A PPAR-alpha agonist and DPP-4 inhibitor mitigate adipocyte dysfunction in obese mice

Abstract

Obesity causes white and brown adipocyte dysfunction, reducing browning and stimulating whitening. Drugs that tackle adipocyte dysfunction through thermogenesis stimulation could be used to treat obesity. This study sought to address whether a combination of the PPAR-alpha agonist (WY14643) and DPP4i (linagliptin) potentiates browning and mitigates adipose tissue dysfunction, emphasizing the pathways related to browning induction and the underlying thermogenesis in high-fat-fed mice. Adult male C57BL/6 mice were randomly assigned to receive a control diet (C, 10% lipids) or a high-fat diet (HF, 50% lipids) for twelve weeks. Experiment 1 aimed to evaluate whether five weeks of combined therapy was able to potentiate browning using a five-group design: C, HF, HFW (monotherapy with WY14643, 2.5 mg/kg body mass), HFL (monotherapy with linagliptin, 15 mg/kg body mass), and HFC (a combination of both drugs). Experiment 2 further addressed the pathways involved in browning maximization using a four-group study design: C, CC (C diet plus the drug combination), HF, and HFC (HF diet plus the drug combination). The HF group showed overweight, oral glucose intolerance, sWAT adipocyte hypertrophy, and reduced numerical density of nuclei per area of BAT, confirming whitening. Only the combined treatment normalized these parameters in addition to body temperature increases, browning induction, and whitening rescue. The high expression of thermogenic marker genes parallel to reduced expression of inflammatory and endoplasmic reticulum stress genes mediated the beneficial findings. Hence, the PPAR-alpha agonist and DPP-4i combination is a promising target for obesity control by inducing functional brown adipocytes, browning of sWAT, and enhanced adaptive thermogenesis.

Semaglutide (GLP‐1 receptor agonist) stimulates browning on subcutaneous fat adipocytes and mitigates inflammation and endoplasmic reticulum stress in visceral fat adipocytes of obese mice

“…Herein, semaglutide enhanced Pparalpha and Fndc5 expressions, which in the presence of high Pgc1alpha, recruit sWAT beige adipocytes. 41 Furthermore, there was a Ppar-alpha activation-induced sWAT browning in obese mice, 42 as the concomitant increase of Ppar-alpha and gamma enhanced sWAT browning via Fgf21. 43 FGF21 is a batokine whose deficiency causes the inability of cold adaptation in mice, upregulating Pgc1-alpha in an autocrine or paracrine manner in adipose tissues, causing browning and thermogenesis.…”

Progress and obstacles in transplantation of brown adipose tissue or engineered cells with thermogenic potential for metabolic benefits

“…However, BAT resected from both diet-induced and genetically abnormal obese mice showed decreased UCP1 expression, sparse mitochondria distribution, and increased cell size and lipid content of adipocytes ( 81 ). While transplanting the whitening BAT from obese mice to WT mice, the transplant itself regained some browning features similar to that of the host but had hardly any beneficial effect on the metabolism of the host ( 80 ).…”

Peroxisome proliferator-activated receptor-alpha activation and dipeptidyl peptidase-4 inhibition target dysbiosis to treat fatty liver in obese mice

“…Recently, PPAR-alpha deletion promoted intestinal dysbiosis and inflammation in mice[ 12 ]. The dipeptidyl-peptidase-4 (DPP-4) inhibitor linagliptin extends the glucagon-like peptide-1 (GLP1) time of action through beneficial brown and white adipocyte remodeling, browning induction, and M2 macrophage polarization, in addition to enhancing liver vascularization, supressing de novo lipogenesis, and alleviating endoplasmic reticulum stress[ 13 , 14 ].…”