1 INTRODUCTION

Obesity is a serious global public health problem, responsible for about 4.7 million premature deaths each year.1, 2 The incidence of obesity is increasing dramatically, as reported by the World Health Organization (WHO); it affected over 650 million adults worldwide in 2016.3 Obesity is defined as the excessive accumulation or abnormal distribution of fat tissue.4 The current most widely used criteria for classifying obesity is the body mass index (BMI), which ranges from class 1 of obesity (BMI ≥ 30.0 kg/m2) to severe or morbid obesity (BMI ≥ 40 kg/m2). Obesity can progressively cause and/or exacerbate a wide spectrum of metabolic comorbidities, including type 2 diabetes mellitus (T2DM), hypertension, dyslipidemia, cardiovascular disease (CVD), nonalcoholic fatty liver disease (NAFLD), and fertility problems.5, 6 The severity and duration of obesity are associated with the metabolic syndrome (MS), which occurs in 4.9% of nonobese patients to 35.3% in patients with obesity.7 According to the National Institutes of Health, a subject has MS if it satisfies three or more of the following traits: large waist circumference (≥89 cm for women and ≥102 cm for men), hypertriglyceridemia (≥1.7 mmol/L), reduced high-density lipoprotein cholesterol (HDL-C) (<1.04 mmol/L in men or <1.3 mmol/L in women), hypertension (≥130/≥85 mm Hg), and elevated fasting blood glucose (≥5.6 mmol/L).8 In light of the alarming data, it is of primary importance to elucidate the mechanism through which obesity leads to the adipose tissue dysfunction followed by metabolic derangements. Nevertheless, many cohort studies have reported that some individuals with obesity remain insulin sensitive and are metabolically “healthy” despite similar total fat mass.9-12 Metabolically healthy obese (MHO) subjects exhibit increased subcutaneous adiposity and are characterized by a lower degree of systemic inflammation, but still they are at a higher risk of cardiovascular complications.13-16 Longitudinal studies provide convincing evidence that MHO is only a transient condition.17-19 Therefore, it is important to identify individuals with obesity at increased risk of developing obesity-related metabolic diseases that can benefit most from weight loss. Many factors are responsible for the established obesity-related disease complications, which lead to a not effective treatment and management of patients with obesity. Recently, numerous strategies have been proposed to minimize health-related consequences of obesity, including cell-based therapy. Mesenchymal stem cell (MSC) therapies may represent promising adjunctive therapy for patients with obesity, thus reducing the economic burden of treatment throughout the patient's life.20-23 Both bone marrow-derived MSC and adipose-derived MSCs (ADMSCs) have become the most commonly used stem cells for cellular therapy in a variety of human diseases. ADMSCs seem to be superior to other MSCs in many aspects, including ease of isolation, their abundance, and better immunomodulatory properties. Patients may be treated with autologous or allogenic ADMSCs with low risk of cellular rejection. These advantages together with the minimal immunogenicity and high immunoregulatory capacity make them attractive for clinical use. In this review, we outline the current understanding of ADMSCs—based therapies in obesity and its associated diseases from the animal model to the preclinical and clinical trials.

