Distribution of CART expression
CART can be found in both the central nervous system (CNS) (Spiess et al., 1981; Douglass et al., 1995; Gautvik et al., 1996; Couceyro et al., 1997; Koylu et al., 1997; Smith et al., 1999; Hubert and Kuhar, 2005, 2008; Dominguez, 2006; Vrang, 2006) and the periphery (Koylu et al., 1997; Broberger et al., 1999; Ekblad et al., 2003; Larsen et al., 2003; Wierup et al., 2004; Ekblad, 2006; Vicentic, 2006; de Lartigue et al., 2007; Kasacka et al., 2012). CART mRNA-containing neurons are present in high densities in diverse regions such as the Edinger-Westphal nucleus, ganglion cells in the retina, mitral and tufted cells of the olfactory bulb, sensory barrels in the cerebral cortex, the pituitary, lamina X of the spinal cord, medulla of the adrenal cortex, the vagal nuclei, and a number of hypothalamic nuclei (Douglass et al., 1995; Couceyro et al., 1997). Expression of CART in peripheral blood and pituitary portal has also led to the identification of CART-positive neuroendocrine neurons in the hypothalamus, where CART was demonstrated to constitute a releasing factor delivered to the hypothalamic-pituitary-adrenal (HPA) portal circuit for potential endocrine regulation (Larsen et al., 2003; Vicentic, 2006). Consistent with a role in energy homeostasis, CART expression has also been associated with glucose-sensing sites both centrally and peripherally, in both rodents and humans (Jensen et al., 1999; Wierup et al., 2005, 2006, 2007; Kasacka et al., 2012). In the periphery, CART expression has been identified in the islet endocrine cells, ganglionic cells, as well as the sensory and autonomic nerve fibers of the pancreas (Jensen et al., 1999; Wierup et al., 2006, 2007; Kasacka et al., 2012). A recent paper also reported the expression of CART mRNA and protein in subcutaneous and visceral white adipose tissues from both rat and human (Banke et al., 2013), serving a potential novel role in adipocytes by fine-tuning lipolysis and lipase activation to affect lipid- and glucose-homeostasis (Vasseur et al., 2007; Banke et al., 2013).
In addition to the structural conservancy between CART isoforms across species (Douglass et al., 1995; Douglass and Daoud, 1996; Adams et al., 1999; Dey et al., 2003), functional conservation of CART in the mammalian neuroendocrine system has also been implicated in the resembling CART mRNA and peptide distribution pattern in the brain observed between humans, rodents, as well as monkeys (Douglass and Daoud, 1996; Gautvik et al., 1996; Charnay et al., 1999; Cavalcante et al., 2011). As a leptin-regulated neurotransmitter with potent appetite-suppressing activity (Kristensen et al., 1998), CART expression in the CNS is highly localized to distinct brain areas critically involved in the control of energy homeostasis, limbic and sensory functions, as well as throughout the HPA axis (Douglass et al., 1995; Gautvik et al., 1996; Koylu et al., 1997; Charnay et al., 1999; Dominguez, 2006; Hubert and Kuhar, 2008; Cavalcante et al., 2011). Localization analyses of CART expression at the mRNA and peptide levels have demonstrated concordance across studies applying cDNA sequencing (Douglass et al., 1995), in situ hybridization (Douglass et al., 1995; Couceyro et al., 1997) and immunohistochemistry (Koylu et al., 1997). Indeed, CART mRNA has been shown to constitute the third most abundant transcript identified in rat hypothalamus after subtraction of cerebellar and hippocampal mRNAs (Gautvik et al., 1996).