**3. Subcutaneous ASCs differentiation in obesity**

In obese patients, adipose tissue expands by differentiating preadipocytes into adipocytes (adipogenesis) and/or hypertrophy of existing adipocytes. Adipocytes hyperplasia is the alternative optimal process for sustaining the high demand for lipid storage, through the activation of multipotent stem cells, leading to the generation of new mature adipose cells, but it has a limited and individualized capacity [14, 15].

The low adipogenic capacity of subcutaneous ASCs may result in a dysfunctional tissue, because it leads to adipocyte hypertrophy, causing the accumulation of inflammatory macrophages; insulin resistance; and also the accumulation of ectopic fats in the liver, muscles, kidneys, and pancreas [16–21].

The subcutaneous ASC functions are altered in obese patients. The literature review on the relationship between obesity and adipogenic differentiation capacity of mesenchymal stem cells originating in subcutaneous adipose tissue obtained from pre-surgical obese patients are shown in **Table 1**.

Several studies found that lipid accumulation in hypertrophic subcutaneous adipocytes evaluates the expansion capacity of the pre-adipogenic mesenchymal cell line and lipid overloaded adipocytes are associated with a poor metabolic profile for obese patients [28–30]. The subcutaneous adipose tissue represents 90% of total fat mass, it has the potential to greatly affect systemic insulin resistance via adipokine secretion in obese persons [31].

The obese population is known to be at high risk for cardio-metabolic diseases. Insulin resistance evaluation by HOMA-IR is considered as a good cardiovascular


#### **Table 1.**

*Relationship between subcutaneous ASCs and obesity in pre-surgical patients.*

#### *Subcutaneous Adipose Stem Cells in Obesity: The Impact of Bariatric Surgery DOI: http://dx.doi.org/10.5772/intechopen.95542*

risk predictor [32], is also demonstrated as a valuable criterion for identifying obese individuals with a higher mortality risk by Hinnouho et al. [33].

Insulin resistance and its cardio-metabolic consequences are closely associated with disturbances of fat metabolism, as it was demonstrated that exceeding the subcutaneous adipose tissues storage capacity results in fatty acid infiltration of insulin target tissues like the skeletal muscle and the liver [34], a phenomenon known as lipotoxicity that is intimately related to the development of insulin resistance.

The estimated prevalence of obese patients without metabolic syndrome criteria in a recent meta-analysis is 35% of the obese patients [35], so it becomes important to better understand the particularities of adiposity expansion in these obese patients that do not develop insulin-resistance or associated metabolic disturbances.

*Effects of hyperglycemia and oxidative stress on subcutaneous ASC adipogenesis* Diabetes impairs the angiogenic potential of adipose-derived stem cells by selectively depleting cellular subpopulations. Studying adipogenic potential of adipose tissue-derived from diabetic type 1 or type 2 mice, Rennert et al. [36] observed depletion of putative ASCs (CD45-/CD31-/CD34+ cells) within the diabetic SVF, which was consistent with the signaling dysfunction seen in this environment.

Recent studies have shown the widespread downregulation of mesenchymal stem cell markers in the SAT of diabetic rats. ASCs derived from obese mice [37] and Zucker diabetic fatty rats [38] exhibited a reduced capability for adipogenic differentiation associated with a decreased expression of related genes insulin receptor substrate 1 (IRS1), insulin receptor substrate 2 (IRS2), and adipocyte fatty acid-binding protein (aP2 or FABP4) compared with mouse control ASCs.

The oxidative stress generated by hyperglycemia has deleterious effects on proliferation, survival, homing, and angiogenic capacity of ASCs derived from the stromal vascular fraction [11, 39, 40]. Hyperglycemia up-regulates reactive oxygen species (ROS) production, suppresses the nitric oxide (NO) synthesis pathway, thereby may impair the regenerative function of ASCs. Impaired adipogenesis and IR were associated with increased 4-HNE, increased 8-hydroxy-2-deoxyguanosine (8-OHdG), increased cholesterol oxidation-derived oxysterols [41]. Also, 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 [42].

The mechanism of decreased number of stem cells in murine diabetic adipose tissue may involve the activation of hyaluronan synthases in intracellular membrane compartments [43]. The study by Han et al. [44] showed that extended extracellular hyaluronan matrices were found around adipocytes in obese mice. The matrix was infiltrated with macrophages, which would otherwise accumulate because adipocytes would continue to synthesize and extrude hyaluronan indefinitely in response to sustained hyperglycemia. The stem cells that divide into hyperglycemia (> 2.5 times normal) are heading for pathological adipogenesis in response to glucose stress and that subsequent cell divisions along this pathway could contribute to the expanded population of fat cells in adipose tissue in diabetes.

*Effects of pro-inflammatory signals on subcutaneous ASC adipogenesis*

Obesity is characterized by the accumulation of diverse immune cells in both the subcutaneous and visceral expanding fat depots, even though macrophage infiltration appears to be more prominent in the latter [45]. The presence of macrophages in the human SAT is causally related to impaired ASCs differentiation, which in turn is associated with systemic IR. A negative correlation between SAT adipogenesis, but not VAT, and systemic IR was observed [46]. Moreover, lipid-laden adipocytes produce increased levels of cytokines such as Interleukin 6 (IL-6), IL-1β, IL-8, TNF-α, and monocyte chemoattractant protein-1 (MCP-1), which can inhibit preadipocyte differentiation [41].

To investigate the inflammatory state in diabetes, the levels of IL1β, IL-6, and TNFα were measured. Numerous studies have shown these cytokines reduce adipogenesis. In patients with diabetes, IL-1β has been shown to induce insulin resistance (IR) in adipocytes by reducing IRS-1 regulation. Also, decreased IRS-1 expression has been reported to inhibit adipogenesis by decreasing CEBPα and PPARγ. Finally, the expression of SIRT1 is downregulated compared to that of healthy cells, this finding is consistent with other studies showing that inhibition of this enzyme increases senescence and reduces the proliferation of MSCs, losing their adipogenic potential [21].

Recent studies revealed that IL-6 may be a good marker of subcutaneous adipose tissue inflammation and it is inversely related to adipogenic capacity. Subcutaneous ASCs derived from insulin-resistance obese individuals exhibited a lower proadipogenic and higher anti-adipogenic gene expression profile This diminished adipogenic potential of ASCs may be a consequence of a preponderance of large adipocytes, prone to forming inflammatory foci. Markers of oxidative stress were also elevated in the IR state. Thus the related scenario of inflammation and oxidative stress is a likely mediator of increased IL-6 secretion in this depot [47].
