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Leptin modulates nutrient reward via inhibitory galanin action on orexin neurons.

Laque A, Yu S, Qualls-Creekmore E, Gettys S, Schwartzenburg C, Bui K, Rhodes C, Berthoud HR, Morrison CD, Richards BK, Münzberg H - Mol Metab (2015)

Bottom Line: We showed earlier that LepRb neurons in the lateral hypothalamus (LHA) co-express the inhibitory acting neuropeptide galanin (GAL-LepRb neurons).LHA GAL-LepRb neurons innervate orexin neurons, but not the VTA.We suggest galanin as an important mediator of leptin action to modulate nutrient reward by inhibiting orexin neurons.

View Article: PubMed Central - PubMed

Affiliation: Central Leptin Signaling Laboratory, Pennington Biomedical Research Center, LSU System, Baton Rouge, LA, USA.

ABSTRACT

Objective: Leptin modulates food reward via central leptin receptor (LepRb) expressing neurons. Food reward requires stimulation of midbrain dopamine neurons and is modulated by central leptin action, but the exact central mechanisms remain unclear. Stimulatory and inhibitory leptin actions on dopamine neurons have been reported, e.g. by indirect actions on orexin neurons or via direct innervation of dopamine neurons in the ventral tegmental area.

Methods: We showed earlier that LepRb neurons in the lateral hypothalamus (LHA) co-express the inhibitory acting neuropeptide galanin (GAL-LepRb neurons). We studied the involvement of GAL-LepRb neurons to regulate nutrient reward in mice with selective LepRb deletion from galanin neurons (GAL-LepRb(KO) mice).

Results: We found that the rewarding value and preference for sucrose over fat was increased in GAL-LepRb(KO) mice compared to controls. LHA GAL-LepRb neurons innervate orexin neurons, but not the VTA. Further, expression of galanin and its receptor GalR1 are decreased in the LHA of GAL-LepRb(KO) mice, resulting in increased activation of orexin neurons.

Conclusion: We suggest galanin as an important mediator of leptin action to modulate nutrient reward by inhibiting orexin neurons.

No MeSH data available.


Related in: MedlinePlus

GAL-LepRb neurons innervate orexin neurons and noradrenergic LC neurons. A/B. GalCre mice with LHA Ad-iN/WED injections show that within the LC WGA neurons co-express tyrosine hydroxylase (TH), depicting noradrenergic neurons (A) and within the LHA many WGA neurons are co-expressed with orexin (B). C. LepRbCre mice with LHA Ad-iN/WED injections show that many LHA WGA neurons are co-expressed with orexin. Bar size is 1 mm (Figure 5B and C) and 500 μm (Figure 5A). Gal = galanin; LepRb = long form leptin receptor; LC = locus coeruleus; LHA = lateral hypothalamic area; Ad = adenovirus; WGA = wheat germ agglutinin; ORX = orexin.
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fig5: GAL-LepRb neurons innervate orexin neurons and noradrenergic LC neurons. A/B. GalCre mice with LHA Ad-iN/WED injections show that within the LC WGA neurons co-express tyrosine hydroxylase (TH), depicting noradrenergic neurons (A) and within the LHA many WGA neurons are co-expressed with orexin (B). C. LepRbCre mice with LHA Ad-iN/WED injections show that many LHA WGA neurons are co-expressed with orexin. Bar size is 1 mm (Figure 5B and C) and 500 μm (Figure 5A). Gal = galanin; LepRb = long form leptin receptor; LC = locus coeruleus; LHA = lateral hypothalamic area; Ad = adenovirus; WGA = wheat germ agglutinin; ORX = orexin.

