A Very-Low Energy Fast Involves Increased Adipose Inflammatory Gene Expression: A 6-Day Feeding Trial (FASTOMICS-6)

Background Fasting and ketogenic diets may have health benefits, but we lack a deeper understanding of tissue mechanisms and associated metabolome changes, particularly in humans. Objective Determine changes in subcutaneous adipose tissue (SAT) gene expression, plasma metabolomics and circulating serum markers after a 6-day very-low-energy fast. Methods 13 patients with obesity (mean BMI = 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 day 1 and 7 for metabolomics (GC-MS/MS) and transcriptomics (RNA-sequencing). Biological pathways were inferred from affected gene sets (GSEA) and gene networks that correlated with plasma metabolites (WGCNA). Results Relative mean change (95% CI) in fat mass and fat-free mass was −2.07% (−2.93, −1.20) and −4.42% (−5.53, −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, −26.4)) and HOMA2-IR (−31.8% (−41.4, −20.6)), as well as α-hydroxybutyrate (+103% (69.9, 142)) and the advanced glycation end-products (AGEs) Carboxyethyl-Lysine (−46.0% (−53.6, −37.2)) and Carboxymethyl-Lysine (−50.9% (−59.8, −40.1)). GSEA indicated upregulated inflammatory responses, and downregulated oxidative phosphorylation, adipogenesis, fatty acid metabolism and mTORC1 signaling (p<0.01) in SAT. Conclusion After a 6-day very-low energy fast, adipose inflammatory gene expression increased concomitant with decreased plasma AGEs 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.