Peptides that regulate food intake: appetite-inducing accumbens manipulation activates hypothalamic orexin neurons and inhibits POMC neurons.

Corticolimbic circuits involving the prefrontal cortex, amygdala, and ventral striatum determine the reward value of food and might play a role in environmentally induced obesity. Chemical manipulation of the nucleus accumbens shell (AcbSh) has been shown to elicit robust feeding and Fos expression in the hypothalamus and other brain areas of satiated rats. To determine the neurochemical phenotype of hypothalamic neurons receiving input from the AcbSh, we carried out c-Fos/peptide double-labeling immunohistochemistry in various hypothalamic areas known to contain feeding peptides, from rats that exhibited a significant feeding response after AcbSh microinjection of the GABA(A) agonist muscimol. In the perifornical area, a significantly higher percentage of orexin neurons expressed Fos after muscimol compared with saline injection. In contrast, Fos expression was not induced in melanin-concentrating hormone and cocaine-amphetamine-related transcript (CART) neurons. In the arcuate nucleus, Fos activation was significantly lower in neurons coexpressing CART and proopiomelanocortin, and there was a tendency for higher Fos expression in neuropeptide Y neurons. In the paraventricular nucleus, no significant activation of oxytocin and CART neurons was found. Thus AcbSh manipulation may elicit food intake through coordinated stimulation of hypothalamic neurons expressing orexigenic peptides and suppression of neurons expressing anorexigenic peptides. However, activation of many neurons not expressing these peptides suggests that additional peptides/transmitters in the lateral hypothalamus and accumbens projections to other brain areas might also be involved.

Gastric distension induces c-Fos in medullary GLP-1/2-containing neurons.

A group of neurons in the caudal nucleus of the solitary tract (NTS) processes preproglucagon to glucagon-like peptides (GLP)-1 and -2, peptides that inhibit food intake when administered intracerebroventricularly. The GLP-1/2-containing neural pathways have been suggested to play a role in taste aversion and nausea because LiCl activates these neurons, and LiCl-induced suppression of food intake can be blocked by the GLP-1 receptor antagonist exendin-9. As many gastrointestinal signals related to both satiety and nausea/illness travel via the vagus nerve to the caudal medulla, the present study assessed the capacity of different types of gastric distension (a purely mechanical stimulus) to activate GLP-1 neurons in the caudal NTS. Gastric balloon distension (1.4 ml/min first 5 min, 0.4 ml/min next 5 min, 9 ml total, held for 60 min) in nonanesthetized, freely moving rats produced 12- and 17-fold increases in c-Fos-expressing NTS neurons when distension was mainly in the fundus or corpus, respectively. Fundus and corpus distension increased the percentage of c-Fos-activated GLP-1 neurons to 21 +/- 9% and 32 +/- 5% compared with 1 +/- 1% with sham distension (P < 0.01). Thus gastric distension that may be considered within the physiological range activates GLP-1/2-containing neurons, suggesting some role in normal satiety. The results support the view that the medullary GLP system is involved in appetite control and is activated by stimuli within the behavioral continuum, ranging from satiety to nausea.

Neurochemical phenotype of hypothalamic neurons showing Fos expression 23 h after intracranial AgRP.

Agouti-related protein (AgRP) is coexpressed with neuropeptide Y (NPY) in a population of neurons in the arcuate nucleus (ARC) of the hypothalamus and stimulates food intake for up to 7 days if injected intracerebroventricularly. The prolonged food intake stimulation does not seem to depend on continued competition at the melanocortin-4 receptor (MC4R), because the relatively specific MC4R agonist MTII regains its ability to suppress food intake 24 h after AgRP injection. Intracerebroventricular AgRP also stimulates c-Fos expression 24 h after injection in several brain areas, so the neurons exhibiting delayed Fos expression might be particularly important in feeding behavior. Thus we aimed to identify the neurochemical phenotype of some of these neurons in select hypothalamic areas, using double-label immunohistochemistry. AgRP-injected rats ingested significantly more chow (10.2 +/- 0.6 g) vs. saline controls (3.4 +/- 0.7 g) in the first 9 h (light phase) after injection. In the lateral hypothalamus (particularly the perifornical area) 23 h after injection, AgRP induced significantly more Fos vs. saline in orexin-A (OXA) neurons (25.6 +/- 4.9 vs. 4.8 +/- 3.1%), but not in melanin-concentrating hormone (MCH) or cocaine- and amphetamine-regulated transcript (CART) neurons. In the ARC, AgRP induced significantly more Fos in CART (40.6 +/- 5.9 vs. 13.4 +/- 1.8%) but not NPY neurons. In the paraventricular nucleus, there was no significant difference in Fos expression induced by AgRP vs. saline in oxytocin and CART neurons. We conclude that the long-lasting hyperphagia induced by AgRP is correlated with and possibly partially mediated by hyperactive OXA neurons in the lateral hypothalamus and CART neurons in the ARC, but not by NPY and MCH neurons. The substantial increase in light-phase food intake by AgRP supports a role for the arousing effects of OXA. Activation of CART neurons in the ARC (which likely coexpress proopiomelanocortin) could indicate attempts to activate counterregulatory decreases in food intake.