2 ADIPOSE TISSUE

Adipose tissue was historically considered to be merely an energy store, but this concept was changed after the discovery of leptin in 1990 by Friedman's group.24 Since this discovery, other cytokines, hormones, and peptides, collectively referred to as “adipokines,” have been identified.25 Adipose tissue develops extensively in homeothermic organisms, and the proportions to body weight vary considerably between species. Averagely, it constitutes about 15%–20% of body mass of men and 20%–25% of women. This connective tissue influences the whole body as it is responsible for energy storage and distribution, fat accumulation, thermoregulation, hormone synthesis, glucose, and insulin homeostasis.26, 27 Fat tissue can be classified into brown adipose tissue (BAT) and white adipose tissue (WAT), which differ in function, distribution and morphology.28 In adult humans, BAT had long been considered to be absent; however, recent investigations have shown that BAT is found to be distributed throughout the cervical, supraclavicular, mediastinal, suprarenal, and paravertebral regions.29 The mitochondrial abundance and high vascularization in comparison with the WAT give it a brown color appearance. High expression of uncoupling protein 1 (UCP1) in their inner mitochondrial membrane is responsible for energy dissipation in the process called nonshivering thermogenesis.30 In turn, white adipocytes not only control energy balance by storing and mobilizing triacylglycerols but also secrete a variable amount of hormones and paracrine factors. Although white adipocytes are distributed throughout the body, their principal depots are the subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT).31 SAT is found beneath the skin, some deposits are gluteal, femoral, and abdominal, while visceral fat surrounds internal organs and is concentrated in the abdominal cavity, further subdivided into mesenteric, omental, perirenal, and pertoneal depots. Importantly, WAT depots are functionally distinct, SAT stores excess lipid, and thus preventing ectopic lipid deposition, while VAT protects the visceral organs. Typically, VAT can be identified by a higher number of smaller adipocyte size, whereas SAT by larger adipocytes. In healthy middle-aged adults, only 5%–15% of total body fat is considered VAT; the rest is SAT, the largest body fat deposit. When the storage capacity of adipocytes exceeds (like in obesity), further caloric overload leads to the expansion of adipose tissue in a given fat compartment through increase in adipocyte size (hypertrophy) and/or proliferation of precursor cells (hyperplasia).29, 32 Simultaneously, the precursor cells of the stromal vascular fraction (SVF) in adipose tissue undergo numerous functional changes, begin to be recruited and committed towards adipocyte lineage. This series of events is called “adipose tissue remodeling.”33 However, in obesity, aberrant adipose tissue remodeling may induce dysregulation of fat tissue in secreted cytokines, hormones, and metabolites.34 This causes ectopic lipid deposition in the liver, skeletal muscle, heart, pancreas, as well as in the visceral depots and leads to impaired glucose and lipid metabolism, systemic insulin resistance (IR), an increased risk of T2DM and CVD development.35, 36 It is worth nothing that the distribution of adipose tissue appears to be more important than the total amount of the body fat. Indeed, VAT is more metabolically active, has higher free fatty acids (FFAs) and glucose uptake, is less insulin sensitive, and therefore is thought to be more deleterious in the development of obesity-related metabolic complications.37 In accordance with this statement, Tran et al. transplanted either visceral (intra-abdominal) or subcutaneous fat from donor to visceral or subcutaneous regions of recipient mice.38 Surprisingly, transplantation of SAT in an intra-abdominal site improves glucose tolerance and the whole-body insulin sensitivity, suggesting that adipose tissue depots maintain an intrinsic memory of their site of origin and thus have distinct metabolic properties. Similarly, Satoor et al. have shown that autologous transplantation of visceral fat (intra-abdominal) to subcutaneous (thigh/chest) sites provides metabolic advantage at physiological as well as at molecular levels.39 Three weeks after transplantation, the abundance of adipokine gene transcript (i.e., adiponectin, leptin, visfatin, and resistin) was adjusted to the expression level in the resident (thigh) depot. These observations support the notion that adipose tissue depots have “residence memory” and local factors, such as glucose levels, are involved in the epigenetic regulation of adipokine gene promoters.39

3 MESENCHYMAL STEM CELLS

MSCs also referred to as “mesenchymal stromal cells” are fibroblast-like multipotent cells characterized by the capacity of self-renewal and ability to differentiate into cell types of mesodermal origin, including adipocytes, chondrocytes, and osteoblasts. Stem cell research has advanced considerably since pluripotent cells were first isolated from mouse embryos in 198140; however, the first report with embryonic stem cell lines derived from human blastocysts was published in 1998.41 The clinical relevance of MSCs was initially based on harnessing their potential for tissue regeneration and repair, and the discovery of their paracrine properties has greatly expanded the range of therapeutic applications for which they are currently being explored. MSCs are attractive cell therapy agents in the treatment of various diseases, especially in the treatment of conditions involving autoimmune and inflammatory processes. Several characteristics favor their use in a wide range of diseases, such as their autocrine and paracrine activities, immunomodulatory and immunosuppressive properties, with their minimal immunogenicity and ethical restrictions.42 The cells can be obtained from human's multiple organs and structures like bone marrow, adipose tissue, liver, pancreas, spleen, thymus, skeletal muscle, dental pulp, dermis, and neonatal tissues (umbilical cord, amniotic fluid, fetus, placenta), but the most frequently used sources of MSCs remain bone marrow and adipose tissue.43 To standardize MSCs, in 2006, the International Society for Cell and Gene Therapy (ISCT) proposed the following minimal criteria: (1) They must be plastic adherent when maintained in standard culture conditions; (2) they must express the surface markers CD73, CD90, and CD105 and lack of expression of hematopoietic and endothelial antigens CD14 (or CD11b), CD19 (or CD79α), CD34, CD45, and HLA-DR surface markers; (3) they must be able to differentiate into adipocytes, chondrocytes, and osteocytes in vitro (trilineage potential).44

