A Very-low-energy Fast Involves Increased Adipose Inflammatory Gene Expression: A 6-day Feeding Trial (FASTOMICS-6).

Abstract

Fasting and ketogenic diets may have health benefits, but we lack a deeper understanding of tissue mechanisms and associated metabolome changes, particularly in humans. Determine changes in subcutaneous adipose tissue (SAT) gene expression, plasma metabolomics, and circulating serum markers after a 6-day very-low-energy fast. 13 patients with obesity (mean body mass index = 41.6) underwent a week-long in-hospital feeding study (600 kcal/day). Body composition was assessed by bioimpedance. Blood and SAT were collected on days 1 and 7 for metabolomics (gas chromatography coupled with tandem mass spectrometry) and transcriptomics (RNA-sequencing). Biological pathways were inferred from affected gene sets (gene set enrichment analysis) and gene networks that correlated with plasma metabolites. Relative mean change (95% CI) in fat mass and fat-free mass was -2.07% (-2.93 to -1.20) and -4.42% (-5.53 to -3.28), respectively. Marked significant changes (relative mean change [95% CI]) were observed in total ketone bodies (acetoacetate + β-hydroxybutyrate) (+615% [366-999]), fasting insulin (-41.2% [-53.1 to -26.4]) and homeostatic model assessment for insulin resistance (-31.8% [-41.4 to -20.6]), as well as α-hydroxybutyrate (+103% [69.9-142]) and the advanced glycation end-products carboxyethyl-lysine (-46.0% [-53.6 to -37.2]) and carboxymethyl-lysine (-50.9% [-59.8 to -40.1]). Gene set enrichment analysis indicated upregulated inflammatory responses, and downregulated oxidative phosphorylation, adipogenesis, fatty acid metabolism, and mTORC1 signaling (P < .01) in SAT. After a 6-day very-low-energy fast, adipose inflammatory gene expression increased concomitant with decreased plasma advanced glycation end-products and improved insulin sensitivity. These data suggest a role for inflammatory and autophagy-associated pathways in the metabolic adaptation to a ketogenic very-low-energy fast. NCT02671279 (https://clinicaltrials.gov/study/NCT02671279).