The problem of obesity and related metabolic complications remains one of the urgent challenges of modern medicine (Chong et al., 2023; Boye et al., 2023). Type 2 diabetes (T2DM), which is the crucial obesity metabolic complication, leads to the cardiovascular, renal and other complications development and, finally, to mortality growth (Afkarian et al., 2013; Raghavan et al., 2019). Based on the foregoing, glycemic control and glucose lowering are crucial for the prevention of T2DM progression and better patient’s prognosis.

Today several strategies of T2DM pharmacotherapy are used. At the previous time, the first-line monotherapy of T2DM includes biguanides (metformin, metforminXR), which action is related with AMPK activation and hepatic cAMP lowering (Trasher, 2017; Rena et al., 2017). Further, according to the American Diabetes Association guideline, if Hb1Ac target level is not achieved after 3 months of monotherapy, the use of a combination of two drugs is recommended (El Sayed et al., 2022). Several different classes of compounds can serve as a second drug for glycemic control before the start of insulin based therapy. They can induce insulin secretion from pancreas (sulphonylurea), increase glucose excretion (SGLT2 inhibitors) or activate adipogenic differentiation (thiazolidinediones). Among them, glucagon-like peptide type 1 receptor agonists (GLP-1 RA) take the central place due to positive effects on glycemia, body weight and cardioprotection in T2DM patients. Moreover, according to the latest ADA guidelines, GLP-1 RA can be considered as a preferred first-line therapy (ADA Professional Practice Committee, 2024). GLP-1 analogues can lower blood pressure, which is one of the major risk factors of cardiovascular events (Wang et al., 2013; Almutairi et al., 2019; Zhao et al., 2021). GLP-1 RA therapy can prevent the atherosclerosis development and suppress cardiovascular events incidence (Chang et al., 2019; Gerstein et al., 2020; Trombara et al., 2023). Moreover, GLP-1 RA have one unique advantage for T2DM patients: they have anorexigenic effects (Drucker, 2022; Jensterle et al., 2022). Thus, GLP-1 RA therapy is considered as the preferred second-line therapy option for patients with T2DM due to significant reduction of complication development.

Native GLP-1 and GLP-1 RA influence on different tissues and organs. First, GLP-1 enhances postprandial glucose-dependent insulin release from β-cells. Moreover, GLP-1 sensitizes pancreatic α-cells to glucose, leading to decreased glucagon secretion and low hepatic glucose production (Shaefer et al., 2015). Significantly, GLP-1 acts through central mechanisms, which delay gastric emptying and, consequently, reduce postprandial glucose level (Drucker, 2018). In parallel with the glucose-lowering effect, GLP-1 has anorexigenic effect which can be mediated through hypothalamic AMPK (Beiroa et al., 2014).

Anorexigenic effect of GLP-1 can be attributed to the influence on adipose tissue directly because most of GLP-1 RA pharmaceutical forms are administered subcutaneously. Indeed, the direct action of GLP-1 on mature adipocytes and their progenitors was shown in cell culture and animal models (Vendrell et al., 2011). Recent studies have shown that GLP-1 increases white adipogenesis and insulin sensitivity (Challa et al., 2012). Moreover, GLP-1 RA (liraglutide) have significant effects on thermogenic beige adipocytes. It stimulates beige adipogenesis and improves mitochondrial function, which is essential for heat production (Wang et al., 2018; Mamontova et al., 2021; Vaittinen et al., 2023).

In previous studies we demonstrated that T2DM development is associated with impaired properties of progenitor cells in adipose tissue. Here, we suggest that GLP-1 RA can modulate adipose-derived stem cells (ADSC) progenitor properties, including proliferation and differentiation. All previous studies of the GLP-1 RA effect on ADSC have a critical limitation. They have been performed on isolated cells treated with GLP-1 RA in vitro. We aimed to investigate the influence of GLP-1 RA on human ADSC in vivo.