3.1 Adipose-derived MSCs

ADMSCs hold great promise as a therapeutic strategy in treating a wide spectrum of diseases like obesity, T2DM, fatty liver disease (NAFLD, nonalcoholic steatohepatitis [NASH], liver fibrosis, cirrhosis), CVDs, muscular dystrophy, osteoarthritis, Crohn's disease, cancers, multiple sclerosis, acute kidney injury, and chronic skin wounds.45-53 ADMSC-based clinical trials have grown over the years largely due to their abundance, ease of isolation, rapid expansion, high proliferation capacity, and no ethical issues.54 The secretion of a broad range of paracrine factors, including cytokines, antioxidant factors, and growth factors, into their microenvironment is believed to be a primary mechanism by which ADMSCs achieve their therapeutic effect (Figure 1). ADMSCs show the typical characteristics of MSCs, after in vitro stimulation can differentiate into mesodermal lineages cell types (adipocytes, osteoblasts, chondrocytes, fibroblasts, and myocytes) as well as no mesodermal cell types, such as neurons, hepatocytes, endothelial cells, and cardiomyocytes.55 According to the standard criteria, cultured ADMSCs are plastic-adherent, spindle-shape cells characterized by the expression of positive markers: CD13, CD29, CD44, CD73, CD90, and CD105 and the lack of CD45 and CD31 on their surface. Moreover, the characterization of ADMSCs includes additional positive markers like CD10, CD26, CD36, CD49d, and CD49c and low or negative markers like CD3, CD11b, CD49f, CD106, and podocalyxin-like protein (PODXL).56 ADMSCs constitute up to 2% of SVF, a heterogeneous mesenchymal population of cells, compared with the low cell yield (0.001%–0.002%) of BM-MSCs. A large amount of ADMSCs is isolated from SAT by liposuction or fat excision with an efficiency up to 500 times greater than from bone marrow isolation. The liposuction procedure provides 100 ml to 3 L of lipoaspirate that is routinely discarded. By processing this material, ADMSCs are isolated from the SVF, yielding up to six billion cells in one passage.54, 57 Some features of ADMSCs are similar to BM-MSCs, but numerous properties are different. For instance, ADMSCs are more susceptible to differentiate into pancreatic beta cells, muscle cells, and cardiomyocytes compared with BM-MSCS. In addition, some studies reported a greater osteogenic capacity of BM-MSC than of ADMSC58-60; however, other studies have shown equal or even superior osteogenic capacity of ADMSC,61, 62 making them suitable for bone tissue engineering. Furthermore, phenotypic expression patterns allow to distinguish between stem cell derived from adipose tissue or bone marrow; that is, only ADMSCs express CD36 and CD49d, whereas CD106 antigen is expressed solely by BM-MSCs. Recent evidence indicates that ADMSCs are stronger immunomodulators and are better adapted to oxidative stress, hypoxia-induced apoptosis or have a greater angiogenetic force when exposed to harsh conditions compared with BM-MSCs.63 Their advantage in immune regulation is due to the secretion of higher levels of pro-inflammatory and anti-inflammatory cytokines such as interleukins (IL-6, IL-8), interferon γ (IFN-γ), and transforming growth factor (TGF-β). ADMSCs also release higher amount of growth factors including granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF), nerve growth factor (NGF), or insulin-like growth factor 1 (IGF-1) compared with the BM-MSCc.64-67 Overall, the superior characteristics of ADMSCs compared with other MSCs along with their abundance and easy cell access to cells encourage scientists to complete researchers among ADMSCs.

