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

Abstract

BackgroundLipolysis 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.MethodsEight 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.ResultsLPS 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.ConclusionLPS 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.Trial RegistrationClinicalTrials.gov NCT01705782

High Fat Diets Composed of Palm Stearin and Olive Oil Equally Exacerbate Liver Inflammatory Damage and Metabolic Stress in Mice

“…GPCR40 is highly expressed in pancreatic beta cells and plays a crucial role in FFA‐induced insulin secretion . LPS treatment in humans has been shown to stimulate lipolysis, which is observed in the early stages of acute inflammation and sepsis . It is very much possible that the increase in insulin levels is due to the induction of lipolysis in the HFD supplemented animals, and with surplus of FFAs that can induce insulin release by the fatty acid receptors in the pancreases.…”

Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last?

“…The molecular mechanisms behind this upregulation of lipolysis have hardly been addressed. One study showed that LPS infusion in human subjects led to an increased phosphorylation of hormone sensitive lipase (HSL) at Ser 650 , a modification known to activate the enzyme (Rittig et al , ). HSL is one of the best described lipases (encoded by the LIPE gene) and could, together with the other important enzyme adipose triglyceride lipase (ATGL, PNPLA2 gene), be involved in the (patho)physiological lipolysis in white adipose tissue (WAT).…”

“…HSL is one of the best described lipases (encoded by the LIPE gene) and could, together with the other important enzyme adipose triglyceride lipase (ATGL, PNPLA2 gene), be involved in the (patho)physiological lipolysis in white adipose tissue (WAT). Also, cAMP‐dependent protein kinase A (PKA)‐dependent phosphorylation of perilipin 1 (PLIN1) is a decisive step in the activation of lipolysis (Choi et al , ) and was found to be elevated after LPS infusion (Rittig et al , ). This suggests that increased PKA activity might be one of the driving forces behind the increased lipolysis.…”

Interactive association of lipopolysaccharide and free fatty acid with the prevalence of type 2 diabetes: A community‐based cross‐sectional study

“…A diet rich in saturated fatty acids is considered to elicit a metabolic inflammation by promoting intestinal permeation to LPS. In contrast, injection of LPS causes a significant serum FFA increase in vivo . LPS has been shown to decrease the utilization of FFA by inhibiting triglyceride synthesis, suppressing the oxidation of FFA and stimulating lipolysis in adipose tissue, thereby increasing the circulating levels of FFA.…”

“…In contrast, injection of LPS causes a significant serum FFA increase in vivo . LPS has been shown to decrease the utilization of FFA by inhibiting triglyceride synthesis, suppressing the oxidation of FFA and stimulating lipolysis in adipose tissue, thereby increasing the circulating levels of FFA. A low‐dose lipid infusion increases serum FFA levels, and monocytes exposed to lipid infusion in vivo enhance the in vitro secretion of pro‐inflammatory cytokines stimulated by LPS.…”