Regulation of Lipolysis and Adipose Tissue Signaling during Acute Endotoxin-Induced Inflammation: A Human Randomized Crossover Trial.
BACKGROUND
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.


METHODS
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 (Rapalmitate) 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.


RESULTS
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 Rapalmitate 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.


CONCLUSIONS
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.


BACKGROUND
ClinicalTrials.gov NCT01705782.
Department of Internal Medicne and Endocrinology (MEA) and Medical Research Laboratory, Aarhus University Hospital, Nørrebrogade 44, 8000, Aarhus, C, Denmark.
Nikolaj
N
Rittig
Department of Internal Medicne and Endocrinology (MEA) and Medical Research Laboratory, Aarhus University Hospital, Nørrebrogade 44, 8000, Aarhus, C, Denmark.
Ermina
E
Bach
Department of Internal Medicne and Endocrinology (MEA) and Medical Research Laboratory, Aarhus University Hospital, Nørrebrogade 44, 8000, Aarhus, C, Denmark.
Henrik Holm
HH
Thomsen
Department of Internal Medicne and Endocrinology (MEA) and Medical Research Laboratory, Aarhus University Hospital, Nørrebrogade 44, 8000, Aarhus, C, Denmark.
Steen Bønlykke
SB
Pedersen
The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3b, 6.6.30, DK-2200 N, Copenhagen, Denmark.
Thomas Sava
TS
Nielsen
Department of Internal Medicne and Endocrinology (MEA) and Medical Research Laboratory, Aarhus University Hospital, Nørrebrogade 44, 8000, Aarhus, C, Denmark.
Jens O
JO
Jørgensen
Department of Internal Medicne and Endocrinology (MEA) and Medical Research Laboratory, Aarhus University Hospital, Nørrebrogade 44, 8000, Aarhus, C, Denmark.|Research Laboratory for Biochemical Pathology, Institute for Clinical Medicine, Aarhus University Hospital, Nørrebrogade 44, 8000, Aarhus, C, Denmark.
Niels
N
Jessen
Department of Internal Medicne and Endocrinology (MEA) and Medical Research Laboratory, Aarhus University Hospital, Nørrebrogade 44, 8000, Aarhus, C, Denmark.
Niels
N
Møller
D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D018592:Cross-Over Studies; D004731:Endotoxins / Q000633:toxicity*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced*; D008066:Lipolysis; D008297:Male; D010919:Placebos; D015398:Signal Transduction
D004731:Endotoxins; D010919:Placebos