Abstract
The current treatment options for type 2 diabetes mellitus do not adequately control the disease in many patients. Consequently, there is a need for new drugs to prevent and treat type 2 diabetes mellitus. Among the new potential pharmacological strategies, activators of peroxisome proliferator-activated receptor (PPAR)β/δ show promise. Remarkably, most of the antidiabetic effects of PPARβ/δ agonists involve AMP-activated protein kinase (AMPK) activation. This review summarizes the recent mechanistic insights into the antidiabetic effects of the PPARβ/δ-AMPK pathway, including the upregulation of glucose uptake, muscle remodeling, enhanced fatty acid oxidation, and autophagy, as well as the inhibition of endoplasmic reticulum stress and inflammation. A better understanding of the mechanisms underlying the effects resulting from the PPARβ/δ-AMPK pathway may provide the basis for the development of new therapies in the prevention and treatment of insulin resistance and type 2 diabetes mellitus.
Highlights
Despite the increase in PPARβ/δ levels caused by AMPK activation, the findings of this study suggest that PPARβ/δ phosphorylation inhibits transcriptional activity as a PPARβ/δ-Ser50 mutant showed increased activity compared with wild-type
Pathway is in the spotlight as it metformin induced the phosphorylation of PPARβ/δ at Ser through the common pharmacologically promotes the effects of exercise in skeletal muscle, such as increased
AMPK activation, the findings of this study suggest that PPARβ/δ phosphorylation inhibshow reduced AMPK activation in skeletal muscle, whereas growth differentiation factor 15 (GDF15) administration results its transcriptional activity as a PPARβ/δ-Ser50 mutant showed increased activity compared in AMPK activation in this organ
Summary
The prevalence of type 2 diabetes mellitus has reached global epidemic proportions and is one of the medical challenges of the 21st century [1]. Receptor (PPAR)β/δ agonists show promise [4,5,6] Ligands of this nuclear receptor have been reported to ameliorate insulin resistance and type 2 diabetes mellitus mainly through the activation of AMP-activated protein kinase (AMPK), a central regulator of multiple metabolic pathways. Once AMPK is activated, it phosphorylates key metabolic substrates and transcriptional regulators that affect many aspects of cellular metabolism, increasing glucose uptake, FA oxidation, mitochondrial oxidative capacity, and insulin sensitivity [22,23]. A high-fat diet (HFD) reduces AMPK phosphorylation levels in the skeletal muscle, liver, and other tissues, thereby indicating that restoration of the activity of this kinase can overcome metabolic alterations associated with the overconsumption of fat in animal models. Of the review, we discuss studies that implicate AMPK activation in the antidiabetic effects of PPARβ/δ ligands in the main organs involved in insulin resistance
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