In addition to storing and releasing lipids, adipocytes influence the metabolism of other tissues via an intricate network of secretory factors, such as the adipokines, leptin and adiponectin and the proinflammatory cytokine, IL-6. Leptin, released in response to increased fat storage, is a potent appetite suppressant. Adiponectin induces fat degradation and is protective against atherosclerosis and insulin resistance. IL-6 promotes neolipogenesis by stimulating adipocyte glucose uptake, and adversely affects insulin sensitivity by inhibiting hepatic gluconeogenesis. Obesity is associated with increased leptin and IL-6, and decreased adiponectin. Carnitine (CAR) is an essential nutrient. It plays a pivotal role in cellular energy metabolism, transferring free fatty acids to mitochondria, followed by their oxidation in the Krebs cycle. CAR is essential for cellular energy production and storage, and for membrane synthesis and repair. L-CAR is an essential cofactor of fatty acid (FA) metabolism. Dietary intake accounts for more than 75% of the average normal daily requirement of LCAR (2-4 mg/kg). Data from animal and human studies suggest that LCAR can modulate abdominal fat content, stimulate weight loss and improve glucose disposal. LCAR is highly marketed in the US as a """"""""fat burner"""""""" nutritional supplement and is promoted as an adjunct to weight loss programs. Despite this evidence, the cellular and molecular mechanisms of these apparent effects are not entirely understood. We are evaluating whether these metabolic actions of CAR are mediated, at least in part, via direct effects on adipokine release and lipolytic activity iby isolated human adipocytes derived from subcutaneous fat from nonobese healthy donors. To date, we have observed that L-CAR elicits secretion of adiponectin and leptin, without influencing that of IL-6. CAR also exerts important anabolic and antioxidant-antiapoptotic effects. Acetyl L-CAR prevents mitochondrial oxidative decay and dysfunction, thus potentially retarding age-associated neurodegenerative symptoms such as memory loss. Activation of the AMPK and Carnitine Palmitoyl Transferase-1 (CPT-I) prevents FA induced ceramide synthesis and ERK mediated apoptosis, while the interactions of CPT-I with cytoskeletal components and with BCL-2 in the mitochondrial outer membrane are thought to contribute to the regulation of cell growth and apoptosis. Acetyl L-CAR administration to HIV patients increases serum IGF-1 concentrations, suggesting anabolic effects. We are investigating the effects of L-CAR using cDNA microarrays, including both a mitochondrion-focused chip and a 12K human chip, aiming to identify new target genes related to lipid and glucose metabolism, mitochondrial biogenesis, cell growth and apoptosis. We are also evaluating the potential role of L-CAR as an anabolic-antiapoptotic agent in human myocytes, and it's effects in human models of sarcopenia due to aging, glucocorticoid excess, and HIV infection.
|Alesci, S; Manoli, I; Michopoulos, V J et al. (2006) Development of a human mitochondria-focused cDNA microarray (hMitChip) and validation in skeletal muscle cells: implications for pharmaco- and mitogenomics. Pharmacogenomics J 6:333-42|
|Manoli, Irini; Le, Hanh; Alesci, Salvatore et al. (2005) Monoamine oxidase-A is a major target gene for glucocorticoids in human skeletal muscle cells. FASEB J 19:1359-61|
|Ilias, Ioannis; Manoli, Irini; Blackman, Marc R et al. (2004) L-Carnitine and acetyl-L-carnitine in the treatment of complications associated with HIV infection and antiretroviral therapy. Mitochondrion 4:163-8|