Akinci Baris, Gular Merve Celik, Oral Elif A.
Izmir Biomedicine and Genome Center & DEPARK, Dokuz Eylul University Health Campus, Izmir, Turkey
Metabolism, Endocrinology and Diabetes Division (MEND), Department of Internal Medicine, Michigan Medicine, Brehm Center for Diabetes, and Caswell Diabetes Institute, University of Michigan, Ann Arbor, MI, and Division of Internal Medicine, and Division of Internal Medicine, Dokuz Eylul University, Izmir, Turkey
Lipodystrophy syndromes are a heterogeneous group of diseases, characterized by selective absence of adipose tissue. In one sense, these diseases are lipid-partitioning disorders, where the primary defect is the loss of functional adipocytes, leading to ectopic steatosis, severe dyslipidemia, and insulin resistance. These syndromes have attracted significant attention since the mid-1990s as the understanding of adipose tissue biology grew, initially spurred by the discovery of the pathways leading to adipocyte differentiation and maturation, and then by the discovery of leptin. Although lipodystrophy syndromes are known since the beginning of the 20th century, significant progress in understanding these syndromes were made in the last two decades, placing these syndromes at the forefront of the translational metabolism field. Currently, more than 20 distinctive molecular etiologies have been attributed to cause human diseases most of which map to adipocyte differentiation or lipid droplet pathways. Seemingly acquired syndromes are recently reported to have a genetic basis, suggesting that our “pre-genome” understanding of the syndromes was inadequate and that we need to likely change our classification schemes. Regardless of the etiology, it is the selective absence of adipose tissue and its function, leading to the reduced ability to store long-term energy that perturbs insulin sensitivity and lipid metabolism. The treatment of these syndromes has also attracted considerable interest. The most successful example of the treatment of these syndromes came from the demonstration that leptin replacement strategy improved insulin resistance and dyslipidemia in the most severely affected forms of the disease, leading to an FDA approved therapy for generalized lipodystrophy syndromes. In the partial forms of the disease, the phenotypes are more complex, and the efficacy of leptin is not as uniform. Currently, standard treatment-resistant partial lipodystrophy is an EMA-approved indication, and numerous trials are in progress, either evaluating the efficacy of leptin in familial partial lipodystrophy or aiming to develop potential new treatments for the partial forms of the disease. These rare metabolic diseases are likely to continue to fuel novel breakthroughs in the field of metabolism in the foreseeable future. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.
脂肪营养不良综合征是一组异质性疾病，其特征是选择性缺乏脂肪组织。从某种意义上说，这些疾病是脂质分配紊乱，主要缺陷是功能性脂肪细胞的丧失，导致异位脂肪变性、严重血脂异常和胰岛素抵抗。自20世纪90年代中期以来，随着对脂肪组织生物学认识的不断深入，这些综合征引起了广泛关注。最初是由于导致脂肪细胞分化和成熟途径的发现，随后是瘦素的发现。尽管脂肪营养不良综合征自20世纪初就已为人所知，但在过去二十年中，对这些综合征的认识取得了重大进展，使其处于转化代谢领域的前沿。目前，已有20多种独特的分子病因被认为可导致人类疾病，其中大多数与脂肪细胞分化或脂滴途径有关。最近报道，看似后天获得性的综合征也有遗传基础，这表明我们之前对这些综合征的“前基因组”认识并不充分，可能需要改变我们的分类方案。无论病因如何, 脂肪组织及其功能的选择性缺失导致长期能量储存能力下降，进而扰乱胰岛素敏感性和脂质代谢。这些综合征的治疗也引起了相当大的兴趣。治疗这些综合征最成功的例子是，在最严重的疾病形式中，瘦素替代策略改善了胰岛素抵抗和血脂异常，从而产生了一种获得美国食品药品监督管理局批准的全身脂肪营养不良综合征治疗方法。在疾病的部分形式中，表型更为复杂，瘦素的疗效也不那么一致。目前，标准治疗耐药的部分脂肪营养不良是欧洲药品管理局批准的适应症，许多试验正在进行中，要么评估瘦素在家族性部分脂肪营养不良中的疗效，要么旨在开发针对该疾病部分形式的潜在新疗法。在可预见的未来，这些罕见的代谢疾病可能会继续推动代谢领域的新突破。欲全面涵盖内分泌学的所有相关领域，请访问我们的在线免费网络文本，网址为WWW.ENDOTEXT.ORG。
