Effects of visceral adiposity on glycerol pathways in gluconeogenesis

Abstract

Objective To determine the feasibility of using oral 13C labeled glycerol at assess effects of visceral adiposity on gluconeogenic pathways in obese humans. Research Design and Methods Obese (BMI ≥30 kg/m2) participants without type 2 diabetes underwent visceral adipose tissue (VAT) assessment and stratification by median VAT into high VAT-fasting (n=3), low VAT-fasting (n=4), and high VAT-refed (n=2) groups. Participants ingested [U-13C3] glycerol and blood samples were subsequently analyzed at multiple time points over 3 hours by NMR spectroscopy. The fractions of plasma glucose (enrichment) derived from [U-13C3] glycerol via hepatic gluconeogenesis, pentose phosphate pathway (PPP), and tricarboxylic acid (TCA) cycle were assessed using 13C NMR analysis of glucose. Mixed linear models were used to compare 13C enrichment in glucose between groups. Results Mean age, BMI, and baseline glucose were 49 years, 40.1 kg/m2, and 98 mg/dl, respectively. Up to 20% of glycerol was metabolized in the TCA cycle prior to gluconeogenesis and PPP activity was minor (<1% of total glucose) in all participants. There was a 21% decrease in 13C enrichment in plasma glucose in the high VAT-fasting compared with low VAT-fasting group (p=0.03), suggesting dilution by endogenous glycerol. High VAT-refed participants had 37% less 13C enrichment in glucose compared with high VAT-fasting (p=0.02). There was a trend toward lower [1,2-13C2] (via PPP) and [5,6-13C2]/[4,5,6-13C3] (via TCA cycle) glucose in high VAT versus low VAT groups. Conclusions We applied a simple method to detect gluconeogenesis from glycerol in obese humans. Our findings provide preliminary evidence that excess visceral fat disrupts multiple pathways in hepatic gluconeogenesis from glycerol.

Effects of Empagliflozin Treatment on Glycerol‐Derived Hepatic Gluconeogenesis in Adults with Obesity: A Randomized Clinical Trial

“…In this randomized, placebo-controlled clinical trial, we tested and proved the hypothesis that empagliflozin would increase exogenous glycerolderived 13 C enrichment in blood glucose by likely reducing endogenous glycerol-derived hepatic gluconeogenesis from VAT in adults with obesity without T2DM. We did not observe an effect of empagliflozin on glycerol metabolism via the PPP or TCA pathways, although contribution of these pathways to glycerol gluconeogenesis is relatively minor (7). We also confirmed our prior observation that individuals with high VAT levels had lower glycerol-derived 13 C enrichment in glucose compared with those with low VAT.…”

“…NMR analysis procedures were performed as previously described (7). Briefly, plasma glucose was converted to monoacetone glucose for NMR spectral analysis.…”

An Integrated Understanding of the Molecular Mechanisms of How Adipose Tissue Metabolism Affects Long-term Body Weight Maintenance

“…Comparable glycerol levels between WM and WR seem to contradict differences in lipolysis. However, glycerol levels are also influenced by changes in other metabolic pathways, such as increased gluconeogenesis in the fasting state (21). Thus, our data do not mandatorily exclude differences in adipose tissue lipolysis.…”

Mitochondrial dysfunction in rat splenocytes following hemorrhagic shock

“…Furthermore a concomitant slowdown of Krebs cycle was indicated by the decreased citrate synthase activity. Citrate synthase catalyzes the condensation of oxaloacetate with the incoming acetyl CoA in the generation of citrate, a 6-carbon intermediate, in the citric acid cycle (40). …”