Abstract


The hormones leptin and ghrelin act within the brain to coordinate energy status with appropriate ingestive and locomotor behaviors, and are crucial mediators of adaptive energy balance.  In the lateral hypothalamic area (LHA), separate populations of neurons respond to leptin and ghrelin to modify behavior and resolve energy imbalance.  Ghrelin activates LHA neurons that express the neuropeptide Hypocretin/Orexin (OX) to increase feeding.  Leptin acts at a separate population of LHA neurons that co-express the neuropeptide neurotensin (Nts) and long form of the leptin receptor (LepRb); we view more

The hormones leptin and ghrelin act within the brain to coordinate energy status with appropriate ingestive and locomotor behaviors, and are crucial mediators of adaptive energy balance.  In the lateral hypothalamic area (LHA), separate populations of neurons respond to leptin and ghrelin to modify behavior and resolve energy imbalance.  Ghrelin activates LHA neurons that express the neuropeptide Hypocretin/Orexin (OX) to increase feeding.  Leptin acts at a separate population of LHA neurons that co-express the neuropeptide neurotensin (Nts) and long form of the leptin receptor (LepRb); we refer to these as NtsLepRb neurons.  We have previously shown that NtsLepRb neurons are necessary for the anorectic response to leptin, and that they project to and inhibit OX neurons. We therefore hypothesized that disruption of the NtsLepRb neuronal circuit impairs NtsLepRb neurons and OX neurons from responding to their respective hormonal cues, leptin and ghrelin, and thus disrupts energy balance.  To examine this hypothesis we studied mice with intact action via the NtsLepRb neuronal circuit (Control mice) and mice lacking functional LepRb specifically in NtsLepRb neurons (LRKO mice).   LRKO mice exhibit reduced spontaneous physical activity and volitional wheel running compared to control mice, and as a result they become obese.  Intriguingly, LRKO mice do not exhibit baseline differences in chow intake compared to controls, suggesting that the NtsLepRb circuit is not essential for homeostatic ingestive behavior.  To determine whether the NtsLepRb neuronal circuit is required for adaptive energy balance we examined feeding and sucrose intake of control and LRKO mice in response to leptin or ghrelin treatment.  Leptin treatment suppresses chow-feeding in control mice, as expected, but does not suppress feeding in LRKO animals, suggesting loss of adaptive feeding.  By contrast, ghrelin treatment increases feeding and sucrose preference in control mice, but does not increase sucrose preference in LRKO mice, suggesting loss of adaptive hedonic intake. Since leptin and ghrelin activate LHA neurons that project into and modify activation of the mesolimbic dopamine system, we reasoned that adaptive activation of this circuit might be disrupted in LRKO mice.   Indeed, leptin and ghrelin both increase the number of cFos-positive neurons in the nucleus accumbens of control mice, but not in LRKO mice.  Collectively these data suggest that loss of action via the NtsLepRb neuronal circuit diminishes adaptive response to leptin and ghrelin mediated via NtsLepRb neurons and postsynaptic OX neurons, respectively.  Intact regulation of NtsLepRb neurons is therefore essential for the coordination of hormonal cues and appropriate adaptive behaviors to regulate ingestive behavior, physical activity and body weight.

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