title: Fatty acid metabolism in patients with PPARgamma mutations.
abstract: BACKGROUND
  PPARG mutations may cause insulin resistance and dyslipidemia, but little is known about the mechanisms of the abnormalities of lipid metabolism.
  
  
  OBJECTIVE
  We hypothesized that in PPARG mutations, abnormal adipose tissue triglyceride storage causes insulin resistance.
  
  
  METHODS
  Whole-body and adipose tissue-specific metabolic phenotyping through arteriovenous blood sampling was made before and after a mixed meal including 13C-palmitic acid. Studies were performed in a 32-yr-old male with partial lipodystrophy and type 2 diabetes, heterozygous for the PPARG P467L mutation and in an apparently phenotypically normal 32-yr-old male heterozygous for the PPARG n.AAA553T mutation. Comparator groups were age- and sex-matched healthy participants (n=10) and type 2 diabetes sex-matched participants (n=6).
  
  
  RESULTS
  The P467L patient had elevated unmodulated fasting and postprandial plasma nonesterified fatty acid (NEFA) concentrations, despite a low adipose tissue NEFA output. Instead, NEFA appeared to originate directly from triglyceride-rich lipoproteins: 13C-palmitic acid accumulated rapidly in the NEFA fraction, as a sign of impaired fatty acid trapping in tissues. In contrast to the Pparg haploinsufficient mouse, the patient with n.AAA553T mutation did not exhibit paradoxically insulin sensitive and showed a mostly normal metabolic pattern.
  
  
  CONCLUSIONS
  The lipodystrophic PPARG P467L phenotype include excessive and uncontrolled generation of NEFA directly from triglyceride-rich lipoproteins, explaining high systemic NEFA concentrations, whereas the human PPARG haploinsufficiency is metabolically almost normal.
authors: Oxford Centre for Diabetes, Endocrinology, and Metabolism, Oxford OX3 7LJ, United Kingdom.
authors: Garry D
authors: GD
authors: Tan
authors: David B
authors: DB
authors: Savage
authors: Barbara A
authors: BA
authors: Fielding
authors: Jenny
authors: J
authors: Collins
authors: Leanne
authors: L
authors: Hodson
authors: Sandy M
authors: SM
authors: Humphreys
authors: Stephen
authors: S
authors: O'Rahilly
authors: Krishna
authors: K
authors: Chatterjee
authors: Keith N
authors: KN
authors: Frayn
authors: Fredrik
authors: F
authors: Karpe
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D019943:Amino Acid Substitution; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D006580:Genetic Carrier Screening; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007333:Insulin Resistance / Q000235:genetics; D052496:Lipodystrophy, Familial Partial / Q000150:complications / Q000235:genetics* / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D009154:Mutation; D047495:PPAR gamma / Q000235:genetics*; D019308:Palmitic Acid / Q000378:metabolism; D000077205:Pioglitazone; D012016:Reference Values; D045162:Thiazolidinediones / Q000627:therapeutic use
chemical_list: D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D008074:Lipoproteins; D047495:PPAR gamma; D045162:Thiazolidinediones; D019308:Palmitic Acid; D000077205:Pioglitazone