Obesity‐driven alterations in adipose‐derived stem cells are partially restored by weight loss

Abstract

Objective: The therapeutic potential of adipose-derived stem cells (ASCs) is reduced by various stressinducing conditions that affect tissue homeostasis such as diabetes, aging, and obesity. Previous works have provided evidence of negative effects of obesity on ASC populations, but it is unclear whether this persists after a weight loss. This study evaluated whether weight loss can restore the attenuated properties found in ASCs derived from populations with obesity (oASCs). Methods: In vitro functional analyses were performed to investigate the possible recovery properties in mouse oASCs. Using ASCs isolated from subcutaneous tissue from formerly obese mice (dASCs) and control mice (cASCs), cell proliferation, viability, and some regenerative properties in these cells were analyzed compared with oASCs to evaluate the functional cell state. Results: Cell proliferation, viability, and some regenerative properties are strengthened in dASCs and cASCs compared with oASCs. Nevertheless, metabolic analysis reveals a mitochondrial load misbalance and function leading to impaired respiration in dASCs.Conclusions: This study demonstrates that an initial obese environment triggers a detrimental state in ASCs that is not completely recovered after weight loss.

Insight into the development of obesity: functional alterations of adipose‐derived mesenchymal stem cells

“…The expression of adipogenic genes like glucose transporter type 4 and fatty acid binding protein 4 (FABP4) was lower in obese ASCs derived from subjects with metabolic syndrome than in control ASCs . In further support of these observations, mouse obese ASCs exhibited a reduced capability for adipogenic differentiation associated with a decreased expression of related genes insulin receptor substrate 1 (IRS1), IRS2 and FABP4 compared with mouse control ASCs . In addition, it was demonstrated that the heme oxygenase‐1 inhibited proliferation and differentiation of preadipocytes at the onset of obesity via reactive oxygen species dependent activation of Akt/PKB (protein kinase B) in obese mouse models .…”

“…Moreover, it was shown that the mitochondrial content and function were impaired in ASCs from obese mouse and human adipose tissue . It was further demonstrated in a mouse model that obese ASCs had a significant increase in the abundance of mitochondria mass and significantly higher levels of reactive oxygen species compared with control ASCs . Recently, these authors report that obese derived ASCs display specific differences in metabolic regulators like vitamin D and Gas5, a long non‐coding molecule involved in glucocorticoid resistance .…”

Silencing of the small GTPase DIRAS3 induces cellular senescence in human white adipose stromal/progenitor cells

“…Health-promoting effects of WL exceed however those directly associated with reduction of adipocyte size and fat mass [9]. Increasing evidence suggest beneficial effects of WL on ASCs [10, 11]. We have recently demonstrated that WL leads to upregulation of the small GTPase, GTP-binding RAS-like 3 (DIRAS3) [12, 13], in ASCs of human subcutaneous (s) WAT [14].…”

Deficient primary cilia in obese adipose‐derived mesenchymal stem cells: obesity, a secondary ciliopathy?

“…It has been also shown that obese ASCs with dysfunctional cilia exhibit impaired motility , indicative of their inhibited homing ability and less functioning at distant sites. In addition, the primary cilium has been linked to autophagy, a mechanism for degradation of cellular components in lysosomes facilitating metabolic and energetic homeostasis .…”

“…In line with these properties, ASCs directly contribute to homeostasis, cell renewal and spontaneous tissue repair and immunomodulation through direct cell–cell interaction and secretion of numerous cytokines and chemokines . Obesity alters multiple functionalities and properties of ASCs displaying compromised differentiation capability , impaired undifferentiated multipotent state , defective immunomodulation , deregulated motility and disturbed metabolism . Impaired obese ASCs contribute to the development of obesity by affecting adipose tissue remodelling, inducing hypoxia and secreting pro‐inflammatory cytokines .…”