Leptin Acts via Lateral Hypothalamic Area Neurotensin Neurons to Inhibit Orexin Neurons by Multiple GABA-Independent Mechanisms

Goforth, Paulette B.; Leinninger, Gina M.; Patterson, Christa M.; Satin, Leslie S.; Myers, Martin G.

doi:10.1523/jneurosci.5167-13.2014

Cited by 102 publications

(91 citation statements)

References 45 publications

(16 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous neuroanatomical studies have also implicated these sites in inflammatory anorexia (73)(74)(75)(76). It has also been suggested that melanocortin signaling in GABAergic interneurons contacting orexin neurons in the LHA might contribute to the regulation of appetite (40,77). Interestingly, we and others have previously demonstrated that LPS could reduce the activity of LHA neurons, including orexin neurons, in fasted animals (18,78).…”

Section: Central Viscerosensory Pathways Involved In Inflammatory Anomentioning

confidence: 61%

Lipopolysacharide Rapidly and Completely Suppresses AgRP Neuron-Mediated Food Intake in Male Mice

Liu

Huang

Liu³

et al. 2016

Endocrinology

View full text Add to dashboard Cite

Although Agouti-related peptide (AgRP) neurons play a key role in the regulation of food intake, their contribution to the anorexia caused by proinflammatory insults has yet to be identified. Using a combination of neuroanatomical and pharmacogenetics experiments, this study sought to investigate the importance of AgRP neurons and downstream targets in the anorexia caused by the peripheral administration of a moderate dose of lipopolysaccharide (LPS) (100 μg/kg, ip). First, in the C57/Bl6 mouse, we demonstrated that LPS induced c-fos in select AgRP-innervated brain sites involved in feeding but not in any arcuate proopiomelanocortin neurons. Double immunohistochemistry further showed that LPS selectively induced c-Fos in a large subset of melanocortin 4 receptor-expressing neurons in the lateral parabrachial nucleus. Secondly, we used pharmacogenetics to stimulate the activity of AgRP neurons during the course of LPS-induced anorexia. In AgRP-Cre mice expressing the designer receptor hM3Dq-Gq only in AgRP neurons, the administration of the designer drug clozapine-N-oxide (CNO) induced robust food intake. Strikingly, CNO-mediated food intake was rapidly and completely blunted by the coadministration of LPS. Neuroanatomical experiments further indicated that LPS did not interfere with the ability of CNO to stimulate c-Fos in AgRP neurons. In summary, our findings combined together support the view that the stimulation of select AgRP-innervated brain sites and target neurons, rather than the inhibition of AgRP neurons themselves, is likely to contribute to the rapid suppression of food intake observed during acute bacterial endotoxemia.

show abstract

Section: Central Viscerosensory Pathways Involved In Inflammatory Anomentioning

confidence: 61%

Lipopolysacharide Rapidly and Completely Suppresses AgRP Neuron-Mediated Food Intake in Male Mice

Liu

Huang

Liu³

et al. 2016

Endocrinology

View full text Add to dashboard Cite

show abstract

“…For instance, LHA Nts neurons might co-release GABA onto VTA GABA interneurons, thereby disinhibiting DA neurons and promoting DA signaling (Nieh et al, 2016). LHA Nts neurons also project locally and inhibit neighboring hypocretin/orexin neurons (Goforth et al, 2014; Leinninger et al, 2011), which could decrease food intake, especially in a food-restricted state. Our data thus reveal that LHA Nts neurons are important mediators of central anorectic Nts action via NtsR1.…”

Section: Discussionmentioning

confidence: 99%

Lateral Hypothalamic Neurotensin Neurons Orchestrate Dual Weight Loss Behaviors via Distinct Mechanisms

et al. 2017

View full text Add to dashboard Cite

SUMMARY The central mechanism by which neurotensin (Nts) potentiates weight loss has remained elusive. We leveraged chemogenetics to reveal that Nts-expressing neurons of the lateral hypothalamic area (LHA) promote weight loss in mice by increasing volitional activity and restraining food intake. Intriguingly, these dual weight loss behaviors are mediated by distinct signaling pathways: Nts action via NtsR1 is essential for the anorectic effect of the LHA Nts circuit, but not for regulation of locomotor or drinking behavior. Furthermore, although LHA Nts neurons cannot reduce intake of freely available obesogenic foods, they effectively restrain motivated feeding in hungry, weight-restricted animals. LHA Nts neurons are thus vital mediators of central Nts action, particularly in the face of negative energy balance. Enhanced action via LHA Nts neurons may therefore be useful to suppress the increased appetitive drive that occurs after lifestyle-mediated weight loss, and hence to prevent weight regain.

show abstract

“…Leptin is a circulating anorexigenic and pro-inflammatory adipokine produced by the adipose tissue, which reduces both endocannabinoid (Di Marzo et al, 2001) and OX-A (Goforth et al, 2014) signaling in the hypothalamus. Its levels are altered in obesity as well as during anorexia and bingeeating disorder (Monteleone et al, 2000;Cristino et al, 2014, for review).…”

Section: Introductionmentioning

confidence: 99%

Orexin-A and Endocannabinoid Activation of the Descending Antinociceptive Pathway Underlies Altered Pain Perception in Leptin Signaling Deficiency

Cristino

Luongo

Imperatore

et al. 2015

Neuropsychopharmacol

View full text Add to dashboard Cite

Pain perception can become altered in individuals with eating disorders and obesity for reasons that have not been fully elucidated. We show that leptin deficiency in ob/ob mice, or leptin insensitivity in the arcuate nucleus of the hypothalamus in mice with high-fat diet (HFD)-induced obesity, are accompanied by elevated orexin-A (OX-A) levels and orexin receptor-1 (OX1-R)-dependent elevation of the levels of the endocannabinoid, 2-arachidonoylglycerol (2-AG), in the ventrolateral periaqueductal gray (vlPAG). In ob/ob mice, these alterations result in the following: (i) increased excitability of OX1-R-expressing vlPAG output neurons and subsequent increased OFF and decreased ON cell activity in the rostral ventromedial medulla, as assessed by patch clamp and in vivo electrophysiology; and (ii) analgesia, in both healthy and neuropathic mice. In HFD mice, instead, analgesia is only unmasked following leptin receptor antagonism. We propose that OX-A/endocannabinoid cross talk in the descending antinociceptive pathway might partly underlie increased pain thresholds in conditions associated with impaired leptin signaling.

show abstract

Leptin Acts via Lateral Hypothalamic Area Neurotensin Neurons to Inhibit Orexin Neurons by Multiple GABA-Independent Mechanisms

Cited by 102 publications

References 45 publications

Lipopolysacharide Rapidly and Completely Suppresses AgRP Neuron-Mediated Food Intake in Male Mice

Lipopolysacharide Rapidly and Completely Suppresses AgRP Neuron-Mediated Food Intake in Male Mice

Lateral Hypothalamic Neurotensin Neurons Orchestrate Dual Weight Loss Behaviors via Distinct Mechanisms

Orexin-A and Endocannabinoid Activation of the Descending Antinociceptive Pathway Underlies Altered Pain Perception in Leptin Signaling Deficiency

Contact Info

Product

Resources

About