Adipose Tissue, at the Core of the Action of Incretin and Glucagon-Based Anti-Obesity Drugs

Abstract

Purpose of the review: This review summarizes recent evidence highlighting the specific role of adipose tissue in the systemic effects of incretin agonist-based drugs used in the treatment of obesity.

Recent findings: The development of incretin agonist-based drugs has achieved unprecedented success in the pharmacological treatment of obesity and the improvement of obesity-related comorbidities. While initially shown to significantly reduce adipose tissue through decreased food intake, incretin-based therapy is also increasingly reported to alter the properties of adipose tissue. Recent experimental and human studies indicate that these anti-obesity drugs induce significant changes in the metabolism and inflammatory state of adipose tissue, while also promoting its thermogenic plasticity. The direct and indirect actions of incretin-based anti-obesity drugs, which modify the properties of adipose tissue, are emerging as key contributors to the systemic health benefits of these treatments.

Keywords: Brown adipose tissue; Glucagon; Glucagon-like peptide-1; Glucose-dependent insulinotropic peptide; Obesity; White adipose tissue.

Fig. 1

Mechanisms of action of GLP-1 on WAT. GLP-1 targets the central nervous system via the GLP-1 receptor, promoting satiety and resulting in a negative energy balance that reduces adipocyte size and lipid content. Although this is not a consensually accepted view (as indicated by the dotted arrows and question marks), there is evidence proposing that GLP-1 can directly act on macrophages within WAT to reduce inflammation, on pre-adipocytes to promote adipogenic differentiation, and on white adipocytes to regulate metabolism

Fig. 2

Mechanisms of action of GIP on WAT. GIP can target pre-adipocytes and adipocytes via GIPR. In adipocytes, GIP promotes insulin-dependent glucose uptake and alters lipid metabolism distinctly according to the fed (high insulin levels) or fasted (low insulin levels) state. It also promotes lipid oxidation in the white adipocyte to increase whole body energy expenditure via activation of the SERCA-driven futile calcium cycle. FA, fatty acid, LPL, lipoprotein lipase

Fig. 3

Mechanisms of action of GLP-1 on BAT and WAT browning. GLP-1 targets the central nervous system through the GLP-1 receptor, which activates the sympathetic nervous system and induces noradrenergic signalling to BAT and browning-prone WAT. Additionally, GLP-1 interacts with GLP-1R on invariant natural killer T (iNKT) cells and macrophages, stimulating the secretion of FGF21 and IL-6, both of which promote WAT browning. NE, norepinephrine

Fig. 4

Mechanisms of action of GIP on BAT and WAT browning. GIP targets GIPR in macrophages, resulting in reduced inflammation and increased synthesis of type 2 cytokines, which promote WAT browning. Additionally, GIP induces the thermogenic activation of adipose tissue by interacting with GIPR in brown and beige adipocytes, while also promoting the browning of WAT by acting on pre-adipocytes. Additionally, white adipocytes contribute to energy expenditure via lipid oxidation and activation of the SERCA-driven futile calcium cycle (see 3.3)

Fig. 5

Mechanisms of action of GCG on BAT and WAT browning. GCG acts on GCGR in brown and beige adipocytes inducing thermogenic gene expression and metabolic processes associated with active thermogenesis. In addition, GCG promotes BAT thermogenic activity and WAT browning indirectly through its action in the liver leading to the secretion of FGF21 and bile acids, known inducers of thermogenic activation of adipose tissues