Label-free imaging of lipid-glucose metabolism in cells, tissues, and animals

脂肪和葡萄糖代谢的可塑性和适应性与许多病理情况有关，如糖尿病和肥胖症。然而，代谢灵活性和异质性的分子和细胞机制仍然知之甚少--尽管它与开发新的治疗靶点有关，以缓解因适应不良反应而产生的代谢紊乱。代谢成像可以获得从细胞到系统水平的时空代谢动态信息。在这种情况下，代谢成像是一个强大的手段，以方便诊断和评估治疗反应。然而，大多数可用于代谢成像的技术仅限于与外源标记或标记物结合使用。这些标签和标记物的生物分布有限，可能会潜在地扰乱正常反应，或者根本无法获得。中红外光声显微镜(MIROM)是一种基于中红外光和光声探测对生物分子进行直接振动激发的新型无标记成像方法。MIROM为无标记、非侵入性和纵向代谢成像提供了一个独特的机会，可以在单细胞水平上了解代谢动力学和异质性。在这里，我们建议利用并进一步发展MEROM的非侵入性和无标记的成像能力来研究脂肪细胞和骨骼肌细胞的代谢可塑性和功能异质性。我们的目标是能够探讨提高骨骼肌和脂肪组织代谢灵活性的机制，以便为糖尿病和肥胖症的预防、早期诊断、治疗和管理带来新的见解。此外，我们还将探索使用mirom的皮肤体内非侵入性代谢成像是否能反映整体代谢状态，并可作为个性化诊断的健康和疾病指标。我们的研究将为该项目的未来阶段奠定基础，该项目涉及MEROM技术的临床转移，以无创地在人体内连续监测脂类和碳水化合物的代谢。

Lipid and glucose metabolic plasticity and adaptation are associated with many pathological conditions, such as diabetes and obesity. However, the molecular and cellular mechanisms of metabolic flexibility and heterogeneity remains poorly understood – despite its relevance for the development of new therapeutic targets to alleviate metabolic disorders derived from maladaptive responses. Metabolic imaging allows obtaining spatio-temporal metabolic dynamic information from cellular to system level. In this way, metabolic imaging is a powerful approach to facilitate diagnosis and evaluate therapeutic response. However, most of the technologies available for metabolic imaging are restricted to be used in combination with exogenous labels or markers. These labels and markers have limited biodistribution, can potentially perturb normal response¬, or are simply not available. Mid-infraRed Optoacoustic Microscopy (MiROM) is a novel label-free imaging method based on direct vibrational excitation of biomolecules by mid-infrared light and optoacoustic detection. MiROM provides a unique opportunity for label-free, non-invasive, and longitudinal metabolic imaging to understand the metabolic dynamics and heterogeneity at single-cell level. Here, we propose to take advantage and further develop the non-invasive and label-free imaging capacity of MiROM to study the metabolic plasticity and functional heterogeneity of adipocytes and skeletal muscle cells. Our goal is to be able to interrogate mechanisms for improved metabolic flexibility in skeletal muscle and adipose tissue in order to bring new insights to the prevention, early diagnosis, treatment and management of diabetes and obesity. Additionally, we will explore whether non-invasive in vivo metabolic imaging in skin, using MiROM, reflects the overall metabolism status and can serve as an indicator of health and disease for personalized diagnostics. Our study will set the foundation for future phases of this project involving clinical transfer of MiROM technology for continuous metabolic monitoring of lipids and carbohydrates non-invasively in human.