Paracrine functions of ADMSCs. It is now believed that the therapeutic effects of ADMSCs are due to their ability to secrete a wide range of bioactive molecules, including cytokines, chemokines, antioxidant factors, and growth factors. The paracrine mechanism plays a major role in immunomodulation, limitation of apoptosis, and stimulation of local angiogenesis. The immunomodulatory activity of ADMSCs consists of inhibition of dendritic cells (DCs) differentiation, suppression of immunoglobulin synthesis, inhibition of the CD8+ and CD4+ T lymphocytes and natural killer (NK) cells proliferation, and promotion of M2 macrophage polarization and regulatory T cells (Treg) proliferation. Abbreviations: ADMSCs, adipose-derived mesenchymal stem cells; ANG1, angiopoietin-1; CCL2, chemokine (C-C motif) ligand 2; CCL20, chemokine (C-C motif) ligand 20; CCL26, chemokine (C-C motif) ligand 26; CCL3, chemokine (C-C motif) ligand 3; CCL4, chemokine (C-C motif) ligand 4; CCL5, chemokine (C-C motif) ligand 5; CCL6, chemokine (C-C motif) ligand 6; CX3CL1, chemokine (C-X3-C motif) ligand 1; CXCL1, chemokine (C-X-C motif) ligand 1; CXCL10, chemokine (C-X-C motif) ligand 10; CXCL11, chemokine (C-X-C motif) ligand 11; CXCL12, chemokine (C-X-C motif) ligand 12; CXCL2, chemokine (C-X-C motif) ligand 2; CXCL5, chemokine (C-X-C motif) ligand 5; CXCL8, chemokine (C-X-C motif) ligand 8; FGF, fibroblast growth factor; GM-CSF, granulocyte macrophage colony-stimulating factor; HGF, hepatocyte growth factor; HIF, hypoxia inducible factor; IDO, indoleamine 2,3-dioxygenase; IGF-1, insulin-like growth factor 1; IL-10, interleukin 10; IL-6, interleukin 6; LIF, leukemia inhibitory factor; MCP-1, monocyte chemoattractant protein 1; NK, natural killer cells; NO, nitric oxide; PGE2, prostaglandin 2; TGF-β, tumor growth factor β; VEGF, vascular endothelial growth factor

In recent years, it has been proven that there are differences between ADMSCs isolated form lean and individuals with obesity. Approximately 10% of adipocytes are renewed annually at all BMI levels; however, in subjects with obesity, an excess of adipocyte generation results from an increased abilities of ADMSCs to differentiate to adipocyte lineage.68 ADMSCs collected from morbidly obese patients exhibit diminished expression of two fundamental developmental transcription factors, that is, T-box 15 (TBX15) and the homeobox C10 (HOXC10), and ACTA2, a marker of ADMSCs. Downregulation of these factors indicates that obesity interferes with ADMSCs multipotency, especially in obese patients with MS. On the contrary, the inflammatory genes IL-1β and IL-8 and monocyte chemoattractant protein 1 (MCP-1, aka CCL2) were upregulated in ADMSCs acquired from individuals with obesity.69 This significant release of inflammatory cytokines by ADMSC is associated with the development of low-grade chronic systemic inflammation during obesity progression. Summing up, ADMSCs isolated from patients with obesity and MS have a lower proliferative and differentiation capacity and therefore are less effective in immunomodulation compared with lean, metabolically healthy individuals. This knowledge is of great interest as ADMSCs have been used in various preclinical models and clinical trials, especially in choosing the adequate ADMSCs subpopulation for therapies.

