Reinisch Isabel, Enzenhofer Sarah, Prokesch Andreas
Department of Health Sciences and Technology, Institute of Food Nutrition and Health, Eidgenössische Technische Hochschule Zürich (ETH), Schwerzenbach, Switzerland.
Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Division of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria.
Bioessays. 2025 Apr;47(4):e202400203. doi: 10.1002/bies.202400203. Epub 2025 Jan 19.
Adipose tissue (AT) inflammation, a hallmark of the metabolic syndrome, is triggered by overburdened adipocytes sending out immune cell recruitment signals during obesity development. An AT immune landscape persistent throughout weight loss and regain constitutes an immune-obesogenic memory that hinders long-term weight loss management. Lipid-associated macrophages (LAMs) are emerging as major players in diseased, inflamed metabolic tissues and may be key contributors to an obesogenic memory in AT. Our previous study found that LAM abundance increases with weight loss via intermittent fasting (IF) in obese mice, which is driven by adipocyte p53 signalling. However, the specific signals causing LAM accumulation in AT under IF remain unknown. In this piece, we hypothesise on a range of adipocyte-secreted signals that can harbor immune-attractive features upon fasting/refeeding cycles. We highlight possible mechanisms including cell death signalling, matrikines, and other damage-associated molecular patterns (DAMPs), as well as adipo(-cyto)kines, lipid mediators, metabolites, extracellular vesicles, and epigenetic rewiring. Finally, we consider how advances in mechanisms of AT LAM recruitment gleaned from preclinical models might be translatable to long-term weight management in humans. Thus, we provide vantage points to study signals driving monocyte recruitment, polarisation towards LAMs, and LAM retention, to harness the therapeutic potential of modulating AT LAM levels by impacting the immune-obesogenic memory in metabolic disease.
脂肪组织（AT）炎症是代谢综合征的一个标志，在肥胖发展过程中，不堪重负的脂肪细胞发出免疫细胞招募信号，从而引发这种炎症。在体重减轻和恢复过程中持续存在的AT免疫格局构成了一种免疫致肥胖记忆，阻碍了长期体重管理。脂质相关巨噬细胞（LAMs）正在成为患病的、发炎的代谢组织中的主要参与者，可能是AT中致肥胖记忆的关键促成因素。我们之前的研究发现，在肥胖小鼠中，通过间歇性禁食（IF）减肥时，LAM丰度会增加，这是由脂肪细胞p53信号驱动的。然而，在IF条件下导致LAM在AT中积累的具体信号仍然未知。在这篇文章中，我们对一系列脂肪细胞分泌的信号进行了假设，这些信号在禁食/再喂养周期中可能具有免疫吸引特性。我们强调了可能的机制，包括细胞死亡信号、基质因子和其他损伤相关分子模式（DAMPs），以及脂肪（细胞）因子、脂质介质、代谢物、细胞外囊泡和表观遗传重编程。最后，我们考虑从临床前模型中获得的AT LAM招募机制的进展如何转化为人类的长期体重管理。因此，我们提供了有利的视角来研究驱动单核细胞招募、向LAMs极化和LAM保留的信号，以通过影响代谢疾病中的免疫致肥胖记忆来利用调节AT LAM水平的治疗潜力。
