Abstract
Uncovering the biological role of nuclear receptor peroxisome proliferator-activated receptors (PPARs) has greatly advanced our knowledge of the transcriptional control of glucose and energy metabolism. As such, pharmacological activation of PPARγ has emerged as an efficient approach for treating metabolic disorders with the current use of thiazolidinediones to improve insulin resistance in diabetic patients. The recent identification of growth hormone releasing peptides (GHRP) as potent inducers of PPARγ through activation of the scavenger receptor CD36 has defined a novel alternative to regulate essential aspects of lipid and energy metabolism. Recent advances on the emerging role of CD36 and GHRP hexarelin in regulating PPARγ downstream actions with benefits on atherosclerosis, hepatic cholesterol biosynthesis and fat mitochondrial biogenesis are summarized here. The response of PPARγ coactivator PGC-1 is also discussed in these effects. The identification of the GHRP-CD36-PPARγ pathway in controlling various tissue metabolic functions provides an interesting option for metabolic disorders.
Highlights
In years to come, metabolic defects are predicted to remain one of the principal causes of death and disability in industrialized countries, and their occurrence is seen to be increasing in several developing countries
The exact mechanism for such distinct regulation remains unclear, but we found that the ligand binding domain was not necessary for PPARγ activation by hexarelin, thereby avoiding any effect of exogenous PPARγ ligands that might arise from oxidized low-density lipoproteins (oxLDL) entry
Gene expression and functional studies have indicated that adipocytes respond to hexarelin with an increased mobilization of fatty acids rather than the expected adipogenic effect of PPARγ activation seen with TZDs, revealing an unexpected effect of hexarelin to promote the β-oxidation of fatty acids [113]
Summary
Metabolic defects are predicted to remain one of the principal causes of death and disability in industrialized countries, and their occurrence is seen to be increasing in several developing countries. The clinical efficacy of TZDs on insulin sensitivity has become limited [9,23] This is partly due to their side effect of stimulating adiposity by upregulating PPARγ target genes, such as fatty acid synthase (FAS) and scavenger receptor CD36 involved in FA formation and storage [24,25]. Tissues such as vascular endothelium, heart, adrenals, monocytes/macrophages, β pancreatic cells, and bone were shown to express GHS-R1a [53,54,55] Consistent with such a GH-independent role, peripheral ghrelin actions have been linked to clinical implications of cardiovascular disease, insulin resistance, and obesity [31,56,57,58,59]. The potential of CD36 as a therapeutic target for atherosclerosis and other complications of metabolic syndrome is emphasized by our increasing knowledge of its mode of action and certainly warrants the development of novel alternatives aimed to correct for these metabolic defects
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