4 RESEARCH AMONG ADMSCS USAGE IN THE TREATMENT OF OBESITY-RELATED MORBIDITIES

Obesity is a complex, multifactorial disease. Usually excessive fat deposition in obesity is closely related to environmental factors such as an increased consumption of saturated fats, carbohydrates, sugars, and decreased physical activity as well as to genetic and epigenetic factors.70 Consumption of excess nutrients causes fat to accumulate in deposits of WAT (subcutaneous and visceral), leading to adipocyte hypertrophy and systemic metabolic dysfunction. Appropriate weight loss is the cornerstone of obesity treatment and should be promptly offered to patients with obesity to prevent and/or delay the onset of obesity-related complications. Throughout the past half century, a variety of interventions have been proposed for management of obesity. ADMSCs therapy is gaining more and more attention as an attractive strategy for obesity and related comorbidities. The results obtained in in vivo animal models confirmed their therapeutic potential in weight loss and changes in the composition of adipose tissue. Jaber et al. investigated the effect of ADMSCs on body weight and composition in mouse model of high-fat diet (HFD)-induced obesity.20 Male C57BL/6 obese mice received two intraperitoneal doses (4.2 × 107 cells/kg) of ADMSCs. This stem cell therapy was sufficient to reduce body fat mass in diet-induced obesity (DIO) animals, despite no change in body weight. In line with these findings also Wang et al. shown that ADMSCs transplantation did not affect HFD-induced weight gain.71 Furthermore, no significant changes in body weight were noted in a diabetic and obese mouse model following Sod2 or catalase (CAT)-upregulated ADMSCs therapy.72 Likewise, in the mouse, NASH model injection of ADMSCs or their small extracellular vesicles (sEVs) did not significantly change body weight and liver-to-body weight ratio.73 However, these results contradict with other study demonstrating that obese mice treated with brown ADMSCs significantly reduced body weight.74 Similarly, ADMSCs infusion significantly suppress the increase in body weight in db/db obese mice and DIO mice.75 On the other hand, Cao et al. confirmed the ADMSCs effectiveness, however, isolated from mice not humans, in reducing body weight in DIO animals.76 In another study, a single ADMSCs transplantation did not change overall body weight, while a second ADMSCs injection significantly decreased the weight of the obese mice.77 Interesting results were provided by the work of Shree et al.78 C57BL/6 HFD-fed mice were administered with human ADMSCs or metformin-preconditioned ADMSCs. It turned out that mice treated with ADMSCs alone did not change body weight, but significant weight reduction was observed in the metformin-preconditioned ADMSCs group.78 Discrepancies between studies may result from different animal models used in the experiments, distinct adipose tissue depots chosen for ADMSCs isolation, or different protocols used for cells harvesting and culture.

Studies have confirmed that ADMSCs therapy could effectively ameliorate a wide range of obesity-related comorbidities such as IR, T2DM, women infertility, vascular disorders, NAFLD, and systemic inflammation (Figures 2 and 3, Table 1). The most significant studies are highlighted in this review.

Mechanisms of ADMSCs actions on glucose homeostasis and liver functions. ADMSCs therapy is effective in restoring glycemic status i.e. promotes insulin production and improves insulin sensitivity. Additionally, transplantation of ADMSCs reverses liver steatosis, through reduced inflammation, reduced apoptosis, and improved hepatocyte regeneration. Abbreviations: ADMSCs, adipose-derived mesenchymal stem cells; AKT, serine/threonine kinase 1; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GLUT4, glucose transporter 4; G6Pase, glucose-6-phosphatase; HLCs, hepatocyte-like cells; HO-1, heme oxygenase-1; IL-1β, interleukin 1β; IL-6, interleukin 6; IL-8, interleukin 8; IPCs, insulin producing cells; IRS-1, insulin receptor substrate 1; LDH, lactate dehydrogenase; MCP-1, aka CCL2, monocyte chemoattractant protein 1; NQO1, NAD(P)H quinone oxidoreductase 1; PEPCK, phosphoenolpyruvate carboxykinase; PPAR-γ, peroxisome proliferator-activated receptor gamma; SOD, superoxide dismutase; TBIL, total bilirubin level; TNF-α, tumor necrosis factor α

Mechanisms underlying the effects of ADMSCs in improving serum lipid profile, reducing atherosclerosis, and restoring ovarian function. Abbreviations: ADMSCs, adipose-derived mesenchymal stem cells; FGF, fibroblast growth factor; HDL, high-density lipoprotein; IGF-1, insulin-like growth factor 1; LDL, low-density lipoprotein; TC, total cholesterol; TG, triglycerides; VEGF, vascular endothelial growth factor

