title: Differential regulation of lipid and protein metabolism in obese vs. lean subjects before and after a 72-h fast.
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.
authors.affiliation: Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Denmark; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark; ambak@clin.au.dk.
authors.forename: Ann Mosegaard
authors.initials: AM
authors.lastname: Bak
authors.affiliation: Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Faculty of Health, Aarhus University, Denmark;
authors.forename: Andreas Buch
authors.initials: AB
authors.lastname: Møller
authors.affiliation: Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Denmark; Department of Nuclear Medicine, Aarhus University Hospital, Denmark;
authors.forename: Mikkel Holm
authors.initials: MH
authors.lastname: Vendelbo
authors.affiliation: The Novo Nordisk Foundation Center for Basic Metabolic Research, Section on Integrative Physiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark;
authors.forename: Thomas Svava
authors.initials: TS
authors.lastname: Nielsen
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark; Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Faculty of Health, Aarhus University, Denmark;
authors.forename: Rikke
authors.initials: R
authors.lastname: Viggers
authors.affiliation: Centre for Diabetes Research, Gentofte University Hospital, Hellerup, Denmark; and.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Rungby
authors.affiliation: Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark;
authors.forename: Steen Bønløkke
authors.initials: SB
authors.lastname: Pedersen
authors.affiliation: Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Denmark; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark;
authors.forename: Jens Otto Lunde
authors.initials: JO
authors.lastname: Jørgensen
authors.affiliation: Research Laboratory for Biochemical Pathology, Department of Clinical Medicine, Faculty of Health, Aarhus University, Denmark; Department of Molecular Medicine, Aarhus University Hospital, Denmark.
authors.forename: Niels
authors.identifier: http://orcid.org/0000-0001-5613-7274
authors.initials: N
authors.lastname: Jessen
authors.affiliation: Medical Research Laboratory, Department of Clinical Medicine, Faculty of Health, Aarhus University, Denmark; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark;
authors.forename: Niels
authors.initials: N
authors.lastname: Møller
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000071189:Autophagy-Related Protein-1 Homolog / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000378:metabolism; D018592:Cross-Over Studies; D005215:Fasting / Q000378:metabolism*; D005542:Forearm; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics*; D008066:Lipolysis / Q000235:genetics*; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism*; D002787:Sterol Esterase / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D000070584:Tripartite Motif Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D014508:Urea / Q000378:metabolism; D055815:Young Adult; D000217:Acyltransferases
chemical_list: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D000071189:Autophagy-Related Protein-1 Homolog; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008049:Lipase; D009124:Muscle Proteins; D012333:RNA, Messenger; D002787:Sterol Esterase; D058570:TOR Serine-Threonine Kinases; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D014508:Urea; C508073:G0S2 protein, human; C439972:ABHD5 protein, human; C440908:TRIM63 protein, human; C546842:MTOR protein, human; C484754:ULK1 protein, human; C494794:PNPLA2 protein, human; D000217:Acyltransferases
keywords: fasting; human; lipolysis; obesity; protein breakdown; skeletal muscle; subcutaneous adipose tissue