Melanocortin activity in the amygdala controls appetite for dietary fat

Abstract

The amygdala is rich in melanocortin 4 receptors. Because the reduction in dietary fat intake after enterostatin is injected in the central nucleus of the amygdala (CeA) is blocked by a melanocortin 4 receptor antagonist, we investigated the role of melanocortin activity in the CeA in regulating food intake and macronutrient choice. Sprague-Dawley rats, fitted with CeA cannulas, were fed either chow, a high-fat (HF) diet, or adapted to a two-choice HF or low-fat (LF) diet. Injections of the MC4R agonist melanotan II (MTII) in the CeA had a dose-dependent inhibitory effect on food intake that lasted for at least 24 h. This response was greater in rats fed a HF diet. The inverse agonist agouti-related protein (AgRP) and antagonist SHU-9119 increased food intake in a dose-dependent manner, with the hyperphagia lasting for 60 h. In rats adapted to a two-choice HF/LF diet, MTII decreased HF consumption but had no effect on LF consumption, resulting in a long-lasting decrease in total calorie intake (Ϫ35.5% after 24 h, P Ͻ 0.05). Total calorie intake increased in both AgRP-and SHU-9119-treated rats (32 and 109% after 24 h, respectively) as the result of increased intake of HF diet. There was no modification of LF consumption with AgRP treatment and a transient nonsignificant decrease with SHU-9119 treatment. Amygdala brain-derived neurotrophic factor expression was increased by AgRP in fed rats. These results identify the amygdala as a site of action for the melanocortin system to control food intake and dietary preferences.agouti-related protein; melanotan II; SHU-9119; brain derived neurotrophic factor, food intake FOR YEARS, HYPOTHALAMIC CENTERS have been considered as the major brain centers regulating food intake and/or macronutrient selection (45). The neural circuits involved in the regulation of feeding behavior are complex, and more recent studies implicate other parts of the brain in the regulation of ingestive behaviors. Areas such as the nucleus accumbens, the amygdala, the brain stem, and many others form together with the hypothalamic areas a complex circuitry regulating all levels of feeding behavior (6,8,55). Indeed, the paraventricular nucleus (PVN) is not essential for either neuropeptide Y (NPY)-induced feeding or the anorexic response to melanocortin activity (16) since both are evident in PVN-lesioned rats. Furthermore, the anorectic response to melanotan II (MTII) is evident in the dorsovagal complex of the brain stem (52,58).A number of neuropeptides and compounds are known to selectively affect macronutrient intake when administered centrally. For example, the orexigenic NPY (47, 48, 50) , norepinephrine (30, 50), or agouti-related protein (AgRP) (23) have been reported to induce specific selection of macronutrients. Enterostatin, a satiety factor secreted in the gastrointestinal tract and expressed also in the central nervous system, induces an immediate reduction in food intake and inhibits appetite specifically for dietary fat when injected peripherally or centrally (31,37,39).It has been hy...

Identification of hypothalamic neuron-derived neurotrophic factor as a novel factor modulating appetite

“…5A: control vs. AGRP: F 1,12 ϭ 7.00, P ϭ 0.03; control vs. SHU-9119: F 1,12 ϭ 6.66, P ϭ 0.03). As expected (11), Bdnf mRNA levels were increased in the hypothalamus after intracerebroventricular injection of either AGRP or SHU-9119 (Fig. 5B: control vs. AGRP: F 1,12 ϭ 6.39, P ϭ 0.03; control vs. SHU-9119: F 1,12 ϭ 10.94, P ϭ 0.01).…”

“…To determine whether and where NENF may function with the BDNF and melanocortin signaling pathways, we used an experimental paradigm based on studies of Boghossian et al (11), who demonstrated that AGRP delivery to the amygdala increases Bdnf mRNA levels after allowing animals 2 h of food access following injection. We hypothesized that central delivery of AGRP or SHU-9119 would induce increased food intake, and this, in turn, would induce hypothalamic Nenf gene expression as a signal to reduce food intake, likely in response to satiety factors.…”

Pituitary Adenylate Cyclase-Activating Peptide in the Central Amygdala Causes Anorexia and Body Weight Loss via the Melanocortin and the TrkB Systems

“…Furthermore, infusion of MC4R agonists decreases food intake, whereas antagonism results in increased food intake (Rossi et al, 1998). Interestingly, alpha melanocyte-stimulating hormone (α-MSH) and the MC4R are abundantly expressed not only in hypothalamic nuclei but also in the amygdala and, when administered into the CeA, MC4R agonists inhibit feeding (Boghossian et al, 2010;Kask and Schioth, 2000b), suggesting a role for CeA MC4R in the regulation of feeding.…”

“…Blockade or absence of MC4R induces hyperphagia, reduced energy expenditure and obesity (Balthasar et al, 2005;Butler and Cone, 2003). Interestingly, MC4R are expressed not only in the hypothalamus but also in the amygdala (Mountjoy et al, 1994); melanocortin signaling in the CeA can indeed regulate feeding behavior bidirectionally, with MC4R exerting a tonic inhibitory role on feeding (ie, producing anorexia) (Boghossian et al, 2010;Kask et al, 2000a).…”

Melanocortin-4 receptor mutations paradoxically reduce preference for palatable foods

“…Similar experiments in the mouse demonstrate that the MC3R/MC4R agonist MTII acutely decreased intake of fat, but not carbohydrate or protein, in a three-choice diet model (9). The consumption of dietary fat in a two-choice model may also be increased by administration of MC3R/MC4R antagonists AgRP or SHU9119 directly into the central nucleus of the amygdala (CeA) (10). The amygdala has been demonstrated to play a role in emotion, reward, and motivation (11), and several studies link the amygdala to macronutrient preference and intake (10,12,13).…”