Leptin action in the forebrain regulates the hindbrain response to satiety signals.

Morton GJ, Blevins JE, Williams DL, Niswender KD, Gelling RW, Rhodes CJ, Baskin DG, Schwartz MW
J Clin Invest. 2005 115 (3): 703-10

PMID: 15711637 · PMCID: PMC548313 · DOI:10.1172/JCI22081

The capacity to adjust energy intake in response to changing energy requirements is a defining feature of energy homeostasis. Despite the identification of leptin as a key mediator of this process, the mechanism whereby changes of body adiposity are coupled to adaptive, short-term adjustments of energy intake remains poorly understood. To investigate the physiological role of leptin in the control of meal size and the response to satiety signals, and to identify brain areas mediating this effect, we studied Koletsky (fa(k)/fa(k)) rats, which develop severe obesity due to the genetic absence of leptin receptors. Our finding of markedly increased meal size and reduced satiety in response to the gut peptide cholecystokinin (CCK) in these leptin receptor-deficient animals suggests a critical role for leptin signaling in the response to endogenous signals that promote meal termination. To determine if the hypothalamic arcuate nucleus (ARC) (a key forebrain site of leptin action) mediates this leptin effect, we used adenoviral gene therapy to express either functional leptin receptors or a reporter gene in the area of the ARC of fa(k)/fa(k) rats. Restoration of leptin signaling to this brain area normalized the effect of CCK on the activation of neurons in the nucleus of the solitary tract and area postrema, key hindbrain areas for processing satiety-related inputs. This intervention also reduced meal size and enhanced CCK-induced satiety in fa(k)/fa(k) rats. These findings demonstrate that forebrain signaling by leptin, a long-term regulator of body adiposity, limits food intake on a meal-to-meal basis by regulating the hindbrain response to short-acting satiety signals.

MeSH Terms (21)

Animals Cholecystokinin Eating Feeding Behavior Genetic Therapy Homeostasis Humans Leptin Male Neurons Obesity Prosencephalon Proto-Oncogene Proteins c-fos Rats Rats, Inbred Strains Receptors, Cell Surface Receptors, Leptin Recombinant Fusion Proteins Rhombencephalon Satiety Response Signal Transduction

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