Abstract
ObjectiveDipeptidyl peptidase (DPP)-4 is responsible for the degradation of several peptides that contain an alanine or proline at the penultimate position or position P1. DPP-4 inhibitors (DPP-4is) have protective effects against type-2 diabetes and several metabolic disorders.MethodsIn the present study, we examined the effects of des-fluoro-sitagliptin (DFS), a DDP-4i, on body adiposity and levels of peroxisome proliferator-activated receptor (PPAR)-α, PPAR-γ coactivator-1 (PGC-1), and uncoupling proteins (UCPs) in mice with diet-induced obesity.ResultsTreatment with DFS dose-dependently decreased the weight of white adipose tissue and serum levels of glucose, compared with controls, without influencing food intake (P<0.05). Additionally, DFS treatment increased the levels of PPAR-α, PGC-1, and UCPs in brown adipose tissue (BAT), and of PPAR-α and UCP3 in skeletal muscle (P<0.05). Furthermore, the effects on BAT PGC-1 and muscle PPAR-α levels were attenuated by treatment with the glucagon-like peptide 1 (GLP-1) antagonist exendin (9–39). Interestingly, hypothalamic levels of proopiomelanocortin (POMC) were increased by DFS treatment and the effects of DFS on PPAR-α, PGC-1, and UCP levels were attenuated in melanocortin (MC)-4 receptor-deficient mice.ConclusionsIn conclusion, high-dose DFS appeared to regulate body adiposity and UCPs in mice with diet-induced obesity, at least partly through a GLP-1 and/or MC-4 pathway.
Highlights
Dipeptidyl peptidase (DPP)-4 is responsible for the degradation of numerous biologically active peptides and chemokines that contain an alanine or proline at the penultimate position or position P1
Almost 61% of patients showed decreased body weight when they used metformin and sitagliptin in the DURATION study [12]. These results suggest that DPP-4 inhibitors (DPP-4is) influences adipose tissue and has functional roles in regulating energy metabolism as well as its anti-diabetic effects
We investigated the effects of DFS on food intake, body weight, and adiposity, in addition to serum metabolic parameters, such as glucose, free fatty acids (FFAs), triglycerides, and insulin, uncoupling proteins (UCPs) expression in peripheral tissues, O2 consumption, and the respiratory quotient
Summary
Dipeptidyl peptidase (DPP)-4 is responsible for the degradation of numerous biologically active peptides and chemokines that contain an alanine or proline at the penultimate position or position P1. The clinical benefits of DPP-4i therapy are not fully explained by the increased insulin release alone, and other mechanisms are thought to involve effects on b-cell mass, b-cell apoptosis, and other tissues [2]. Studies performed in isolated adipocytes have demonstrated that GLP-1 has the ability to induce both lipogenic and lipolytic mechanisms in white adipose tissue (WAT) [7,8]. These GLP-1 effects in WAT were exerted through a GLP-1-specific receptor, structurally and/or functionally distinct from that expressed in the pancreas [9]. Chronic DFS treatment decreased body weight gain in mice with diet-induced obesity [10]
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