Leptin deficiency unmasks the deleterious effects of impaired peroxisome proliferator-activated receptor γ function (P465L PPARγ) in mice
Leptin deficiency unmasks the deleterious effects of impaired peroxisome proliferator-activated receptor γ function (P465L PPARγ) in mice
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DOI：
10.2337/db06-0389
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发表时间：
2006-10-01
期刊：
影响因子：
7.7
通讯作者：
Vidal-Puig, Antonio
中科院分区：
文献类型：
--
作者：
Gray, Sarah L.;Nora, Edoardo Dalla;Vidal-Puig, Antonio
过氧化物酶体增殖物激活受体(PPAR) γ是一种关键的转录因子，通过其促脂肪和增脂作用促进脂肪在脂肪组织中的沉积。PPAR γ显性负突变的人类患者表现为脂肪营养不良和极端胰岛素抵抗。因此，完全出乎意料的是，在PPAR γ中携带相同突变（P465L）的小鼠产生了正常数量的脂肪组织，并且对胰岛素敏感。这一发现对PPAR γ相关发现的种间可译性提出了重要质疑，并对其他PPAR γ小鼠模型的相关性提出了质疑。在这里，我们证明，当在贪食的ob/ob背景下表达时，P465L PPAR γ突变体严重加剧了胰岛素抵抗和与瘦素缺乏相关的代谢紊乱，但减少了全身肥胖和脂肪细胞大小。在小鼠中，P465L PPAR γ突变和瘦素缺乏状态的共存造成了脂肪组织可扩展性不足和能量可用性过高之间的不匹配，揭示了PPAR γ突变对碳水化合物代谢的有害影响，并复制了PPAR γ突变为显性阴性的人类患者所观察到的典型临床症状。因此，在正能量平衡的情况下，脂肪组织的可扩展性被认为是胰岛素抵抗发展的重要因素。
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.