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A Growth Hormone-Releasing Peptide Promotes Mitochondrial Biogenesis and a Fat Burning-Like Phenotype through Scavenger Receptor CD36 in White Adipocytes

Research Center (A.R.-W., A.D., A.T.), Ste-Justine Hospital, and Departments of Biochemistry (A.R.-W., A.T.) and Obstetrics and Gynecology (A.T.), Faculty of Medicine, University of Montréal, Montréal, Québec, Canada H3T 1C5; and Faculty of Pharmacy (A.D., H.O.), Pavillon Jean-Coutu, University of Montréal, Montréal, Québec, Canada H3C 3J7

Address all correspondence and requests for reprints to: André Tremblay, Research Center, Ste-Justine Hospital, 3175 Côte Ste-Catherine, Montréal (Québec), Canada H3T 1C5. E-mail: andre.tremblay{at}recherche-ste-justine.qc.ca.

Whereas the uptake of oxidized lipoproteins by scavenger receptor CD36 in macrophages has been associated with foam cell formation and atherogenesis, little is known about the role of CD36 in regulating lipid metabolism in adipocytes. Here we report that treatment of 3T3-L1 adipocytes with hexarelin, a GH-releasing peptide that interacts with CD36, resulted in a depletion of intracellular lipid content with no significant change in CD36 expression. Microarray analysis revealed an increased pattern in several genes involved in fatty acid mobilization toward the mitochondrial oxidative phosphorylation process in response to hexarelin. Interestingly, many of these up-regulated genes are known targets of peroxisomal proliferator-activated receptor (PPAR)-, such as FATP, CPT-1, and F₁-ATPase, suggesting that adipocyte response to hexarelin may involve PPAR activation. Expression studies also indicate an increase in thermogenic markers PPAR coactivator 1 and uncoupling protein-1, which are normally expressed in brown adipocytes. Electron microscopy of hexarelin-treated 3T3-L1 adipocytes showed an intense and highly organized cristae formation that spans the entire width of mitochondria, compared with untreated cells, and cytochrome c oxidase activity was enhanced by hexarelin, two features characteristic of highly oxidative tissues. A similar mitochondrial phenotype was detected in epididymal white fat of mice treated with hexarelin, along with an increased expression of thermogenic markers that was lost in treated CD36-null mice, suggesting that the ability of hexarelin to promote a brown fat-like phenotype also occurs in vivo and is dependent on CD36. These results provide a potential role for CD36 to impact the overall metabolic activity of fat usage and mitochondrial biogenesis in adipocytes.

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