Body composition may be improved either by increasing lean body mass or decreasing fat mass. Subcutaneous adipose tissue is the main storage site for TAG. Lipid accumulation in human adipose tissue is determined by the balance between lipogenesis and lipolysis (Ormsbee et al., 2009). For reductions in adiposity to occur lipids must first be mobilized and released from adipose tissue, transported to muscles and/or liver, taken up by the active tissue, activated and translocated into the mitochondria, and then undergo β-oxidation (Brooks et al., 2005a).
To better understand how betaine may improve body composition by influencing adiposity, the following physiological processes will be reviewed: lipogenesis, lipolysis, and fatty acid translocation.
Lipogenesis
Lipogenesis occurs in liver and adipose tissue, and describes a series of processes in fatty acid and TAG synthesis (Perrone et al., 2008). The majority of lipid deposition in adipose tissue is provided by TAG synthesis; however, some is also provided from the formation of fatty acids from glucose via de novo lipogenesis (Hellersteine, 1999). TAG synthesis involves describes the uptake and synthesis of free fatty acids (FFA) into triglycerdies. In brief, FFA are liberated by chylomicrons and very low density lipoproteins via lipoprotein lipase (LPL). Next, FFA enters the adipocyte both passively and via the subcutaneous adipose tissue fatty acid transporter (Bonen, Tandon, Glatz, Luiken, & Heigenhauser, 2006). Intracellular FFA is activated by the attachment of a coenzyme A molecule via aceyl-CoA synthase (ACS), then attached to glycerol 3-phosphate to form monoacylglycerol (Houston, 2006). Finally, monoacylglycerol undergoes two parallel TAG synthetic pathways in the endoplasmic reticulum to form TAG (Shi & Burn, 2004).
Insulin is most potent activator of lipogensis in adipose tissue. By binding its receptor, insulin facilitates the translocation of GLUT-4 and fatty acid transport proteins to the plasma membrane, thereby increasing the uptake of glucose and free fatty acids. Additionally, insulin activates lipogenic and glycolytic via peroxisome proliferator activated receptor γ (PPARγ; Kersten, 2001). PPARγ stimulates several lipogenic enzymes, including adipocyte binding proteins, LPL, fatty acid transport protein, ACS, and phosphoenol pyruvate carboxykinase (Kersten et al., 2000). Further, insulin stimulates the translation of element binding protein-1 (SREBP-1). SREBP-1 regulates the expression of PPARγ in adipose tissue and the hepatic lipogenic enzymes HMG-CoA reductase, LDL receptor, and fatty acid synthase (Horton & Shimomura, 1999).
Compared with the pro-lipogenic effects of insulin, growth hormone inhibits lipogenesis in adipose tissue (Kersten, 2001). According to Etherton (2000), GH reduces specifically increase adipocyte insulin resistance without affecting whole body insulin sensitivity. As a result, GH decreases adipocyte acetyl-CoA carboxylase (ACC), fatty acid synthase, and glucose-6-phosphate dehydrogenase. GH also reduces lipogenesis by inactivating transcription factors Stat5a and Stat5b (Teglund et al., 1998), which stimulate lipogenesis via increased PPARγ expression (Wakao, Wakao, Oda, & Fujita, 2011).
Lypolysis
The catabolic process whereby TAG is broken down into a glycerol and three non esterfied fatty acids is referred to as lipolysis. In adipose tissue, intracellular TAG are acted upon by adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL) and monoacylglycerol lipase (MGL; Lafontan & Langin, 2009). Regulation of lipolysis is achieved via the opposing actions of catecholamines and insulin modulating cAMP concentrations. In brief, catecholamines bind β-adreneric receptors (β-AR) coupled to G proteins, resulting in the generation of cAMP, activation of PKA, and phosphorlyation of HSL (Houston, 2006). In contrast, the interaction of insulin and the receptor activates the PI-3K/Akt pathway, resulting in the generation of phosphodiesterase-3B and hydrolysis of cAMP (Carmen & Victor, 2006). Other factors also positively and negatively affect lipolysis, such as glucocorticoids and prostaglandins, respectively (Lafontan & Langin, 2009). In particular, GH positively influences lipolysis (Samra et al., 1999). Although the exact mechanism has yet to be elucidated, Vijayakumar, Novosyadlyy, Wu, Yakar, and LeRoith (2010) suggested that GH increases HSL activity and translocation to the lipid droplet by augmenting β-AR cAMP generation.
Fatty Acid Translocation
Once fatty acids are taken up by skeletal muscles they must be activated and transferred across the two membranes of the mitochondria before participating in beta oxidation. Activation occurs on the outer mitochondrial membrane and involves the attachment of a coenzyme to the fatty acid via muscle ACS. Next, the fatty acyl-CoA is transported across the outer and inner mitochondrial membranes via the carnitine palmitoyl transferase (CPT) I and II complex, respectively (Brookes et al., 2005a). In addition to CPT, fatty acyl-CoA are also transported across the mitochondrial membrane via fatty acid translocase (FAT/CD36; Holloway, Bonen, & Spriet, 2009).
Variances in mitochondrial fatty acid oxidation rates between individuals have been correlated with differences in the content of mitochondrial CPT and FAT/CD36 (Holloway, Luiken, Glatz, Spriet, & Bonen, 2008). Based on the involvement of intramuscular carnitine in fatty acid oxidation, supplement companies have advertised l-carnitine as an ergogenic aid that may improve body composition and exercise performance (Borum, 2000). Ingestion of l-carnitine, however, does not elevate intramuscular carnitine levels (Kraemer, Volek, & Dunn-Lewis, 2008), improve fat oxidation (Broad, Maughan, & Galloway, 2011), aerobic and anaerobic performance (Smith, Fry, Tschume, & Bloomer, 2008), or body composition (Wutzke & Lorenz, 2004). In contrast oral ingestion, carnitine infusion in humans (Stemphens et al., 2006) and increased expression of CPT in rats has been shown to increase fatty acid oxidation (Bruce et al., 2009). Therefore, methods that increase intramuscular carnitine concentrations may improve body composition by increasing mitochondrial fatty acid oxidation via enhanced translocation.
