CART was identified in 1995   and found to be co-localised with POMC, and expressed in the hypothalamus. CART mRNA is up-regulated in the nucleus accumbens by psychostimulants as cocaine and amphetamine J Neurosci. 1995 Mar;15(3 Pt 2):2471-81 and hence the name.
CART peptides have been shown to be involved in feeding, reward and reinforcement. Curr Drug Targets CNS Neurol Disord. 2003 Jun;2(3):201-5.

 The human pro-peptide, an 89 amino-acid peptide, has 95% homology with the rat pro-peptide, and  is processed into two active forms namely CART _42-89  and CART _49-89. Tissue specific post translational processing results in variable expression of the active forms in different tissues. Thus, CART_42-89  is expressed in the anterior pituitary and CART _49-89  is expressed in the posterior pituitary, while both are expressed in the hypothalamus and nucleus accumbens. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2722-7.    No receptors have been identified for CART yet. The CART gene in humans have been mapped to chromosome 5q13-14, which has been shown to be a susceptible locus for obesity,  Nat Genet. 1998 Nov;20(3):304-8.   implying a role for CART in human obesity. In fact, further confirmation of the role of CART in human obesity is now available with demonstration of a family with a heterozygous mis-sense mutation of pro-CART who were afflicted with severe obesity from childhood. Diabetes. 2001 Sep;50(9):2157-60.

Central and Peripheral Localisation of CART

CART has been shown to be co-localised with other neurotransmitters involved in feeding including  MCH an orexigenic peptide in the DMN, Brain Res. 1999 Nov 27;848(1-2):101-13   CRH an anorexigenic peptide in the PVN, Neurosci Lett. 2002 May 3;323(3):203-6    and MSH an anorexigenic peptide in the arcuate nucleus. Neuron. 1998 Dec;21(6):1375-85  CART immunoreactivity is localised to regions of the brain associated with feeding  J Neuroendocrinol. 1997 Nov;9(11):823-33    namely the PVN, VMN, DMN, Lateral hypothalamus, Arcuate Nucleus and Nucleus Accumbens.  J Comp Neurol. 1998 Feb 2;391(1):115-32.     Intracerebroventricular administration of CART induces c-Fos expression in CRH containing neurons in the PVN, as well as in the nucleus of tractus solitarius (NTS). Immunocytochemical studies show that in the PVN, NPY containing neurones are in close apposition to the perikarya of CART immunoreactive neurons, suggesting the likelihood of intercommunication between these fibres.

CART peptide has been localized in the anterior pituitary gland. CART peptide and gonadotropin were co-localized in the same secretory granules. Prolactin release was suppressed by CART in a dose-related manner in rats. Endocrinology. 2004 May;145(5):2542-50  TRH and CART are co-contained in hypophysiotropic neurons in the PVN of the hypothalamus. CART dose-dependently inhibited TRH-induced Prolactin release in rats. Endocrinology. 2004 Apr;145(4):1695-9   CART can activate the HPA axis Brain Res. 2001 Mar 2;893(1-2):186-94.  mediated via a CRH.

CART has been shown to be present peripherally in somatostatin cells of the pancreatic islets, FEBS Lett. 1999 Mar 26;447(2-3):139-43.   the antral gastrin G cells, Neurogastroenterol Motil. 2003 Oct;15(5):545-57.  as well as myenteric plexus of the gut. Synapse. 1998 Sep;30(1):1-8.  CART levels are detectable in circulation, and is thought to be from a pituitary source Endocrinology. 2004 Sep;145(9):4119-24.   with a possible contribution from the gut.  CART levels in blood show a circadian rhythm. Fasting increases blood levels of CART. Adrenalectomy reduces CART levels. Replacement of corticosteroids reverses the effect of adrenalectomy. CART rhythm shows similarity to corticosteroid rhythm with a morning peak in primates. Endocrinology. 2004 Sep;145(9):4119-24.

CART and feeding

Food-deprived animals show a pronounced decrease in expression of CART mRNA in the arcuate nucleus. Hypo-leptinaemic animals also showed decreased mRNA expression for CART. CART mRNA in the arcuate nucleus (ARC) was significantly increased in rats  fed a high-fat diet (HFD) compared to low-fat diet (LFD). The hypothalamic CART mRNA expression is higher in obese rats.

Mice with a targeted deletion of the CART gene become obese when fed a high fat diet, than wild type littermates.  Endocrinology. 2001 Oct;142(10):4394-400   A delay of up to 14 weeks has been noted for this effect on weight gain to be produced highlighting the crucial contribution of environmental factors to obesity production in this mouse model.

