Metformin and Vitamin D Modulate Inflammation and Autophagy during Adipose-Derived Stem Cell Differentiation

Abstract

Adipose-derived stem cells (ADSCs) came out from the regenerative medicine landscape for their ability to differentiate into several phenotypes, contributing to tissue regeneration both in vitro and in vivo. Dysregulation in stem cell recruitment and differentiation during adipogenesis is linked to a chronic low-grade inflammation and macrophage infiltration inside the adipose tissue, insulin resistance, cardiovascular disease and obesity. In the present paper we aimed to evaluate the role of metformin and vitamin D, alone or in combination, in modulating inflammation and autophagy in ADSCs during adipogenic commitment. ADSCs were cultured for 21 days in the presence of a specific adipogenic differentiation medium, together with metformin, or vitamin D, or both. We then analyzed the expression of FoxO1 and Heat Shock Proteins (HSP) and the secretion of proinflammatory cytokines IL-6 and TNF-α by ELISA. Autophagy was also assessed by specific Western blot analysis of ATG12, LC3B I, and LC3B II expression. Our results showed the ability of the conditioned media to modulate adipogenic differentiation, finely tuning the inflammatory response and autophagy. We observed a modulation in HSP mRNA levels, and a significant downregulation in cytokine secretion. Taken together, our findings suggest the possible application of these molecules in clinical practice to counteract uncontrolled lipogenesis and prevent obesity and obesity-related metabolic disorders.

Metformin Inhibits Lipid Droplets Fusion and Growth via Reduction in Cidec and Its Regulatory Factors in Rat Adipose-Derived Stem Cells

“…It should be noted that blockade of AMPK signaling could not entirely rescue metformin-inhibited expression of Cidec. These data suggest that metformin might decrease Cidec expression via other pathways, such as inflammation and autophagy [ 78 , 79 , 80 ], integrin/ERK pathway [ 81 ], AKT, and MAPK pathways [ 41 , 55 ] The more details of metformin inhibition on Cidec expression still need to be further explored.…”

Metformin and vitamin D modulate adipose-derived stem cell differentiation towards the beige phenotype

“…Moreover, 1,25(OH) 2 D 3 /VDR signalling suppressed differentiation of 3T3-L1 white adipocytes together with increased expression of uncoupling proteins (Ucp1 and Ucp2) and development of BAT [ 48 ] . Within this context, we previously evaluated the ability of the two molecules to modulate adipogenic differentiation, finely tuning the inflammatory response, cytokines secretion and autophagy [ 38 ] In the present paper we evaluated for the first time, the effect of these molecules in inducing a different phenotype during ADSC adipogenic differentiation. In addition to white and brown adipose tissue, beige or brite adipocytes also have a role in body glucose regulation and thermogenesis [ 49 ] .…”

“…Moreover, overweight and obesity are often associated with Vitamin D deficiency [ 36 ] . Within this context, we previously demonstrated that the combination of vitamin D and metformin is able to counteract ADSC adipogenic differentiation, modulating vitamin D metabolism and the expression of specific epigenetic factors [ 37 , 38 ] . In the present paper, we aimed at evaluating the capability of these two molecules in orchestrating stem cell differentiation towards the beige phenotype, with particular attention to the main adipogenic markers and UCP1 expression, as a potential therapeutic strategy to counteract obesity.…”

NLRP3 downregulation enhances engraftment and functionality of adipose-derived stem cells to alleviate erectile dysfunction in diabetic rats

“…These proteins tend to induce proliferation and angiogenesis and can protect against vascular ED (12). Furthermore, ASCs function in reducing autophagy to treat diabetic nephropathy and inflammation by secreting exosomes and via differentiation (13,14). However, the erectile-protective function of ASCs in treating DMED rats has not yielded satisfactory results and has not yet been applied in clinical work (15).…”