Multinodal regulation of the arcuate/paraventricular nucleus circuit by leptin

Abstract

Melanocortin-4 receptor (MC4R) is critical for energy homeostasis, and the paraventricular nucleus of the hypothalamus (PVN) is a key site of MC4R action. Most studies suggest that leptin regulates PVN neurons indirectly, by binding to receptors in the arcuate nucleus or ventromedial hypothalamus and regulating release of products like α-melanocyte-stimulating hormone (α-MSH), neuropeptide Y (NPY), glutamate, and GABA from firstorder neurons onto the MC4R PVN cells. Here, we investigate mechanisms underlying regulation of activity of these neurons under various metabolic states by using hypothalamic slices from a transgenic MC4R-GFP mouse to record directly from MC4R neurons. First, we show that in vivo leptin levels regulate the tonic firing rate of second-order MC4R PVN neurons, with fasting increasing firing frequency in a leptin-dependent manner. We also show that, although leptin inhibits these neurons directly at the postsynaptic membrane, α-MSH and NPY potently stimulate and inhibit the cells, respectively. Thus, in contrast with the conventional model of leptin action, the primary control of MC4R PVN neurons is unlikely to be mediated by leptin action on arcuate NPY/agouti-related protein and proopiomelanocortin neurons. We also show that the activity of MC4R PVN neurons is controlled by the constitutive activity of the MC4R and that expression of the receptor mRNA and α-MSH sensitivity are both stimulated by leptin. Thus, leptin acts multinodally on arcuate nucleus/PVN circuits to regulate energy homeostasis, with prominent mechanisms involving direct control of both membrane conductances and gene expression in the MC4R PVN neuron.melanocortin signaling | electrophysiology | obesity N eurons expressing melanocortin-4 receptor (MC4R) in the paraventricular nucleus of the hypothalamus (PVN) play a crucial role in energy homeostasis. The genetic and pharmacological disruption of MC4R increases energy intake and decreases thermogenesis (1, 2). Thus, these neurons sense peripheral signals of adiposity and maintain energy homeostasis by coordinating energy intake and expenditure (2, 3). The adipocyte hormone leptin relays information on changes in peripheral energy stores to melanocortin and other circuits in the brain to regulate energy homeostasis (4). Neurons in the arcuate nucleus of the hypothalamus (ARC) and other nuclei, including the ventromedial nucleus (VMH), dorsomedial nucleus, and lateral nucleus, express leptin receptors and play an important role in transmitting the leptin signal to PVN neurons (5-7). Despite functional evidence suggesting expression of the leptin receptor in PVN (8), direct action of leptin on PVN neurons has not been thoroughly investigated, perhaps because of the low density of leptin-receptor expression (9, 10).Circulating leptin, by affecting the activity of neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons in the ARC, regulates synthesis of NPY/agouti-related protein (AgRP) and α-melanocyte-stimulating hormone (α-MSH) as well as their putative release from nerve...

Melanocortin 4 receptor distribution in the human hypothalamus

“…In mice, green fluorescent protein under the Mc4r-promoter Y1-receptor and GFP co-localization was found in subnuclei of the PVN (46). Using the same mouse model, a strong inhibitory effect of NPY on MC4R-positive cells was measured by electrophysiology (47). NPY receptors inhibit adenylyl cyclase via activation of G i or G o proteins (48,49,50), thus opposing the G a s-activation of adenylate cyclases that occurs due to MC4R stimulation.…”

An Essential Role for the K+-dependent Na+/Ca2+-exchanger, NCKX4, in Melanocortin-4-receptor-dependent Satiety

“…The targets of POMC and AgRP neurons are principally melanocortin-4 receptor (MC4R) expressing neurons found in the paraventricular nucleus (PVN) as well as other hypothalamic areas (11)(12)(13). MSH, released from POMC neurons, is an agonist for MC4R and acts to stimulate the firing rates of downstream neurons (15). AgRP, on the other hand, is an antagonist of MC4R, thereby inhibiting these neurons (11)(12)(13)15), although AgRP neurons have also been shown to induce feeding directly, without melanocortin involvement (14,16).…”

“…So activated, G␣ q goes on to bind and stimulate PLC-␤, which subsequently cleaves phosphatidylinositol 1,4-bisphosphate (PIP 2 ) to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP 3 ). The membrane-bound diacylglycerol then activates the Ca 2ϩ -selective entry channel, TRPC6, which results in an elevation of cytosolic [Ca 2ϩ ] and consequent neuronal activation, which may include the initiation of action potentials (15) and the release of oxytocin (16, 41) (lower row). Normally, NCKX4 acts locally to extrude the Ca 2ϩ that enters via TRPC6, thus moderating the signaling pathway so only strong signals drive neuronal activation.…”

Gender differences in thyroid function and obesity among finnish women and men. The FIN-D2D-study

“…Leptin serves as a signal to the central nervous system regarding energy balance and the presence of energy stores. Leptin promotes thyrotropin-releasing hormone gene expression directly in the paraventricular nucleus, ultimately stimulating TSH release [16][17][18]. Leptin may also increase T4 to T3 conversion by deiodinases in a tissue-specific fashion [19].…”