R.S. Dow Neurobiology, Legacy Research Institute, Portland, OR, USA.
BMC Neurosci. 2024 Jan 2;25(1):1. doi: 10.1186/s12868-023-00840-1.
Obesity rates in the U.S. continue to increase, with nearly 50% of the population being either obese or morbidly obese. Obesity, along with female sex, are leading risk factors for sporadic Alzheimer's Disease (AD) necessitating the need to better understand how these variables impact cellular function independent of age or genetic mutations. Animal and clinical studies both indicate that autophagy-lysosomal pathway (ALP) dysfunction is among the earliest known cellular systems to become perturbed in AD, preceding cognitive decline, yet little is known about how obesity and sex affects these cellular functions in the hippocampus, a brain region uniquely susceptible to the negative effects of obesity. We hypothesized that obesity would negatively affect key markers of ALP in the hippocampus, effects would vary based on sex, and that caloric restriction would counteract obesity effects.
Female and male mice were placed on an obesogenic diet for 10 months, at which point half were switched to caloric restriction for three months, followed by cognitive testing in the Morris watermaze. Hippocampus was analyzed by western blot and qPCR.
Cognitive function in female mice responded differently to caloric restriction based on whether they were on a normal or obesogenic diet; male cognition was only mildly affected by caloric restriction and not obesity. Significant male-specific changes occurred in cellular markers of autophagy, including obesity increasing pAkt, Slc38a9, and Atg12, while caloric restriction reduced pRPS6 and increased Atg7. In contrast females experienced changes due to diet/caloric restriction predominately in lysosomal markers including increased TFE3, FLCN, FNIP2, and pAMPK.
Results support that hippocampal ALP is a target of obesity and that sex shapes molecular responses, while providing insight into how dietary manipulations affect learning and memory based on sex.
美国的肥胖率持续上升，近 50%的人口要么肥胖要么病态肥胖。肥胖症和女性性别是散发性阿尔茨海默病（AD）的主要危险因素，这就需要更好地了解这些变量如何在独立于年龄或基因突变的情况下影响细胞功能。动物和临床研究都表明，自噬溶酶体途径（ALP）功能障碍是 AD 中最早出现的已知细胞系统之一，早于认知能力下降，但对于肥胖症和性别如何影响海马体中的这些细胞功能知之甚少，海马体是大脑中对肥胖症负面影响特别敏感的区域。我们假设肥胖症会对海马体中的 ALP 的关键标志物产生负面影响，这些影响会因性别而异，而热量限制会抵消肥胖症的影响。
雌性和雄性小鼠被置于致肥胖饮食中 10 个月，此时一半的小鼠被切换到热量限制饮食三个月，然后在 Morris 水迷宫中进行认知测试。通过 Western blot 和 qPCR 分析海马体。
雌性小鼠的认知功能对热量限制的反应因它们是否处于正常或致肥胖饮食而不同；雄性认知仅受到热量限制和肥胖症的轻微影响。自噬的细胞标志物发生了显著的雄性特异性变化，包括肥胖症增加了 pAkt、Slc38a9 和 Atg12，而热量限制降低了 pRPS6 并增加了 Atg7。相比之下，女性由于饮食/热量限制主要在溶酶体标志物中发生变化，包括增加 TFE3、FLCN、FNIP2 和 pAMPK。
结果支持海马体 ALP 是肥胖的靶点，并且性别塑造了分子反应，同时提供了关于饮食干预如何根据性别影响学习和记忆的见解。
