Apelin and the proopiomelanocortin system: a new regulatory pathway of hypothalamic α-MSH release

Abstract

Neuronal networks originating in the hypothalamic arcuate nucleus (Arc) play a fundamental role in controlling energy balance. In the Arc, neuropeptide Y (NPY)-producing neurons stimulate food intake, whereas neurons releasing the proopiomelanocortin (POMC)-derived peptide ␣-melanocyte-stimulating hormone (␣-MSH) strongly decrease food intake. There is growing evidence to suggest that apelin and its receptor may play a role in the central control of food intake, and both are concentrated in the Arc. We investigated the presence of apelin and its receptor in Arc NPY-and POMC-containing neurons and the effects of apelin on ␣-MSH release in the hypothalamus. We showed, by immunofluorescence and confocal microscopy, that apelin-immunoreactive (IR) neuronal cell bodies were distributed throughout the rostrocaudal extent of the Arc and that apelin was strongly colocalized with POMC, but weakly colocalized with NPY. However, there were numerous NPY-IR nerve fibers close to the apelin-IR neuronal cell bodies. By combining in situ hybridization with immunohistochemistry, we demonstrated the presence of apelin receptor mRNA in Arc POMC neurons. Moreover, using a perifusion technique for hypothalamic explants, we demonstrated that apelin-17 (K17F) increased ␣-MSH release, suggesting that apelin released somato-dendritically or axonally from POMC neurons may stimulate ␣-MSH release in an autocrine manner. Consistent with these data, hypothalamic apelin levels were found to be higher in obese db/db mice and fa/fa Zucker rats than in wild-type animals. These findings support the hypothesis that central apelin is involved in regulating body weight and feeding behavior through the direct stimulation of ␣-MSH release.␣-melanocyte-stimulating hormone; neuropeptide Y; hypothalamus; arcuate nucleus; obesity THE ARCUATE NUCLEUS (Arc) in the hypothalamus plays a key role in regulating food intake and energy homeostasis (62). This structure contains two distinct groups of first-order neurons: a population-synthesizing proopiomelanocortin (POMC)-derived ␣-melanocyte-stimulating hormone (␣-MSH) and the cocaine-and amphetamine-regulated transcript (CART), and a second population-synthesizing neuropeptide Y (NPY) and Agouti gene-related peptide (AgRP) (62). Arc POMC-immunoreactive (IR) neurons are activated in response to positive energy balance, whereas the NPY/AgRP-IR system is activated in response to negative energy balance, such as caloric restriction or starvation (6). The NPY system stimulates food intake and decreases energy expenditure, whereas the activation of POMC neurons, via ␣-MSH release, has the opposite effect (44, 68). NPY exerts its orexigenic effect by stimulating Y1 and Y5 receptors (43, 46), whereas the anorectic activity of ␣-MSH is mediated by the activation of melanocortin receptor (MCR) subtypes 3 and 4 (62). The Arc also responds to circulating leptin (26,72). Leptin suppresses the synthesis and release of NPY and AgRP and increases the synthesis and release of ␣-MSH and CART (64). Missense mutations of the lept...

Hypothalamic Apelin/Reactive Oxygen Species Signaling Controls Hepatic Glucose Metabolism in the Onset of Diabetes

“…4A). The relative expression of apelin mRNA was increased by about 1.5-fold, similar to that observed at the protein level in obese/diabetic mice (42), demonstrating that this overexpression of apelin in normal mice corresponds to the level found in pathological conditions. To identify the impact on glucose homeostasis, we performed insulin tolerance test (ITT).…”

“…On the contrary, obese/ diabetic mice fed a HFD show a disruption of circadian apelin regulation (11). Then, over-increased hypothalamic apelin expression observed in obese/diabetic (11,42) is associated to abnormal regulation of glycemia (11). To reinforce this hypothesis, an icv injection of a high dose of apelin (used in this study and similar to that observed in obese/diabetic mice) in normal mice induces fasted hyperglycemia and insulin resistance (11), characterizing a type 2 diabetes.…”

“…We have previously shown that obese/diabetic mice present an increase in plasma apelin (11) and in hypothalamic apelin expression (42). The hypothalamus is a neurohemal structure that facilitates communication with peripheral signal, including hormones and metabolites.…”

“…from the normal to diabetic state. First, apelin expression is increased in the hypothalamus of obese/diabetic mice (42). Second, acute and chronic intracerebroventricular (icv) injections of a high quantity of apelin (similar to that observed in obese/diabetic mice) in fasted normal mice induce type 2 diabetes symptoms such as hyperinsulinemia, hyperglycemia, glucose intolerance, and insulin resistance (11).…”

Apelin-13 increased food intake with serum ghrelin and leptin levels in male rats

“…However, some studies reported i.c.v administration of apelin-13 decreases food intake in animal models (11,25). Reaux-Le Goanzigo et al (26) revealed that K17F, a known active apelin fragment levels are elevated in POMC neurons of ARN leads to α-MSH release in an autocrine manner decreasing the food intake while R10F inactive form of apelin has not generated this effect.…”