TABLE 1. The most relevant preclinical studies pertaining to the therapeutic exploitation of adipose-derived mesenchymal stem cells (ADMSCs) in the treatment of obesity and its metabolic complications in various animal models ADMSCs source Administration route and dose Animal model Age Diet composition Mean follow-up period Body weight and composition Lipid profile Glucose, HbA1c levels, GTT Insulin secretion and insulin sensitivity Pancreatic islets growth Pro-inflammatory and anti-inflammatory cytokines Liver function Author Human ADMSCs Intraperitoneal injection of ADMSCs at a dose of 4.2 × 107 cells/kg. A second dose followed after 10 weeks. Male C57BL/6 mice 9 weeks Normal chow (9% fat) HFD (60% fat) for 15 weeks 6 weeks after the second injection Decreased body weight. The percentages of fat mass decreased significantly. Atherogenic index of plasma (AIP) was significantly reduced. Significant decrease in plasma glucose level. Positive effect on glycemic status. Not defined Not defined IL-6 and TNF-α secretion was decreased. Not defined Jaber et al.20 Human ADMSCs Intramuscular injection of ADMSCs suspension at a dose of 5 × 105 cells. Male C57BL/6 mice 6 weeks Chow diet (10% kcal from fat) or high-fat diet (HFD) (60% kcal from fat) for 10 weeks 8 weeks Body weight did not significantly change. Decrease in serum triglyceride levels. Reduction in oxidized LDL level. Decrease in glucose concentration. Improvement in the glucose tolerance. Reduction in the serum insulin levels. A remarkable decrease in HOMA IR. Increase in the insulin sensitivity. Not defined A dramatic reduction in the secreted IL6 cytokine. Decrease in liver triglycerides. Shree et al.21 Human ADMSCs 5 × 105 ADMSCs injected intramuscularly in the thigh. Additionally, metformin preconditioned ADMSCs (Met-ADMSCs) were studied. Male C57BL/6 mice 6 weeks Chow diet or HFD for 10 weeks 4 weeks Mice treated with ADMSCs did not show reduction in body weight, whereas Met-ADMSCs decreased body weight. TG, oxidized LDL were decreased only in Met-ADMSCs group. Met-ADMSCs decreased fasting glucose level. Both ADMSCs and Met-ADMSCs reduced serum insulin levels and increased HOMA IR. Not defined Only Met-ADMSCs treated group showed significant decrease in IL6 levels. Decrease in IL6 and PAI1 levels in the liver tissue. Shree et al.78 Murine ADMSCs A single intravenous infusion of ADMSCs at a dose of 2 × 106 cells/ml. Male C57BL/6 mice 6 weeks Standard chow diet or high-fat diet for 20 weeks 2 and 6 weeks after cell infusion Slightly reduced body weight, but the difference was insignificant. Decreased TG and increased HDL levels. Decreased blood glucose level and faster glucose disposal. Increased Preservation of β-cells mass mRNA expression of F4/80 and TNF-α was reduced. Less fat accumulation, suppression of inflammation was observed. Cao et al.76 Human ADMSCs and UC-MSCs Intraperitoneally injected ADMSCs (2 × 106 cells), and UC-MSCs (2 × 106 cells) once a week for 3 weeks. Male db/db mice with deleted leptin receptor + C57BL/6J mice 6 weeks Standard diet or HFD for 6 weeks 6 weeks from first ADMSCdelivery ADMSCs decreased total body weight and adipose tissue weight in db/db and obese mice. Reduction in TG, TC, LDL-C levels. Decrease in fasting blood glucose levels. Decrease in plasma C-peptide and glucagon levels. ADMSCs enhanced insulin sensitivity. Recovery of pancreatic islets. Increase in pancreatic β-cell mass. Not defined Recovery of liver structures. Decrease in IFN-γ. Liu et al.75 Human brown adipose-derived MSCs 1 × 106 cells/kg body weight via intraperitoneal injection (every 2 weeks for 10 weeks) Male C57BL/6J mice 4 weeks Normal chow diet or HFD for 30 weeks 10 weeks Decrease in body weight Decrease in TG, TC. Increase in HDL/LDL ratio Decrease in fasting glucose level and improved glucose intolerance. Upregulation of GLUT4 in muscle. Not defined Not defined Downregulation of TNF-α and IL-4. Upregulation of the anti-inflammatory cytokines. Reduction in lipid accumulation in the liver. Decreased serum concentration of AST and ALT, but increased albumin level. Suppression of liver fibrosis and inflammation. Lee et al.74 Human ADMSCs Systemic transplantation of ADMSCs at a dose of 4.2 × 107 cells/kg body weight Male B6 mice 7 weeks Chow diet or HFD