Lipolysis is accelerated during the acute phase of inflammation, a process being regulated by pro-inflammatory cytokines (e.g. TNF-α), stress-hormones, and insulin. The intracellular mechanisms remain elusive and we therefore measured pro- and anti-lipolytic signaling pathways in adipocytes after in vivo endotoxin exposure. Eight healthy, lean, male subjects were investigated using a randomized cross over trial with two interventions: i) bolus injection of saline (Placebo) and ii) bolus injection of lipopolysaccharide endotoxin (LPS). A ³H-palmitate tracer was used to measure palmitate rate of appearance (Ra_palmitate) and indirect calorimetry was performed to measure energy expenditures and lipid oxidation rates. A subcutaneous abdominal fat biopsy was obtained during both interventions and subjected to western blotting and qPCR quantifications. LPS caused a mean increase in serum free fatty acids (FFA) concentrations of 90% (CI-95%: 37–142, p = 0.005), a median increase in Ra_palmitate of 117% (CI-95%: 77–166, p<0.001), a mean increase in lipid oxidation of 49% (CI-95%: 1–96, p = 0.047), and a median increase in energy expenditure of 28% (CI-95%: 16–42, p = 0.001) compared with Placebo. These effects were associated with increased phosphorylation of hormone sensitive lipase (pHSL) at ser⁶⁵⁰ in adipose tissue (p = 0.03), a trend towards elevated pHSL at ser⁵⁵² (p = 0.09) and cAMP-dependent protein kinase A (PKA) phosphorylation of perilipin 1 (PLIN1) (p = 0.09). Phosphatase and tensin homolog (PTEN) also tended to increase (p = 0.08) while phosphorylation of Akt at Thr³⁰⁸ tended to decrease (p = 0.09) during LPS compared with Placebo. There was no difference between protein or mRNA expression of ATGL, G0S2, and CGI-58. LPS stimulated lipolysis in adipose tissue and is associated with increased pHSL and signs of increased PLIN1 phosphorylation combined with a trend toward decreased insulin signaling. The combination of these mechanisms appear to be the driving forces behind the increased lipolysis observed in the early stages of acute inflammation and sepsis. ClinicalTrials.gov NCT01705782

Background D-3-hydroxybutyrate (D-3-OHB) is a ketone body that serves as an alternative nutritional fuel but also as an important signalling metabolite. Oral ketone supplements containing D/L-3-OHB are becoming a popular approach to achieve ketosis. Aim To explore the gut-derived effects of ketone supplements. Methods Eight healthy lean male volunteers were investigated on two separate occasions: i)Following an oral D/L-3-OHB consumption (oral) and, ii)following isoketonemic intravenous ketone (D/L-3-OHB) infusion (iv). An acetaminophen test was performed to evaluate gastric emptying and blood samples were obtained consecutively throughout the study period. Results We show that oral consumption of D/L-3-OHB stimulates cholecystokinin release (p=0.02), elevates insulin (p=0.03) and C-peptide (p<0.001) concentrations, and slows gastric emptying (p=0.01) compared with intravenous D/L-3-OHB administration. Measures of appetite and plasma concentrations of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) were unaffected by interventions. Conclusion Our findings show that D/L-3-OHB exert incretin effects and indicate luminal sensing in the gut endothelium. This adds to our understanding of ketones as signalling metabolites and displays the important difference between physiological ketosis and oral ketone supplements.