Effects of short-term prednisolone treatment on indices of lipolysis and lipase signaling in abdominal adipose tissue in healthy humans

Metabolism. 2019 Oct:99:1-10. doi: 10.1016/j.metabol.2019.06.013. Epub 2019 Jun 29.

Abstract

Background: Glucocorticoid (GC) excess increases lipolysis, circulating free fatty acid concentrations and lipid oxidation rates in humans. In vitro and animal studies have shown that GCs increase adipocyte ATGL and HSL mRNA contents and HSL phosphorylations, but the effects of GC on in vivo lipase signaling in humans are uncertain. Our study was designed to test how GC administration affects ATGL and HSL related signals in human adipose tissue.

Material and methods: Nine healthy young men underwent 5 days administration of 37.5 mg prednisolone/d in a randomized, double-blinded, placebo-controlled crossover design. At the end of each 5 d period the subjects were studied after an overnight fast for 6.5 h including a basal period and a 2½ h hyperinsulinemic euglycemic clamp. Adipose tissue biopsies were sampled from the abdominal subcutaneous adipose tissue at the end of the basal period and the clamp.

Results: GC treatment increased serum FFA concentrations and comparative gene identification-58 (CGI-58) mRNA - an ATGL activator - and decreased G0/G1 switch 2 gene (G0S2) mRNA - an ATGL inhibitor - in adipose tissue biopsies. In addition, pro-lipolytic ser563 HSL phosphorylations and protein kinase A (PKA) phosphorylation of PLIN1 (Perilipin-1) increased. The transcripts of ANGPTL4 (Angiopoietin-like 4) mRNA - a regulator of circulating triglycerides - were elevated by GC; as were CIDE (Cell-death Inducing DNA fragmentation factor-α-like Effector)-A and CIDE-C mRNA transcripts indicative of concurrent stimulation of lipolysis and lipogenesis. Finally GCs reduced insulin receptor phosphorylation, and Akt protein levels.

Conclusions: High dose GC administration to humans leads to pro-lipolytic alterations of CGI-58, G0S2 and ANGPTL4 mRNA transcripts, increases PKA signaling to lipolysis and inhibits the insulin signal in adipose tissue. The increased CIDE-A and CIDE-C mRNA levels suggest concomitant stimulation of lipolysis and lipid storage.

Trial registration: ClinicalTrials.gov NCT01762540.

Keywords: Adipose tissue; Glucocorticoid; Insulin resistance; Lipolysis; cAMP/PKA pathway.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abdominal Fat / metabolism*
  • Adult
  • Glucocorticoids / pharmacology
  • Glucose Clamp Technique
  • Healthy Volunteers
  • Humans
  • Insulin / metabolism
  • Lipase / metabolism*
  • Lipid Metabolism / drug effects
  • Lipolysis / drug effects*
  • Male
  • Perilipin-1 / metabolism
  • Prednisolone / pharmacology*
  • Prednisolone / therapeutic use
  • Signal Transduction / drug effects*
  • Time Factors
  • Young Adult

Substances

  • Glucocorticoids
  • Insulin
  • Perilipin-1
  • Prednisolone
  • Lipase

Associated data

  • ClinicalTrials.gov/NCT01762540