Dipeptidyl Peptidase 4 (DPP4) as A Novel Adipokine: Role in Metabolism and Fat Homeostasis

Abstract

Dipeptidyl peptidase 4 (DPP4) is a molecule implicated in the regulation of metabolic homeostasis and inflammatory processes, and it exerts its main action through its enzymatic activity. DPP4 represents the enzyme most involved in the catabolism of incretin hormones; thus, its activity impacts appetite, energy balance, and the fine regulation of glucose homeostasis. Indeed, DPP4 inhibitors represent a class of antidiabetic agents widely used for the treatment of Type 2 diabetes mellitus (T2DM). DPP4 also acts as an adipokine and is mainly secreted by the adipose tissue, mostly from mature adipocytes of the visceral compartment, where it exerts autocrine and paracrine activities. DPP4 can disrupt insulin signaling within the adipocyte and in other target cells and tissues, where it also favors the development of a proinflammatory environment. This is likely at the basis of the presence of elevated circulating DPP4 levels in several metabolic diseases. In this review, we summarize the most recent evidence of the role of the DPP4 as an adipokine-regulating glucose/insulin metabolism and fat homeostasis, with a particular focus on clinical outcomes associated with its increased secretion in the presence of adipose tissue accumulation and dysfunction.

Immunomodulatory activity of dipeptidyl peptidase‐4 inhibitors in immune‐related diseases

“…DPP‐4i have been shown to reduce the liver fat content, markers of inflammation, and oxidative stress and prevent the progression of simple steatosis to nonalcoholic steatosis hepatitis [62]. In addition, DPP‐4 inhibition was followed by a decrease in adipocyte size and infiltration of CD8+ T cells and M1 macrophages in visceral adipose tissue, including down‐regulation of inflammatory genes in macrophages [63].…”

The Role of Adipokines in Inflammatory Mechanisms of Obesity

“…It is a widely expressed serine protease that regulates the biological activity of many peptides through cleavage and inactivation, including incretin hormones, glucagon-like peptide-1 (GLP-1), and glucose-dependent insulinotropic polypeptide (GIP) [ 79 ]. DPP4 is a pro-inflammatory adipokine that is elevated in several metabolic diseases and can impair insulin signaling in adipocytes, as well as other target cells and tissues [ 80 ]. In obesity, DPP4 serum concentration was associated with increased macrophage infiltration of vWAT, high serum levels of leptin, and reduced adiponectin levels, as well as increased circulating levels of inflammatory cytokines, particularly IL-6, IL-12, and TNF-α [ 81 ].…”

Dipeptidyl peptidase‐4 disturbs adipocyte differentiation via the negative regulation of the glucagon‐like peptide‐1/adiponectin‐cathepsin K axis in mice under chronic stress conditions

“…Dipeptidyl peptidase‐4 (DPP4) is a multifunctional enzyme that is commonly expressed in visceral, epididymal, and omental adipose tissue 8 . DPP4, also known as T cell activation antigen CD26, is a serine protease that acts as a membrane‐anchored extracellular peptidase 9 .…”