Research Group Nutrigenomics of Obesity and Department of Experimental Diabetology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany; German Center for Diabetes Research (DZD e.V.), München, Neuherberg, Germany.
Helmholtz Institute for Metabolic Obesity and Vascular Research (HI-MAG), Helmholtz Zentrum München, University of Leipzig and University Hospital Leipzig, Leipzig, Germany.
Mol Metab. 2024 Oct;88:102014. doi: 10.1016/j.molmet.2024.102014. Epub 2024 Aug 28.
Picalm (phosphatidylinositol-binding clathrin assembly protein), a ubiquitously expressed clathrin-adapter protein, is a well-known susceptibility gene for Alzheimer's disease, but its role in white adipose tissue (WAT) function has not yet been studied. Transcriptome analysis revealed differential expression of Picalm in WAT of diabetes-prone and diabetes-resistant mice, hence we aimed to investigate the potential link between Picalm expression and glucose homeostasis, obesity-related metabolic phenotypes, and its specific role in insulin-regulated GLUT4 trafficking in adipocytes.
Picalm expression and epigenetic regulation by microRNAs (miRNAs) and DNA methylation were analyzed in WAT of diabetes-resistant (DR) and diabetes-prone (DP) female New Zealand Obese (NZO) mice and in male NZO after time-restricted feeding (TRF) and alternate-day fasting (ADF). PICALM expression in human WAT was evaluated in a cross-sectional cohort and assessed before and after weight loss induced by bariatric surgery. siRNA-mediated knockdown of Picalm in 3T3-L1-cells was performed to elucidate functional outcomes on GLUT4-translocation as well as insulin signaling and adipogenesis.
Picalm expression in WAT was significantly lower in DR compared to DP female mice, as well as in insulin-sensitive vs. resistant NZO males, and was also reduced in NZO males following TRF and ADF. Four miRNAs (let-7c, miR-30c, miR-335, miR-344) were identified as potential mediators of diabetes susceptibility-related differences in Picalm expression, while 11 miRNAs (including miR-23a, miR-29b, and miR-101a) were implicated in TRF and ADF effects. Human PICALM expression in adipose tissue was lower in individuals without obesity vs. with obesity and associated with weight-loss outcomes post-bariatric surgery. siRNA-mediated knockdown of Picalm in mature 3T3-L1-adipocytes resulted in amplified insulin-stimulated translocation of the endogenous glucose transporter GLUT4 to the plasma membrane and increased phosphorylation of Akt and Tbc1d4. Moreover, depleting Picalm before and during 3T3-L1 differentiation significantly suppressed adipogenesis, suggesting that Picalm may have distinct roles in the biology of pre- and mature adipocytes.
Picalm is a novel regulator of GLUT4-translocation in WAT, with its expression modulated by both genetic predisposition to diabetes and dietary interventions. These findings suggest a potential role for Picalm in improving glucose homeostasis and highlight its relevance as a therapeutic target for metabolic disorders.
磷酯酰肌醇结合网格蛋白装配蛋白（Picalm）是一种广泛表达的网格蛋白衔接蛋白，是阿尔茨海默病的易感基因，但它在白色脂肪组织（WAT）功能中的作用尚未得到研究。转录组分析显示，糖尿病易感和抵抗的小鼠的 WAT 中 Picalm 的表达存在差异，因此，我们旨在研究 Picalm 表达与葡萄糖稳态、肥胖相关代谢表型之间的潜在联系，以及其在胰岛素调节脂肪细胞中 GLUT4 转运中的特定作用。
分析了糖尿病抵抗（DR）和糖尿病易感（DP）新西兰肥胖（NZO）雌性小鼠的 WAT 中 Picalm 的表达及其受 microRNAs（miRNAs）和 DNA 甲基化的调控，并分析了限时喂养（TRF）和隔日禁食（ADF）后雄性 NZO 中的 Picalm 表达。在横断面队列中评估了人类 WAT 中的 PICALM 表达，并评估了减肥手术后的表达。通过 3T3-L1-细胞中的 siRNA 介导的 Picalm 敲低，阐明了 GLUT4 易位以及胰岛素信号和脂肪生成的功能结果。
与 DP 雌性小鼠相比，DR 小鼠的 WAT 中 Picalm 表达明显降低，胰岛素敏感的 NZO 雄性与抵抗的相比也是如此，TRF 和 ADF 后 NZO 雄性的 Picalm 表达也降低。鉴定出 4 种 miRNAs（let-7c、miR-30c、miR-335、miR-344）作为 Picalm 表达糖尿病易感性相关差异的潜在调节剂，而 11 种 miRNAs（包括 miR-23a、miR-29b 和 miR-101a）参与了 TRF 和 ADF 的作用。脂肪组织中人类 PICALM 的表达在无肥胖个体中低于肥胖个体，并且与减肥手术后的体重减轻结果相关。在成熟的 3T3-L1 脂肪细胞中，siRNA 介导的 Picalm 敲低导致内源性葡萄糖转运蛋白 GLUT4 的胰岛素刺激易位增加，并且 Akt 和 Tbc1d4 的磷酸化增加。此外，在 3T3-L1 分化之前和期间耗尽 Picalm 会显著抑制脂肪生成，表明 Picalm 可能在预成熟脂肪细胞的生物学中具有不同的作用。
Picalm 是 WAT 中 GLUT4 易位的新型调节剂，其表达受糖尿病遗传倾向和饮食干预的调节。这些发现表明 Picalm 可能在改善葡萄糖稳态方面发挥作用，并突出了其作为代谢紊乱治疗靶点的相关性。
