MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus

Abstract

Activation of melanocortin-4 receptors (MC4Rs) restrains feeding and prevents obesity; however, the identity, location, and axonal projections of the neurons bearing MC4Rs that control feeding remain unknown. Reexpression of MC4Rs on single-minded 1 (SIM1) + neurons in mice otherwise lacking MC4Rs is sufficient to abolish hyperphagia. Thus, MC4Rs on SIM1 + neurons, possibly in the paraventricular hypothalamus (PVH) and/or amygdala, regulate food intake. It is unknown, however, whether they are also necessary, a distinction required for excluding redundant sites of action. Hence, the location and nature of obesity-preventing MC4R-expressing neurons are unknown. Here, by deleting and reexpressing MC4Rs from cre-expressing neurons, establishing both necessity and sufficiency, we demonstrate that the MC4R-expressing neurons regulating feeding are SIM1 + , located in the PVH, glutamatergic and not GABAergic, and do not express oxytocin, corticotropin-releasing hormone, vasopressin, or prodynorphin. Importantly, these excitatory MC4R-expressing PVH neurons are synaptically connected to neurons in the parabrachial nucleus, which relays visceral information to the forebrain. This suggests a basis for the feeding-regulating effects of MC4Rs.M elanocortins, working through melanocortin-4 receptors (MC4Rs), regulate energy balance (1-3). Proopiomelanocortin (POMC)-expressing neurons release the MC4R agonist α-melanocyte-stimulating hormone (α-MSH) and promote negative energy balance, whereas agouti-related protein (AgRP)-expressing neurons, releasing the antagonist AgRP, do the opposite. Consistent with these roles, optogenetic (4) and chemogenetic (5) stimulation of POMC neurons causes hypophagia and weight loss. Conversely, optogenetic (4) or chemogenetic (6) stimulation of AgRP neurons produces hyperphagia and weight gain, with prolonged effects being mediated by AgRP through its action on MC4Rs (7). Importantly, the α-MSH/MC4R pathway also operates in humans, as evidenced by massive obesity in individuals lacking either α-MSH or MC4Rs (8, 9).Despite the established importance of MC4Rs (3), the neural mechanisms by which they regulate energy balance, and in particular feeding, are still unknown. In a prior study, we investigated the role of MC4Rs in the paraventricular hypothalamus (PVH), specifically on SIM1 (single-minded 1)-expressing neurons (2). The impetus for focusing on the PVH included the following: (i) MC4R expression is dense in the PVH (10-12), (ii) it receives strong input from AgRP and POMC neurons (13, 14), (iii) injection of MC3/4R ligands into the PVH affects feeding (14-16), (iv) PVH-directed lesions cause obesity (17, 18), and most importantly, (v) haploinsufficiency of SIM1, a transcription factor required for PVH development, results in obesity (19,20). Accordingly, using transgenic approaches, we restored Mc4r expression selectively in SIM1 neurons in mice that otherwise lack MC4Rs (2). Of note, restoration in SIM1 neurons rescued ∼60% of the obesity and 100% of the hyperphagia of MC4R-null mice, ...

High-Sugar, but Not High-Fat, Food Activates Supraoptic Nucleus Neurons in the Male Rat

“…Many studies demonstrate that melanocortin signalling, particularly in the PVN, plays a fundamental role in appetite control (57). Despite this, a recent study has shown that re-expression of the MC4 receptor specifically in PVN oxytocin neurones in MC4 knock-out mice does not reverse the obesity phenotype seen in these animals (58). However, this study does not address a potential role for SON oxytocin neurones.…”

Translational and therapeutic potential of oxytocin as an anti-obesity strategy: Insights from rodents, nonhuman primates and humans

“…While it will be important to determine if optogenetic activation of PVN OT neurons is sufficient to elicit release of OT from long axonal projections to the hindbrain [115,116], these findings are, however, consistent with what appears to be a relatively minor role of PVN OT neurons to suppress the refeeding response following a prolonged fast in rats [117]. Shah and colleagues demonstrated that reexpression of MC4Rs in PVN OT neurons in oxytocin-Ires-Cre;Mc4R loxTB / loxTB mice failed to attenuate the obesity phenotype in MC4R null MC4R loxTB / loxTB mice [118]. These findings suggest that direct MC4R signaling through PVN OT neurons may not be required to regulate body weight in mice.…”

Cognitive and autonomic determinants of energy homeostasis in obesity

“…74 How the hypothalamus relays information on energy homeostasis to the rostral forebrain appetite network has yet to be fully investigated but might function via a hypothalamic-thalamic-striatal axis or hypothalamic-brainstem-striatal axis. [78][79][80] The brainstem includes several nuclei involved in the regulation of energy balance. The nucleus of the solitary tract (NTS), the area postrema (AP) and the dorsal motor nucleus of the vagus nerve, which make up the dorsal vagal complex (DVC) are key structures that integrate homeostatic signals from peripheral mediators to inform the forebrain about energy balance.…”

“…125 PVH-initiated catabolic MC4R signalling to the forebrain which modulates appetite might also occur via the PBN, a site innervated by PVH MC4R neurons. 79,126 Finally, one cannot exclude a direct link between the melanocortin system and reward circuits because POMC neurons in the ARC send direct projections to the NAc and VTA, 107,127 which express MC4R 128 and MC3R 129 respectively. Melanocortins might modulate the cortico mesolimbic dopamine circuit.…”