Fatty acid metabolism in patients with PPARgamma mutations

J Clin Endocrinol Metab. 2008 Nov;93(11):4462-70. doi: 10.1210/jc.2007-2356. Epub 2008 Aug 19.


Context: 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.

Design, patients, and main outcome measures: 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.

MeSH terms

  • Adipose Tissue / metabolism*
  • Adult
  • Amino Acid Substitution
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Fatty Acids / metabolism*
  • Fatty Acids, Nonesterified / metabolism
  • Genetic Carrier Screening
  • Humans
  • Hypoglycemic Agents / therapeutic use
  • Insulin Resistance / genetics
  • Lipodystrophy, Familial Partial / complications
  • Lipodystrophy, Familial Partial / genetics*
  • Lipodystrophy, Familial Partial / metabolism
  • Lipoproteins / metabolism
  • Male
  • Mutation*
  • PPAR gamma / genetics*
  • Palmitic Acid / metabolism
  • Pioglitazone
  • Reference Values
  • Thiazolidinediones / therapeutic use


  • Fatty Acids
  • Fatty Acids, Nonesterified
  • Hypoglycemic Agents
  • Lipoproteins
  • PPAR gamma
  • Thiazolidinediones
  • Palmitic Acid
  • Pioglitazone