Metabolic Rescue of Obese Adipose-Derived Stem Cells by Lin28/Let7 Pathway

Adipose-derived stem cells (ASCs) are promising candidates for autologous cell-based regeneration therapies by virtue of their multilineage differentiation potential and immunogenicity; however, relatively little is known about their role in adipose tissue physiology and dysfunction. Here we evaluated whether ASCs isolated from nonobese and obese tissue differed in their metabolic characteristics and differentiation potential. During differentiation to mature adipocytes, mouse and human ASCs derived from nonobese tissues both increased their insulin sensitivity and inhibition of lipolysis, whereas obese-derived ASCs were insulin-resistant, showing impaired insulin-stimulated glucose uptake and resistance to the antilipolytic effect of insulin. Furthermore, obese-derived ASCs showed enhanced release of proinflammatory cytokines and impaired production of adiponectin. Interestingly, the delivery of cytosol from control ASCs into obese-derived ASCs using a lipid-based, protein-capture methodology restored insulin sensitivity on glucose and lipid metabolism and reversed the proinflammatory cytokine profile, in part due to the restoration of Lin28 protein levels. In conclusion, glucose and lipid metabolism as well as maturation of ASCs is truncated in an obese environment. The reversal of the altered pathways in obese cells by delivery of normal subcellular fractions offers a potential new tool for cell therapy.Adipose tissue is now recognized as an important endocrine and metabolic organ that, when accumulated in excess, increases the risk of chronic diseases such as diabetes, stroke, and arterial hypertension (1). Recently, new mechanisms that control the obesity phenotype have been identified such as the equilibrium between white and brown adipose tissue, the localization of adipose mass (visceral vs. ventral), and the presence of adipose stem cells (ASCs) and mesenchymal stem cells (MSCs) (1–4). Although the relative importance of fat tissue type and localization are being actively unraveled, the role of stem cells in adipose tissue physiology and dysfunction is still poorly understood.Adult stem cells are multipotent cells that contribute to the homeostasis of various organs, including adipose tissue. ASCs are a class of MSCs localized in adipose tissue that have attracted increasing interest because of their potential to differentiate into adipogenic, osteogenic, chondrogenic, and other mesenchymal lineages (5–8). Other clinically attractive properties attributed to ASCs include proangiogenic and anti-inflammatory actions (9–11). Moreover, depending on the environmental conditions, ASCs can be beneficial or detrimental to health. ASCs thus represent a possible target for therapies aimed at modulating the response of the body to obesity and diabetes as well as a potential tool for regenerative medicine.Adipocytes are central to the control of energy balance and lipid homeostasis (12). In response to prolonged obesity, adipocytes become hypertrophic, and new adipocytes are required to counter the metabolic dysfunction of the hypertrophic cells (13,14). It has been postulated that the adipose tissue depots of obese individuals have already committed all of their stem cell reserves to the adipocyte lineage and, therefore, have no capacity to generate new adipocytes (15–17).In this study, we demonstrate that the differentiation of mouse and human adipose MSCs into mature well-functioning adipocytes is truncated in an obese environment, resulting in impaired metabolic function. We also validate a novel approach to restore normal adipocyte metabolic responsiveness in obese-derived stem cells by cytosolic transfer.