Characterization of CART neurons in the rat and human hypothalamus

Abstract

Cocaine- and amphetamine-regulated transcript (CART) is a recently described neuropeptide widely expressed in the rat brain. CART mRNA and peptides are found in hypothalamic sites such as the paraventricular nucleus (PVH), the supraoptic nucleus (SON), the lateral hypothalamic area (LHA), the dorsomedial nucleus of the hypothalamus (DMH), the arcuate nucleus (Arc), the periventricular nucleus (Pe), and the ventral premammillary nucleus (PMV). Intracerebroventricular administration of recombinant CART peptide decreases food intake and CART mRNA levels in the Arc are regulated by leptin. Leptin administration induces Fos expression in hypothalamic CART neurons in the PVH, the DMH, the Arc, and the PMV. In the current study, we used double label in situ hybridization histochemistry to investigate the potential direct action of leptin on hypothalamic CART neurons and to define the chemical identity of the hypothalamic CART neurons in the rat brain. We found that CART neurons in the Arc, DMH, and PMV express long form leptin-receptor mRNA, and the suppressor of cytokine signaling-3 (SOCS-3) mRNA after an acute dose of intravenous leptin. We also found that CART neurons in the parvicellular PVH, in the DMH and in the posterior Pe coexpress thyrotropin-releasing hormone (TRH) mRNA. CART neurons in the magnocellular PVH and in the SON coexpress dynorphin (DYN), and CART cell bodies in the LHA and in the posterior Pe coexpress melanin-concentrating hormone (MCH) and glutamic acid decarboxylase (GAD-67) mRNA. In the Arc, a few CART neurons coexpress neurotensin (NT) mRNA. In addition, we examined the distribution of CART immunoreactivity in the human hypothalamus. We found CART cell bodies in the PVH, in the SON, in the LHA, in the Arc (infundibular nucleus) and in the DMH. We also observed CART fibers throughout the hypothalamus, in the bed nucleus of the stria terminalis, and in the amygdala. Our results indicate that leptin directly acts on CART neurons in distinct nuclei of the rat hypothalamus. Furthermore, hypothalamic CART neurons coexpress neuropeptides involved in energy homeostasis, including MCH, TRH, DYN, and NT. The distribution of CART cell bodies and fibers in the human hypothalamus indicates that CART may also play a role in the regulation of energy homeostasis in humans.

Cocaine- and amphetamine-regulated transcript (CART) expression is differentially regulated in the hypothalamic paraventricular nucleus of lactating rats exposed to suckling or cold stimulation

“…The distribution of CART mRNA in PVN neurons of control lactating rats was similar to that reported for male rats (Douglass et al, 1995;Elias et al, 2001); CART mRNA was observed in parvocellular and magnocellular PVN neurons (Fig. 3 B-D).…”

“…Most of these "hypophysiotropic" TRH neurons contain a second peptide, cocaine and amphetamine-regulated transcript (CART) (Broberger, 1999;Elias et al, 2001;Fekete et al, 2000), originally identified in the striatum as a transcript up-regulated by psychostimulants (Douglass et al, 1995). While CART neurons from the arcuate nucleus have been shown to exert important effects on energy homeostasis including those on the hypothalamic-pituitary-thyroid axis through their action on hypophysiotropic TRH neurons (Fekete et al, 2000;Stanley et al, 2001), the importance of the coexistence of CART with TRH in the PVN is not yet understood.…”

Analysis of the network of feeding neuroregulators using the Allen Brain Atlas

“…For example, ARC neurons give rise to POMC and NPY that have been linked with the consumption of both palatable and high-energy tastants (Levine and Billington, 1997;Olszewski and Levine, 2007). This hypothalamic structure also contains anorexigenic peptides and receptors, including CART and the leptin receptor (Elias et al, 2001). It is therefore impossible to refer to the ARC as a "satiety", "orexigenic", "reward" or "hunger" center.…”

Hyperleptinemia in Ay/a mice upregulates arcuate cocaine- and amphetamine-regulated transcript expression

“…Central administration of CART induces c-fos expression in several hypothalamic nuclei related with feeding control (11,42). Recombinant CART fragments decreased food intake in rodents (1,29,42), whereas anti-CART antibodies increased it (24).…”