Fatty acid metabolism in patients with PPARgamma mutations.

Journal article

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.

Authors: Tan, G; Savage, D; Fielding, B; Collins, J; Hodson, L

• Publication status: Published
• Journal: Journal of clinical endocrinology and metabolism
• Volume: 93
• Issue: 11
• Pages: 4462-4470
• Publication date: 2008-11-01
• DOI: 10.1210/jc.2007-2356
• EISSN: 1945-7197
• ISSN: 0021-972X
• Language: English
• Keywords: Lipodystrophy, Familial Partial; Adipose Tissue; Fatty Acids; Mutation; Humans; Reference Values; Diabetes Mellitus, Type 2; Adult; Thiazolidinediones; Amino Acid Substitution; Fatty Acids, Nonesterified; PPAR gamma; Hypoglycemic Agents; Palmitic Acid; Male; Heterozygote Detection; Insulin Resistance; Lipoproteins