Efeitos da associação do agonista PPAR-alfa e inibidor do dipeptidil peptidase 4 na indução de adipócitos bege no tecido adiposo branco subcutâneo de camundongos obesos

Abstract

Excessive dietary intake of saturated fat causes an imbalance in energy homeostasis, which is one of the leading causes for the development of obesity and, consequently, adipocyte dysfunction. Peroxisome proliferator-activated receptor-α (PPAR-α) plays a paramount role in the browning of white adipocytes, as well as dipeptidyl peptidase-4 inhibitors (DPP-4i) can enhance thermogenesis. This study sought to evaluate the association of the PPAR-alpha agonist (WY14643) and DPP-4i (linagliptin) on the subcutaneous white adipose tissue remodeling and thermogenesis induction in mice fed a high-fat diet. Forty male C57BL/6 mice (three months old) were randomly assigned to receive a control diet (C, 10% energy as lipids) or a high-fat diet (HF, 50% energy as lipids) for twelve weeks. Then, each group was subdivided into two groups to start the treatment that lasted five weeks: C, CT (C diet plus PPAR-α agonist and DPP-4i), HF, and HFT (HF diet plus PPAR-α agonist and DPP-4i). Drugs were mixed to the diets at a dose of 2.5 mg/kg body mass for WY14643 and 15 mg/kg body mass for linagliptin. The animals in the HF group showed overweight, oral glucose intolerance, adipocyte hypertrophy, substantial accumulation of intra-abdominal and subcutaneous fat. Conversely, the treatment was able to normalize these parameters, besides increasing the body temperature, the presence of multilocular adipocytes (beige), and the high expression of thermogenic markers genes. These observations point to the activation of the browning cascade in the subcutaneous white adipose tissue concomitant with noticeable anti-inflammatory effects and endoplasmic reticulum stress alleviation. Hence, the association of the PPAR-α agonist with DPP-4i emerges as a promising target for obesity control through the induction of beige cells and adaptive thermogenesis.