Adipose-derived mesenchymal stem cells improve glucose homeostasis in high-fat diet-induced obese mice

Abstract

IntroductionEffective therapies for obesity and diabetes are still lacking. The aim of this study was to evaluate whether a single intravenous infusion of syngeneic adipose-derived mesenchymal stem cells (ASCs) can reduce obesity, lower insulin resistance, and improve glucose homeostasis in a high-fat diet-induced obese (DIO) mouse model.MethodsSeven-week-old C57BL/6 mice were fed a high-fat diet for 20 weeks to generate the DIO mouse model. Mice were given a single intravenous infusion of ex vivo expanded syngeneic ASCs at 2 × 106 cells per mouse. DIO or CHOW mice injected with saline were used as controls. Body weights, blood glucose levels, glucose, and insulin tolerance test results were obtained before and 2 and 6 weeks after cell infusion. Triglyceride (TG), high-density lipoprotein (HDL), and insulin levels in serum were measured. Expressions of genes related to insulin resistance, including peroxisome proliferator-activated receptor γ (PPARγ) and insulin receptor (InsR), and inflammation (IL-6,F4/80, and nucleotide-binding oligomerization domain containing 2, or NOD2), were measured in livers at mRNA level by real-time-polymerase chain reaction analysis. Beta-cell mass in pancrheases from CHOW, DIO, and DIO + ASC mice was quantified. GFP+ ASCs were injected, and the presence of GFP+ cells in livers and pancreases was determined.ResultsDIO mice that had received ASCs showed reduced body weights, reduced blood glucose levels, and increased glucose tolerance. ASC treatment was found to reduce TG levels and increase serum HDL levels. In livers, less fat cell deposition was observed, as were increased expression of InsR and PPARγ and reduction in expressions of IL-6 and F4/80. Treated mice showed well-preserved pancreatic β-cell mass with reduced expression of F4/80 and TNF-α compared with DIO controls. GFP+ cells were found in liver and pancreas tissues at 1 and 2 weeks after cell injection.ConclusionsASC therapy is effective in lowering blood glucose levels and increasing glucose tolerance in DIO mice. The protective effects of ASCs arise at least in part from suppression of inflammation in the liver. In addition, ASCs are associated with better-preserved pancreatic β-cell mass.

Time-dependent behavioral, neurochemical, and metabolic dysregulation in female C57BL/6 mice caused by chronic high-fat diet intake

“…Although, in the female mice, HFD's effect on body weight was apparent as early as after 6 weeks on the diet, it became more pronounced with continued HFD consumption. Prolonged HFD consumption resulted in an advanced obese phenotype characterized by exaggerated weight gain and increased absolute liver and kidney weights, suggesting that the weight gain is at this stage is not only due to intra-abdominal, but also to intra-organ (liver, kidneys) fat deposition as chronic HFD-induce increase in absolute liver weight correlates with increased intra-organ fat deposition [43]. Preferentially increased visceral fat accumulation has been observed in female, but not male mice, fed HFD for a chronic period, suggestive of the sex-specific differences in the visceral adiposity upon exposure to HFD [44].…”

Genetic Modification of Stem Cells in Diabetes and Obesity

“…However, after mouse adipose tissue-derived MSC transplantation, DIO mice demonstrated a reduction in blood glucose levels and improved glucose disposal [42]. Interestingly, the DIO mice that had received MSCs showed reduced body weights, a decrease in serum triacylglycerol coupled concomitantly with an increase in HDL levels [42]. The mechanisms by which MSCs can reverse the complications caused by diabetes and obesity are still unclear.…”

“…Diet-induced obese (DIO) mice fed with high fat diet (60% of calories from fat) for several weeks do become obese with a decreased glucose tolerance and insulin sensitivity. However, after mouse adipose tissue-derived MSC transplantation, DIO mice demonstrated a reduction in blood glucose levels and improved glucose disposal [42]. Interestingly, the DIO mice that had received MSCs showed reduced body weights, a decrease in serum triacylglycerol coupled concomitantly with an increase in HDL levels [42].…”

“…The literature indicates that MSCs can migrate to an injured pancreas, suppress pro-inflammatory cytokines and prevent β-cell apoptosis. However, one cannot exclude the fact that MSCs could also differentiate into pancreatic β-cells [42,43].…”

“…Different studies suggest that the "homing-in" and benefits of MSCs (genetically modified or not) depends on the route of cell delivery. Thus, the target of this cell-based therapy might change considering intra-peritoneal versus cells delivered into the tail vein [42,44].…”