This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tan, G. D. Articles by Karpe, F. Search for Related Content PubMed PubMed Citation Articles by Tan, G. D. Articles by Karpe, F. Related Collections Lipid Diabetes and Insulin Metabolism

Fatty Acid Metabolism in Patients with PPAR Mutations

Oxford Centre for Diabetes, Endocrinology, and Metabolism (G.D.T., B.A.F., J.C., L.H., S.M.H., K.N.F., F.K.) and National Institute for Health and Research (NIHR) Oxford Biomedical Research Centre (F.K.), University of Oxford, Churchill Hospital, Oxford OX3 7LJ, United Kingdom; and Departments of Medicine and Clinical Biochemistry (D.B.S., S.O., K.C.), Addenbrooke’s Hospital, Cambridge CB2 2QQ, United Kingdom

Address all correspondence and requests for reprints to: Dr. Fredrik Karpe, Oxford Centre for Diabetes, Endocrinology, and Metabolism, Churchill Hospital, Oxford OX3 7LJ, United Kingdom. E-mail: fredrik.karpe{at}oxlip.ox.ac.uk.

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.

This article has been cited by other articles:

				D. B. Savage Mouse models of inherited lipodystrophy Dis. Model. Mech., November 1, 2009; 2(11-12): 554 - 562. [Abstract] [Full Text] [PDF]