for 8 weeks 22 weeks after induction of diabetes Reduction in body weight. Not defined Glucose tolerance and homeostasis were improved Increased serum level of human insulin. Increase in insulin sensitivity evidenced by GLUT4 upregulation. Promoted pancreatic islet growth. Downregulation of IL-1a, IL-1b and TNF-1α. Decrease in circulating TNF-α and IL-1 levels. Reduction in Cpt 1A expression in the liver Tung-Qian et al.77 Human ADMSCs Commercially obtained human ADMSCs Intraperitoneal injection of commercially obtained human ADMSCs at a dose of 1.5 × 106; Sod2-ADMSCs; Cat-upregulated ADMSCs C57BL/6J male mice 4–6 weeks Mice were fed with two different diets: 1) HFD (45% fat) for 14–16 weeks; 2) HFD (60% fat) for 8–10 weeks. 4 weeks post injection Body weight remained stable. A significant decrease in liver fat content in animals received Sod2- or Cat-ADMSCs. Not defined Improved glucose tolerance in studied groups. Not defined Not defined Sod2- or Cat- upregulated ADMSCs reduce plasma level of TNF-α. Reduction in liver triglyceride content. Domingues et al.72 Murine sheet ADMSCs ADMSCs sheet at a dose 1 × 106 cells/dish were transplanted on the subcutaneous sites of back MaleC57BL/6J mice 4 weeks Mice were fed HF/HSD (55% fat, 28% carbohydrate) or normal diet (5% fat, 50% carbohydrate) for 14–16 weeks. 10 days after the surgical procedures. Decreased Not defined ADMSCs sheet transplantation significantly improved glucose intolerance ADMSCs sheet transplantation improved insulin resistance. Not defined ADMSCs sheet transplantation increased and decreased plasma levels of adiponectin and TNF-α in mice. Not defined Ishida et al.79 Rat ADMSCs 3 × 106 ADMSCs were injected through the tail vein once a week for 24 weeks. Male Sprague–Dawley (SD) rats A long-term T2DM complication rat model. 8 weeks Normal chow diet (NCD) or a high-fat diet (HFD; 60% fat) for 8 weeks 24 weeks Decreased The level of circulating TGs, TC and LDL-C was markedly reduced. Persistent and gradual decrease in blood glucose level. Glucose clearance was improved in the ADMSCs-treated group. A marked enhancement in insulin sensitivity after the ADMSCs multiple infusions. Pancreatic islet function was markedly restored. The ratio of insulin-positive cells per islet was increased. Reduction in TNF-α, IL1β, TGF-β and increase in anti-inflammatory molecule IL-10. ADMSCs significantly decreased col1 transcripts and TIMP-1, MMP-2, 8, and 9. Yu et al.80 Murine ADMSCs ADMSCs from C57BL/6, db/db, or T2D mice were infused intravenously (5 × 105/mouse via the tail vein. Male C57BL/6 mice and T2DM mice C57BL/6–4 weeks old and db/db at 8 weeks of age Standard chow diet or HFD for a total of 24 weeks 5 weeks after cell infusion No significant difference in body weight Not defined Reduction in blood glucose level There were no significant differences in plasma insulin levels. Insulin sensitivity was increased. Ameliorated the destruction to pancreatic islets and restored β-cell mass. TNF-α expression was reduced ADMSCs infusion reduced liver weight, steatosis and expression of IL-6, TNF-a, and F4/80. Wang et al.81 Rat ADMSCs ADMSCs were injected via tail vein at a dose of 3 × 106 of ADMSCs Male Sprague–Dawley (SD) rats 8 week-old Standard chow diet or HFD (40% fat, 41% carbohydrate and 19% protein) for 8 weeks 24 h after ADMSCinfusion Not defined Not defined Decrease in blood glucose levels. Improvement in glucose homeostasis. Improvement of insulin sensitivity proved by insulin tolerance tests (IPITT) and HOMA-IR index value. Not defined Not defined ADMSCs alleviated hyperglycemia Xie et al.82 Murine ADMSCs ADMSCs (1 × 105 cells) were injected into the spleens of NASH mice. C57BL/6J mice Nonalcoholic steatohepatitis murine model. 12–14 weeks old Standard chow diet or atherogenic high-fat (AT-HF) diet or HFD for up to 12 weeks 4 weeks Not defined Not defined Not defined Not defined Not defined Decrease in IL-6, TGF-β, IL-23, Acta2, Rorc levels ADMSCs ameliorate the development of fibrosis during the progression of nonalcoholic steatohepatitis Col4a1 and Col1a1 were significantly downregulated. Yamato et al.83 Rat ADMSCs Intravenous infusion of ADMSCs through vena caudalis at a dose of 2 × 106/rat Male Sprague–Dawley rats 8 weeks Standard chow diet or HFD for 4 weeks