Beneficial Effects of Evogliptin, a Novel Dipeptidyl Peptidase 4 Inhibitor, on Adiposity with Increased Ppargc1a in White Adipose Tissue in Obese Mice

Abstract

Although dipeptidyl peptidase 4 (DPP4) is an adipokine known to positively correlate with adiposity, the effects of pharmacological DPP4 inhibition on body composition have not been fully understood. This study was aimed to assess the effects of DPP4 inhibitors on adiposity for the first time in the established obese mice model. The weight loss effects of multiple DPP4 inhibitors were compared after a 4 week treatment in diet-induced obese mice. In addition, a 2 week study was performed to explore and compare the acute effects of evogliptin, a novel DPP4 inhibitor, and exenatide, a glucagon-like peptide-1 (GLP-1) analogue, on whole body composition, energy consumption, various plasma adipokines and gene expression in white adipose tissue (WAT). After the 4 week treatment, weight loss and blood glucose reductions were consistently observed with multiple DPP4 inhibitors. Moreover, after 2-week treatment, evogliptin dose-dependently reduced whole body fat mass while increasing the proportion of smaller adipocytes. However, insulin sensitivity or plasma lipid levels were not significantly altered. In addition to increased active GLP-1 levels by plasma DPP4 inhibition, evogliptin also enhanced basal metabolic rate without reduction in caloric intake, in contrast to exenatide; this finding suggested evogliptin's effects may be mediated by pathways other than via GLP-1. Evogliptin treatment also differentially increased Ppargc1a expression, a key metabolic regulator, in WAT, but not in skeletal muscle and brown adipose tissue. The increased expression of the downstream mitochondrial gene, Cox4i1, was also suggestive of the potential metabolic alteration in WAT by DPP4 inhibitors. We are the first to demonstrate that pharmacological DPP4 inhibition by evogliptin directly causes fat loss in established obese mice. In contradistinction to exenatide, the fat-loss effect of DPP4 inhibitor is partly attributed to enhanced energy expenditure along with metabolic changes in WAT. These results provide insight into the regulation of energy storage in WAT caused by DPP4 inhibition.

Glucagon-like peptide-1 receptor agonist stimulates mitochondrial bioenergetics in human adipocytes

“…The effect of GLP-1 receptor signaling in central nervous system on stimulation of brown adipose tissue thermogenesis through adrenergic neurons in rodents is well documented, but these results do not exclude the possibility of direct influence of GLP-1 on adipocyte browning (Lockie et al, 2012;Beiroa et al, 2014). While some reports from the rodent studies confirm this hypothesis (Mostafa et al, 2015;Xu et al, 2016), other reports suggest that increased BAT thermogenesis did not play a significant role in the food intake-independent body weight lowering effect of GLP-1RAs (Heppner et al, 2015;Chae et al 2015).…”

“…Due to the growing interest in incretin therapy, several clinical as well as experimental studies are in progress, although the mechanism of GLP-1RAs action in adipose tissue is not yet sufficiently understood (Majumdar & Weber, 2010;Chae et al, 2015;Pastel et al, 2016). Thus, our study was aimed to verify the hypothesis that the GLP-1 RA mechanism of action involves mitochondria and that GLP-1RA administration can improve mitochondrial functions.…”

Dipeptidyl peptidase 4 inhibitor use is associated with a lower risk of incident acute kidney injury in patients with diabetes

“…In vitro and preclinical data also suggest that DPP4i reduces the activity of sodium-hydrogen exchanger 3 (NHE3) in proximal tubules, resulting in increased urinary sodium excretion and potentially lower blood pressure [ 20 ]. However, DPP4 is an adipokine that is positively correlated with adiposity; pharmacological suppression of DPP4 increased peroxisome proliferator-activated receptor γcoactivator 1 (PPARGC1) expression, thereby reducing body fat content [ 21 ]. Dysglycaemia and hypertension have long been known to increase the risk of AKI in various clinical settings, while obesity and increased adiposity also predict higher incidence of AKI [ 22 , 23 ].…”

Myeloid Sirtuin 6 Deficiency Causes Insulin Resistance in High-Fat Diet–Fed Mice by Eliciting Macrophage Polarization Toward an M1 Phenotype

“…The intraperitoneal glucose tolerance test (GTT) (1 g/kg of body weight) and insulin tolerance test (ITT) (0.5 units/kg of body weight) were performed after 16 and 6 h of fasting, respectively. A hyperinsulinemic-euglycemic clamp study (17), indirect calorimetry measurements (18), and stromal vascular fraction (SVF) isolation and FACS analysis (15) were performed as previously described. All experimental procedures were approved by the Institutional Animal Care and Use Committees of Chonbuk National University (permit no.…”