Differential regulation of lipid and protein metabolism in obese vs. lean subjects before and after a 72-h fast

Am J Physiol Endocrinol Metab. 2016 Jul 1;311(1):E224-35. doi: 10.1152/ajpendo.00464.2015. Epub 2016 May 31.

Abstract

Increased availability of lipids may conserve muscle protein during catabolic stress. Our study was designed to define 1) intracellular mechanisms leading to increased lipolysis and 2) whether this scenario is associated with decreased amino acid and urea fluxes, and decreased muscle amino acid release in obese subjects under basal and fasting conditions. We therefore studied nine lean and nine obese subjects twice, after 12 and 72 h of fasting, using measurements of mRNA and protein expression and phosphorylation of lipolytic and protein metabolic signaling molecules in fat and muscle together with whole body and forearm tracer techniques. Obese subjects displayed increased whole body lipolysis, decreased urea production rates, and decreased forearm muscle protein breakdown per 100 ml of forearm tissue, differences that persisted after 72 h of fasting. Lipolysis per fat mass unit was reduced in obese subjects and, correspondingly, adipose tissue hormone-sensitive lipase (HSL) phosphorylation and mRNA and protein levels of the adipose triglyceride lipase (ATGL) coactivator CGI58 were decreased. Fasting resulted in higher HSL phosphorylations and lower protein levels of the ATGL inhibitor G0S2. Muscle protein expressions of mammalian target of rapamycin (mTOR) and 4EBP1 were lower in obese subjects, and MuRf1 mRNA was higher with fasting in lean but not obese subjects. Phosphorylation and signaling of mTOR decreased with fasting in both groups, whereas ULK1 protein and mRNA levels increased. In summary, obese subjects exhibit increased lipolysis due to a large fat mass with blunted prolipolytic signaling, together with decreased urea and amino acid fluxes both in the basal and 72-h fasted state; this is compatible with preservation of muscle and whole body protein.

Keywords: fasting; human; lipolysis; obesity; protein breakdown; skeletal muscle; subcutaneous adipose tissue.

Publication types

  • Comparative Study

MeSH terms

  • 1-Acylglycerol-3-Phosphate O-Acyltransferase / genetics
  • 1-Acylglycerol-3-Phosphate O-Acyltransferase / metabolism
  • Adipose Tissue / metabolism
  • Adult
  • Autophagy-Related Protein-1 Homolog / genetics
  • Autophagy-Related Protein-1 Homolog / metabolism
  • Case-Control Studies
  • Cell Cycle Proteins / metabolism
  • Cross-Over Studies
  • Fasting / metabolism*
  • Forearm
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Lipase / genetics
  • Lipase / metabolism
  • Lipid Metabolism / genetics*
  • Lipolysis / genetics*
  • Male
  • Muscle Proteins / metabolism*
  • Muscle, Skeletal / metabolism*
  • Obesity / genetics*
  • Obesity / metabolism
  • Phosphorylation
  • RNA, Messenger / metabolism*
  • Sterol Esterase / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • Time Factors
  • Tripartite Motif Proteins / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Urea / metabolism
  • Young Adult

Substances

  • Cell Cycle Proteins
  • G0S2 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Muscle Proteins
  • RNA, Messenger
  • Tripartite Motif Proteins
  • Urea
  • 1-Acylglycerol-3-Phosphate O-Acyltransferase
  • ABHD5 protein, human
  • TRIM63 protein, human
  • Ubiquitin-Protein Ligases
  • MTOR protein, human
  • Autophagy-Related Protein-1 Homolog
  • TOR Serine-Threonine Kinases
  • ULK1 protein, human
  • Sterol Esterase
  • Lipase
  • PNPLA2 protein, human