CART-derived peptides acutely inhibit food intake.  In both normal and obese rats, intracerebroventricular infusion of CART  produced sustained inhibitory effects on food intake and weight gain, and reduced plasma insulin and Leptin levels with increased lipid oxidation Int J Obes Relat Metab Disord. 2002 Feb;26(2):143-9.   and completely blocked the feeding response induced by neuropeptide Y.  Nature. 1998 May 7;393(6680):72-6.  ;  Obes Res. 2000 Nov;8(8):590-6

Intra-nuclear injection of CART has produced effects different from intracerebroventricular injections. CART injection into PVN, DMN, VMN LH, and Arcuate nucleus produced an increase in feeding after 1 hour of injection. Endocrinology. 2001 Aug;142(8):3457-63.    Acute repeated injection of CART _42-89 into the Arcuate nucleus also produces increased food intake. FASEB J. 2003 Sep;17(12):1688-90.  On a similar note, chronic over-expression of CART in the Arcuate nucleus produces significant increases in body weight. The different responses in feeding elicited with intra-nuclear and intracerebroventricular injections of CART were at  different time periods (decreased feeding within one hour of intracerebroventricular CART vs. increased feeding after one hour of intra-nuclear CART)   suggesting the possibility of a rebound effect. Also, the intra-nuclear injections were of the same doses as intracerebroventricular injections, which could have resulted in  diffusion of the high CART levels produced, into adjacent brain areas. Note that one would expect more exquisite responses to CART injection into the nucleus as opposed to intracerebroventricular injections, and hence lower doses of intra-nuclear injection would have produced an effect similar to a higher dose of intracerebroventricular injection.

An antiserum against CART increased feeding in normal rats suggesting the role of CART as an endogenous satiety factor. Synapse. 1998 Aug;29(4):293-8.  Transgenic mice lacking the CART gene show higher food consumption compared to wild-type littermates fed the same diet. Endocrinology. 2001 Oct;142(10):4394-400.    The possibility of compensation from other systems in this kind of a mouse model needs to be taken into account while interpreting the role of CART.

Chronic over-expression of CART in the Arcuate nucleus increases the thermogenic responses in the rat. Chronic cold increases Arcuate CART levels. FASEB J. 2003 Sep;17(12):1688-90.

CART injection centrally reduces gastric emptying and motility Horm Metab Res. 2001 Sep;33(9):554-8   contributing to its actions on food intake. This effect seems to be CRH dependent. Endocrinology. 2000 Aug;141(8):2854-60

CART and lipids

CART infusion increases lipid oxidation in normal and in obese rats. Central injection thus  increased circulating non-esterified fatty acid (NEFA) levels and decreased lipoprotein lipase activity in adipose tissue. Thus on a fat-rich diet, the Leptin-CART pathway originating in the ARC causes a shift from lipid storage toward lipid mobilization preventing excessive body fat accumulation. Regul Pept. 2004 Feb 15;117(2):89-99
 

CART regulators

CART mRNA expression in hypothalamus is positively regulated by Leptin. Nature. 1998 May 7;393(6680):72-6.    CART is co-localised in leptin-activated neurons in the DMN, and arcuate. J Comp Neurol. 2000 Jul 24;423(2):261-81.  Leptin receptors are present on CART  neurons in the arcuate nucleus. Neuron. 1998 Dec;21(6):1375-85.  Peripheral administration of Leptin to obese mice stimulates CART mRNA expression. In a study of 91 severely obese children with early onset obesity, a novel amino acid change was detected in two patients but did not co-segregate with obesity in family studies.   

CART also co-localises with CB1 cannabinoid receptor. J Clin Invest. 2003 Aug;112(3):423-31.CB1 knock out mice have lower levels of CART mRNA in the DMN and lateral hypothalamus.

Glucocorticoids regulate CART expression in the hypothalamus,  Brain Res. 2001 Oct 26;917(1):15-20.   pituitary Am J Physiol Endocrinol Metab. 2004 Sep;287(3):E583-90   and blood. Endocrinology. 2004 Sep;145(9):4119-24.

Two common polymorphisms have been described for the CART gene in humans, but there was no significant relationship of these polymorphisms with obesity. Int J Obes Relat Metab Disord. 2000 Apr;24(4):520-1.   ;  Obes Res. 1999 Nov;7(6):532-6.    It is postulated that genetic variation in the CART locus might influence fat   distribution as evidenced by the association of reduced waist-to-hip size in men with another polymorphism of the CART gene. Diabetes. 2000 May;49(5):872-5.

CART receptors need to be identified to further our understanding of its physiological role. CART levels and distribution in lean and obese humans also needs to be defined.

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    This page was last updated on: 07/03/2007

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