u-0126 and Anorexia

Peripheral amylin inhibits eating via the area postrema (AP). Because amylin activates the extracellular-signal regulated kinase 1/2 (ERK) pathway in some tissues, and because ERK1/2 phosphorylation (pERK) leads to acute neuronal responses, we postulated that it may be involved in amylin's eating inhibitory effect. Amylin-induced ERK phosphorylation (pERK) was investigated by immunohistochemistry in brain sections containing the AP. pERK-positive AP neurons were double-stained for the calcitonin 1a/b receptor, which is part of the functional amylin-receptor. AP sections were also phenotyped using dopamine-β-hydroxylase (DBH) as a marker of noradrenergic neurons. The effect of fourth ventricular administration of the ERK cascade blocker U0126 on amylin's eating inhibitory action was tested in feeding trials. The number of pERK-positive neurons in the AP was highest ∼10-15 min after amylin treatment; the effect appeared to be dose-dependent (5-20 μg/kg amylin). A portion of pERK-positive neurons in the AP carried the amylin-receptor and 22% of the pERK-positive neurons were noradrenergic. Pretreatment of rats with U0126 decreased the number of pERK-positive neurons in the AP after amylin injection. U0126 also attenuated the ability of amylin to reduce eating, at least when the animals had been fasted 24 h prior to the feeding trial. Overall, our results suggest that amylin directly stimulates pERK in AP neurons in a time- and dose-dependent manner. Part of the AP neurons displaying pERK were noradrenergic. At least under fasting conditions, pERK was shown to be a necessary part in the signaling cascade mediating amylin's anorectic effect.

Topics: Animals; Anorexia; Appetite Regulation; Area Postrema; Butadienes; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fourth Ventricle; Islet Amyloid Polypeptide; Male; MAP Kinase Signaling System; Nitriles; Rats; Rats, Sprague-Dawley; Receptors, Islet Amyloid Polypeptide; Time Factors

In response to nutrient stimuli, the mediobasal hypothalamus (MBH) drives multiple neuroendocrine and behavioral mechanisms to regulate energy balance. While central leucine reduces food intake and body weight, the specific neuroanatomical sites of leucine sensing, downstream neural substrates, and neurochemical effectors involved in this regulation remain largely unknown. Here we demonstrate that MBH leucine engages a neural energy regulatory circuit by stimulating POMC (proopiomelanocortin) neurons of the MBH, oxytocin neurons of the paraventricular hypothalamus, and neurons within the brainstem nucleus of the solitary tract to acutely suppress food intake by reducing meal size. We identify central p70 S6 kinase and Erk1/2 pathways as intracellular effectors required for this response. Activation of endogenous leucine intracellular metabolism produced longer-term reductions in meal number. Our data identify a novel, specific hypothalamus-brainstem circuit that links amino acid availability and nutrient sensing to the control of food intake.

Topics: Animals; Anorexia; Body Weight; Bone Morphogenetic Protein Receptors, Type I; Brain Stem; Butadienes; Dose-Response Relationship, Drug; Drug Administration Schedule; Eating; Enzyme Inhibitors; Feeding Behavior; Green Fluorescent Proteins; Hypothalamus; In Vitro Techniques; Injections, Intraventricular; Keto Acids; Leucine; Male; Melanocortins; Melanocyte-Stimulating Hormones; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neural Pathways; Neurons; Nitriles; Oxytocin; Pro-Opiomelanocortin; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Signal Transduction; Threonine; Time Factors; Tyrosine; Vasotocin