Abstract
Adipose tissue plays an important role in regulating metabolic homeostasis by storing excess fat and protecting other organs from lipotoxicity. Aging is associated with central fat redistribution, culminating in a decrease in insulin-sensitive subcutaneous and an increase in insulin-resistant visceral adipose depots. Adipose-derived stem cells (ASCs) play an important role in the regeneration of adipose tissue. Aged ASCs show decreased stemness and regenerative potential due to the accumulation of oxidative stress and mitochondrial dysfunction-related cell damage. Metformin is a well-established anti-diabetic drug that has shown anti-aging effects in different organisms and animal models. In this study, we analyzed the effect of metformin treatment on the stemness of human ASCs in cell culture and whole adipose tissue culture models. Our results demonstrate that metformin improves the stemness of ASCs, reducing their rate of proliferation and adipocyte differentiation. Investigating the possible underlying mechanism, we observed a decrease in the mTOR and ERK activity in metformin-treated ASCs. In addition, we observed an increase in autophagy activity upon metformin treatment. We conclude that metformin treatment improves ASCs stemness by reducing mTOR and ERK signaling and enhancing autophagy. Future in vivo evaluations in animal models and humans will pave the way for the clinical adaptation of this well-established drug for reviving the stemness of aged stem cells.
Highlights
Adipose tissue is a dynamic organ that contributes an important homeostatic role in regulating nutrient balance, insulin sensitivity, and immune modulation
To understand the possible signaling cascade responsible for reduced adipocyte differentiation, proliferation, and upregulation of stemness genes in Adipose-derived stem cells (ASCs) upon metformin treatment, we focused on mechanistic target of rapamycin (mTOR), autophagy, and extracellular signal-regulated kinase (ERK) signaling cascades
To underscore the direct role of ERK and mTOR signaling in metformin-treatmentmediated inhibition of differentiation and increase in stemness in ASCs, we separately inhibited ERK signaling and the mTOR pathway using ERK inhibitor U0126 and rapamycin, respectively, and analyzed the effects on ASC differentiation and stemness [19,33]
Summary
Adipose tissue is a dynamic organ that contributes an important homeostatic role in regulating nutrient balance, insulin sensitivity, and immune modulation. Adipose tissue performs this role by storing and oxidizing excess fatty acids, preventing steatosis and lipotoxicity in other organs [1]. Age-associated insulin resistance is the most prevalent metabolic disease. Several studies have since identified reduced insulin sensitivity as the primary cause of the age-related impairment of glucose metabolism [5,6]. The location and function of the adipose tissue depot are important in terms of insulin sensitivity; for example, the visceral depot is more
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