Lorza-Gil E, Strauss O D, Ziegler E, Kansy K, Katschke M-T, Rahimi G, Neuscheler D, Sandforth L, Sandforth A, Sancar G, Kaufmann B, Hartmann D, Singer S, Mihaljevic A L, Jumpertz-von Schwartzenberg R, Sbierski-Kind J, Müller T D, Birkenfeld A L, Gerst F
German Center for Diabetes Research (DZD e.V.), Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center Munich at University of Tübingen, Tübingen, Germany; Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tübingen, Germany.
Department of Internal Medicine IV, Division of Endocrinology, Diabetology and Nephrology, University Hospital Tübingen, Tübingen, Germany.
Mol Metab. 2025 Jan;91:102067. doi: 10.1016/j.molmet.2024.102067. Epub 2024 Nov 14.
Infiltration of adipocytes into the pancreatic parenchyma has been linked to impaired insulin secretion in individuals with increased genetic risk of T2D and prediabetic conditions. However, the study of this ectopic fat depot has been limited by the lack of suitable in vitro models.
Here, we developed a novel 3D model of functionally mature human pancreatic adipose tissue organoids by aggregating human pancreatic adipose tissue-derived stromal vascular fraction (SVF) cells into organoids and differentiating them over 19 days.
These organoids carry biological properties of the in situ pancreatic fat, presenting levels of adipogenic markers comparable to native pancreatic adipocytes and improved lipolytic and anti-lipolytic response compared to conventional 2D cultures. The organoids harbour a small population of immune cells, mimicking in vivo adipose environment. Furthermore, they express GIPR, allowing investigation of incretin effects in pancreatic fat. In accordance, GIP and the dual GLP1R/GIPR agonist tirzepatide stimulate lipolysis but had distinct effects on the expression of proinflammatory cytokines.
This novel adipose organoid model is a valuable tool to study the metabolic impact of incretin signalling in pancreatic adipose tissue, revealing potential therapeutic targets of incretins beyond islets. The donor-specific metabolic memory of these organoids enables examination of the pancreatic fat-islet crosstalk in a donor-related metabolic context.
在2型糖尿病遗传风险增加和糖尿病前期个体中，脂肪细胞浸润胰腺实质与胰岛素分泌受损有关。然而，由于缺乏合适的体外模型，对这种异位脂肪库的研究受到了限制。
在此，我们通过将人胰腺脂肪组织来源的基质血管成分（SVF）细胞聚集成类器官并在19天内使其分化，开发了一种功能成熟的人胰腺脂肪组织类器官的新型3D模型。
这些类器官具有原位胰腺脂肪的生物学特性，其脂肪生成标志物水平与天然胰腺脂肪细胞相当，并且与传统的2D培养相比，脂解和抗脂解反应有所改善。类器官中含有少量免疫细胞，模拟体内脂肪环境。此外，它们表达GIPR，可用于研究肠促胰岛素在胰腺脂肪中的作用。相应地，GIP和双重GLP1R/GIPR激动剂替尔泊肽刺激脂解，但对促炎细胞因子的表达有不同影响。
这种新型脂肪类器官模型是研究肠促胰岛素信号在胰腺脂肪组织中代谢影响的有价值工具，揭示了胰岛以外肠促胰岛素的潜在治疗靶点。这些类器官的供体特异性代谢记忆能够在与供体相关的代谢背景下检查胰腺脂肪-胰岛的相互作用。
