Department of Medical Biochemistry and Molecular Biology and Immunology, Medical School, Virgen Macarena University Hospital, University of Seville, Av. Sánchez Pizjuan 4, 41009 Sevilla, Spain.
Int J Mol Sci. 2022 May 6;23(9):5202. doi: 10.3390/ijms23095202.
Obesity is a growing worldwide health problem, affecting many people due to excessive saturated fat consumption, lack of exercise, or a sedentary lifestyle. Leptin is an adipokine secreted by adipose tissue that increases in obesity and has central actions not only at the hypothalamic level but also in other regions and nuclei of the central nervous system (CNS) such as the cerebral cortex and hippocampus. These regions express the long form of leptin receptor LepRb, which is the unique leptin receptor capable of transmitting complete leptin signaling, and are the first regions to be affected by chronic neurocognitive deficits, such as mild cognitive impairment (MCI) and Alzheimer's Disease (AD). In this review, we discuss different leptin resistance mechanisms that could be implicated in increasing the risk of developing AD, as leptin resistance is frequently associated with obesity, which is a chronic low-grade inflammatory state, and obesity is considered a risk factor for AD. Key players of leptin resistance are SOCS3, PTP1B, and TCPTP whose signalling is related to inflammation and could be worsened in AD. However, some data are controversial, and it is necessary to further investigate the underlying mechanisms of the AD-causing pathological processes and how altered leptin signalling affects such processes.
肥胖是一个全球性的健康问题，由于过度摄入饱和脂肪、缺乏运动或久坐不动的生活方式，许多人受到影响。瘦素是脂肪组织分泌的一种脂肪因子，在肥胖症中会增加，并且不仅在下丘脑水平，而且在中枢神经系统 (CNS) 的其他区域和核团中具有中枢作用，如大脑皮层和海马体。这些区域表达瘦素受体 LepRb 的长形式，这是唯一能够传递完整瘦素信号的瘦素受体，并且是第一个受到慢性神经认知缺陷影响的区域，如轻度认知障碍 (MCI) 和阿尔茨海默病 (AD)。在这篇综述中，我们讨论了可能导致 AD 风险增加的不同瘦素抵抗机制，因为瘦素抵抗常与肥胖有关，肥胖是一种慢性低度炎症状态，而肥胖被认为是 AD 的一个危险因素。瘦素抵抗的关键参与者是 SOCS3、PTP1B 和 TCPTP，它们的信号与炎症有关，并且在 AD 中可能会恶化。然而，一些数据存在争议，有必要进一步研究导致 AD 的病理过程的潜在机制，以及改变的瘦素信号如何影响这些过程。
