We conducted preregistered replications of 28 classic and contemporary published findings, with protocols that were peer reviewed in advance, to examine variation in effect magnitudes across samples and settings. Each protocol was administered to approximately half of 125 samples that comprised 15,305 participants from 36 countries and territories. Using the conventional criterion of statistical significance (p < .05), we found that 15 (54%) of the replications provided evidence of a statistically significant effect in the same direction as the original finding. With a strict significance criterion (p < .0001), 14 (50%) of the replications still provided such evidence, a reflection of the extremely highpowered design. Seven (25%) of the replications yielded effect sizes larger than the original ones, and 21 (75%) yielded effect sizes smaller than the original ones. The median comparable Cohen’s ds were 0.60 for the original findings and 0.15 for the replications. The effect sizes were small (< 0.20) in 16 of the replications (57%), and 9 effects (32%) were in the direction opposite the direction of the original effect. Across settings, the Q statistic indicated significant heterogeneity in 11 (39%) of the replication effects, and most of those were among the findings with the largest overall effect sizes; only 1 effect that was near zero in the aggregate showed significant heterogeneity according to this measure. Only 1 effect had a tau value greater than .20, an indication of moderate heterogeneity. Eight others had tau values near or slightly above .10, an indication of slight heterogeneity. Moderation tests indicated that very little heterogeneity was attributable to the order in which the tasks were performed or whether the tasks were administered in lab versus online. Exploratory comparisons revealed little heterogeneity between Western, educated, industrialized, rich, and democratic (WEIRD) cultures and less WEIRD cultures (i.e., cultures with relatively high and low WEIRDness scores, respectively). Cumulatively, variability in the observed effect sizes was attributable more to the effect being studied than to the sample or setting in which it was studied.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Sociales::Instituto de Investigaciones Psicológicas (IIP