Leptin deficiency unmasks the deleterious effects of impaired peroxisome proliferator-activated receptor γ function (P465L PPARγ) in mice

被引:69
作者
Gray, Sarah L.
Nora, Edoardo Dalla
Grosse, Johannes
Manieri, Monia
Stoeger, Tobias
Medina-Gomez, Gema
Burling, Keith
Wattler, Sigrid
Russ, Andreas
Yeo, Giles S. H.
Chatterjee, V. Krishna
O'Rahilly, Stephen
Voshol, Peter J.
Cinti, Saverio
Vidal-Puig, Antonio
机构
[1] Univ Cambridge, Addenbrookes Hosp, Dept Clin Biochem, Cambridge CB2 2QR, England
[2] Ingenium Pharmaceut, Martinsried, Germany
[3] Univ Ancona, Fac Med, Dept Normal Human Morphol, Ancona, Italy
[4] GSF, Natl Res Ctr Environm & Hlth, Inst Inhalat Biol, Neuherberg, Germany
[5] Univ Oxford, Dept Biochem, Genet Unit, Oxford, England
[6] Univ Cambridge, Addenbrookes Hosp, Dept Med, Cambridge, England
[7] TNO, Div VBO, Leiden, Netherlands
基金
英国医学研究理事会;
关键词
D O I
10.2337/db06-0389
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Peroxisome proliferator-activated receptor (PPAR)gamma is a key transcription factor facilitating fat deposition in adipose tissue through its proadipogenic and lipogenic actions. Human patients with dominant-negative mutations in PPAR gamma display lipodystrophy and extreme insulin resistance. For this reason it was completely unexpected that mice harboring an equivalent mutation (P465L) in PPAR gamma developed normal amounts of adipose tissue and were insulin sensitive. This finding raised important doubts about the interspecies translatability of PPAR gamma-related findings, bringing into question the relevance of other PPAR gamma murine models. Here, we demonstrate that when expressed on a hyperphagic ob/ob background, the P465L PPAR gamma mutant grossly exacerbates the insulin resistance and metabolic disturbances associated with leptin deficiency, yet reduces whole-body adiposity and adipocyte size. In mouse, coexistence of the P465L PPAR gamma mutation and the leptin-deficient state creates a mismatch between insufficient adipose tissue expandability and excessive energy availability, unmasking the deleterious effects of PPAR gamma mutations on carbohydrate metabolism and replicating the characteristic clinical symptoms observed in human patients with dominant-negative PPAR gamma mutations. Thus, adipose tissue expandability is identified as an important factor for the development of insulin resistance in the context of positive energy balance.
引用
收藏
页码:2669 / 2677
页数:9
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