Hyperleptinemia in A^y/a mice upregulates arcuate cocaine- and amphetamine-regulated transcript expression

Abstract

Sakata. Hyperleptinemia in A y /a mice upregulates arcuate cocaine-and amphetamine-regulated transcript expression. Am J Physiol Endocrinol Metab 282: E967-E973, 2002; 10.1152/ajpendo.00292.2001.-The effects of leptin on cocaine-and amphetamine-regulated transcript (CART) and agouti-related protein (AGRP) expression in the hypothalamic arcuate nucleus of obese A y /a mice were investigated. CART mRNA expression was upregulated by 41% and AGRP mRNA downregulated by 78% in hyperleptinemic A y /a mice relative to levels in lean a/a mice. The mRNA expression of these neuropeptides in either young nonobese A y /a mice or rats treated with SHU-9119, a synthetic melanocortin-4 receptor (MC4R) antagonist, did not differ significantly from that in the corresponding controls. After a 72-h fast, which decreased the concentration of serum leptin, CART and AGRP mRNA expression decreased and increased, respectively, in A y /a mice. The expression levels of these neuropeptides in leptin-deficient A y /a ob/ob double mutants were comparable to those in a/a ob/ob mice. Leptin thus modulates both CART and AGRP mRNA expression in obese A y /a mice, whereas leptin signals are blocked at the MCR4R level. Taken together, the present findings indicate that differential expression of these neuropeptides in A y /a and ob/ob mice results in dissimilar progression toward obesity. leptin; lethal yellow mice; agouti-related protein; arcuate nucleus LEPTIN HAS BEEN SHOWN TO INDUCE anorectic effects in rodents, at least in part, by signaling through the melanocortin-4 receptor (MC4R) (36). Agouti protein has a potent antagonistic effect on hypothalamic MC4R (7, 30), and rodents become hyperphagic when signaling is interrupted (19,31). Lethal yellow (A y /a) mice display ectopic overexpression of agouti protein in the brain, which results in defective proopiomelanocortin (POMC)/MC4R signaling and, upon maturation, obesity (7,16,30,44). Because these obese mice are both hyperleptinemic and insensitive to exogenous leptin treatment (16, 44), they are thought to be in a "leptin-resistant state." However, it has been reported that the major effects of POMC-and leptin-induced signals on body weight are independent and additive in A y /a ob/ob doubly mutant mice (3). In addition, full leptin responsiveness is restored in A y /a ob/ob mice (3). These findings indicate that defective signaling through MC4R does not necessarily impair leptin action completely. It is quite likely that leptin continues to act, at least in part, on some hypothalamic neuropeptides in A y /a mice.Cocaine-and amphetamine-regulated transcript (CART) was originally identified as a hypothalamic neuropeptide upregulated by cocaine and amphetamine treatment (6). 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). Asnicar et al. (2) have recently demonstrated that absence of CART results i...

Pre-obese and obese agouti mice are sensitive to the anorectic effects of peptide YY3–36 but resistant to ghrelin

“…AgRP is an important mediator in ghrelin-induced feeding, 21 and NPY-deficient mice have a normal feeding response to peripherally administered ghrelin. 20 Obese A y /a mice, similar in age to those in the current study, have reduced arcuate AgRP mRNA expression 13 and peripheral ghrelin may be unable to sufficiently upregulate AgRP to stimulate feeding. However, pre-obese A y /a mice have similar arcuate AgRP mRNA levels to WT littermates, 13 yet are also insensitive to peripheral ghrelin.…”

“…20 Obese A y /a mice, similar in age to those in the current study, have reduced arcuate AgRP mRNA expression 13 and peripheral ghrelin may be unable to sufficiently upregulate AgRP to stimulate feeding. However, pre-obese A y /a mice have similar arcuate AgRP mRNA levels to WT littermates, 13 yet are also insensitive to peripheral ghrelin. Alternatively, in pre-obese and obese A y /a mice, chronic antagonism of hypothalamic MC4-Rs by agouti protein could prevent a further upregulation of AgRP by ghrelin.…”

“…Obese A y /a mice have reduced arcuate AgRP mRNA expression compared to pre-obese A y /a mice. 13 NPY mRNA expression in preobese A y /a mice is restricted to the arcuate nucleus; however, in obese A y /a mice, NPY mRNA is also expressed in the dorsomedial nucleus (DMN). 14 Mature obese A y /a mice are hyperleptinemic, due to an increased fat mass and are reported to be insensitive to exogenous, peripheral leptin.…”

Leptin Resistance and Enhancement of Feeding Facilitation by Melanin-Concentrating Hormone in Mice Lacking Bombesin Receptor Subtype-3

“…We can explain this phenomenon as a compensatory activation of the neural system, with the receptive site for CART in opposition to the activation of the MCH and MCH-R system. This hypothesis can be assumed after a previous report that hyperleptinemia in A y /a mice upregulates CART expression in the arcuate nucleus (46). However, CART is reported to colocalize not only with POMC in the arcuate nucleus (26) but also with MCH in the lateral hypothalamus (47), i.e., in both anorexigenic and orexigenic pathways in the hypothalamus.…”

Role of Hypothalamic Melanocortin 3/4-Receptors in Mediating Chronic Cardiovascular, Renal, and Metabolic Actions of Leptin

“…21 However, there may be additional changes in the agouti mouse that could influence blood pressure besides inhibition of hypothalamic melanocortin receptors. For example, the agouti mouse has increased cocaine-and amphetamine-regulated transcript (CART) expression in the hypothalamus 22 and excess agouti protein has been reported to directly increase intracellular Ca ϩϩ concentration in many tissues, including vascular smooth muscle. 23 Our observations in the present and previous studies 13 suggest that pharmacological inhibition of the MC3/4-R alone completely abolishes the effects of leptin on HR and arterial pressure.…”