Starvation after AgRP neuron ablation is independent of melanocortin signaling

Abstract

Ablation of inhibitory agouti-related protein (AgRP)-expressing neurons in the arcuate nucleus that also synthesize ␥-aminobutyric acid (GABA) and neuropeptide Y in adult mice leads to starvation within 1 week. The removal of inhibition from the AgRP neurons onto neighboring proopiomelanocortin neurons and their common postsynaptic neurons is predicted to stimulate melanocortin signaling, which is known to inhibit appetite. To examine the importance of uncontrolled melanocortin signaling in mediating starvation in this model, we ablated AgRP neurons in A y /a mice that have chronic blockade of the melanocortin signaling. The blockade of melanocortin signaling did not ameliorate the rate of starvation. On both WT and A y /a genetic backgrounds, there was a progressive decrease in meal frequency after AgRP neuron ablation. Surprisingly, intraoral feeding also was dramatically reduced after the ablation of AgRP neurons. These results indicate that both the appetitive and consummatory aspects of feeding become impaired in a melanocortin-independent manner after AgRP neuron ablation.T he melanocortin signaling pathway in the medial hypothalamus has emerged as a critical mediator of hormonal and neuronal signals that regulate energy balance (1-3). Genetic, pharmacological, anatomical, and electrophysiological techniques have established a pivotal role for proopiomelanocortin (POMC) neurons in the arcuate (ARC) and their signaling via melanocortin (␣-MSH) to cells bearing melanocortin-4 receptors (MC4R) in the paraventricular nucleus (PVN) and other brain regions in the control of appetite and metabolism (1,4,5). Neighboring cells that coexpress neuropeptide Y (NPY) and agouti-related protein (AgRP) also have been implicated in appetite and energy balance because these peptides stimulate robust feeding when injected into the brain, and their mRNA levels increase in the ARC under starvation conditions, as well as in obese animals deficient in leptin signaling (2,(6)(7)(8). Various experiments suggest that NPY acts by inhibiting the activity of POMC neurons and postsynaptic MC4R-bearing cells by activating G␣i-coupled NPY Y1 and/or Y5 receptors (7, 9-12). The activation of these receptors is predicted to counteract melanocortin activation of G␣s-coupled MC4R. AgRP acts in concert with NPY by blocking the binding of ␣-MSH to MC4R (8,13,14). The neurons that make NPY and AgRP also produce GABA, which inhibits POMC neurons and probably MC4R-bearing cells (15,16). Thus, these AgRP neurons are poised to inhibit melanocortin signaling by the neighboring POMC cells.The activation of melanocortin signaling by leptin inhibits appetite while stimulating metabolism (1, 2, 6). Consequently, the inactivation of mouse genes encoding leptin, leptin receptor, POMC, or MC4R leads to obesity (17)(18)(19)(20). However, the inactivation of genes encoding NPY, AgRP, or both has little effect on energy balance (21-23). These genetic results suggest that compensatory mechanisms in the KO mice mask the normal role of these peptides. Nevertheles...

Du nouveau dans la régulation de la prise alimentaire ?

“…Ce mécanisme est invoqué pour rendre compte de l'action centrale anabolique des neurones NPY/AgRP et il a été démontré que l'élimination brutale de ce signal, via l'élimination sélective des neurones NPY/AgRP, conduisait à un arrêt de la prise alimentaire [9]. alimentaire persiste [10]. Ce résultat démontre que l'inhibition de la voie mélanocortine par la sécrétion d'AgRP n'est probablement pas le seul méca-nisme par lequel les neurones NPY/ AgRP antagonisent la voie satiétogène à la mélanocortine et il suggère l'existence d'une autre molécule orexigène par laquelle ces neurones exercent leur action orexigène et/ou l'existence d'un réseau neuronal parallèle au système mélanocortine, sur lequel les neurones NPY/AgRP exercent leur influence inhibitrice [10].…”

“…alimentaire persiste [10]. Ce résultat démontre que l'inhibition de la voie mélanocortine par la sécrétion d'AgRP n'est probablement pas le seul méca-nisme par lequel les neurones NPY/ AgRP antagonisent la voie satiétogène à la mélanocortine et il suggère l'existence d'une autre molécule orexigène par laquelle ces neurones exercent leur action orexigène et/ou l'existence d'un réseau neuronal parallèle au système mélanocortine, sur lequel les neurones NPY/AgRP exercent leur influence inhibitrice [10]. ‡ Goat, a key step mediating ghrelin orexigenic action…”

New inducible genetic method reveals critical roles of GABA in the control of feeding and metabolism

“…Mice were microinjected with 0.8 μL of G418, NB compounds, or saline vehicle into the third ventricle either once or twice (2 d apart). Measurements of GABA and glutamate concentrations, immunohistochemistry, quantitative PCR, and FACS techniques were performed by standard procedures (36,43,44). Food intake, body weight, energy expenditure, and glucose tolerance test (GTT) were measured as described (28,36,45).…”

Neuroendocrine control of satiation

“…First, AgRP exerts its action by blocking the binding of α-MSH to its receptor [271,[281][282][283]. GABA release from AgRP neurons has a direct effect on POMC cells and probably on most postsynaptic MC4R-bearing cells [188,284,285]. GABA co-localizes with NPYimmuno-positive axon terminals that innervate local POMC neurons in both the arcuate and the paraventricular nuclei.…”

“…For example, AgRP still stimulated eating in MC4R-KO mice [30]. In addition, chronic blockade of the melanocortin pathway in A (y)/a genetic background (in which agouti protein is ectopically expressed in the brain, thereby chronically blocking MC4R signaling) failed to ameliorate the severe anorexia after ablation of AgRP neurons [285].…”