Mentions: We further observed many 2nd order neurons in the LC labeled from LHA GAL neurons (Figure 4L), while 2nd order labeling from LHA LepRb neurons (Figure 4I) was less strong and not observed in all cases of injected animals. LC neurons do not express LepRb as shown in a LepRbGFP reporter mouse with prominent GFP labeling in the hypothalamus, but complete absence of GFP labeling within the LC of the same animal (Figure S6A, B, respectively). We further confirmed the projections of GAL-LepRb neurons to the LC with injections of the retrograde tracer fluorogold (FG) into the LC of GalYFP mice. GAL is densely co-expressed with noradrenergic LC neurons as indicated by co-labeling of GalGFP with tyrosine hydroxylase (TH) (Figure S6C), so that the GalGFP signal (green label) served as an excellent visual guide for LC neurons to verify the accuracy of FG injections (red label) (Figure S6A). We found many triple labeled FG/pSTAT3/GalGFP neurons in the LHA surrounding the fornix (Figure S6B), which showed that many GAL-LepRb neurons innervate the LC. Furthermore, GAL neurons derived WGA labeled LC neurons indeed represent noradrenergic TH-positive neurons (Figure 5A).


Leptin modulates nutrient reward via inhibitory galanin action on orexin neurons.

Laque A, Yu S, Qualls-Creekmore E, Gettys S, Schwartzenburg C, Bui K, Rhodes C, Berthoud HR, Morrison CD, Richards BK, Münzberg H - Mol Metab (2015)

GAL-LepRb neurons innervate orexin neurons and noradrenergic LC neurons. A/B. GalCre mice with LHA Ad-iN/WED injections show that within the LC WGA neurons co-express tyrosine hydroxylase (TH), depicting noradrenergic neurons (A) and within the LHA many WGA neurons are co-expressed with orexin (B). C. LepRbCre mice with LHA Ad-iN/WED injections show that many LHA WGA neurons are co-expressed with orexin. Bar size is 1 mm (Figure 5B and C) and 500 μm (Figure 5A). Gal = galanin; LepRb = long form leptin receptor; LC = locus coeruleus; LHA = lateral hypothalamic area; Ad = adenovirus; WGA = wheat germ agglutinin; ORX = orexin.
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Related In: Results  -  Collection

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fig5: GAL-LepRb neurons innervate orexin neurons and noradrenergic LC neurons. A/B. GalCre mice with LHA Ad-iN/WED injections show that within the LC WGA neurons co-express tyrosine hydroxylase (TH), depicting noradrenergic neurons (A) and within the LHA many WGA neurons are co-expressed with orexin (B). C. LepRbCre mice with LHA Ad-iN/WED injections show that many LHA WGA neurons are co-expressed with orexin. Bar size is 1 mm (Figure 5B and C) and 500 μm (Figure 5A). Gal = galanin; LepRb = long form leptin receptor; LC = locus coeruleus; LHA = lateral hypothalamic area; Ad = adenovirus; WGA = wheat germ agglutinin; ORX = orexin.
Mentions: We further observed many 2nd order neurons in the LC labeled from LHA GAL neurons (Figure 4L), while 2nd order labeling from LHA LepRb neurons (Figure 4I) was less strong and not observed in all cases of injected animals. LC neurons do not express LepRb as shown in a LepRbGFP reporter mouse with prominent GFP labeling in the hypothalamus, but complete absence of GFP labeling within the LC of the same animal (Figure S6A, B, respectively). We further confirmed the projections of GAL-LepRb neurons to the LC with injections of the retrograde tracer fluorogold (FG) into the LC of GalYFP mice. GAL is densely co-expressed with noradrenergic LC neurons as indicated by co-labeling of GalGFP with tyrosine hydroxylase (TH) (Figure S6C), so that the GalGFP signal (green label) served as an excellent visual guide for LC neurons to verify the accuracy of FG injections (red label) (Figure S6A). We found many triple labeled FG/pSTAT3/GalGFP neurons in the LHA surrounding the fornix (Figure S6B), which showed that many GAL-LepRb neurons innervate the LC. Furthermore, GAL neurons derived WGA labeled LC neurons indeed represent noradrenergic TH-positive neurons (Figure 5A).

Bottom Line: We showed earlier that LepRb neurons in the lateral hypothalamus (LHA) co-express the inhibitory acting neuropeptide galanin (GAL-LepRb neurons).LHA GAL-LepRb neurons innervate orexin neurons, but not the VTA.We suggest galanin as an important mediator of leptin action to modulate nutrient reward by inhibiting orexin neurons.

View Article: PubMed Central - PubMed

Affiliation: Central Leptin Signaling Laboratory, Pennington Biomedical Research Center, LSU System, Baton Rouge, LA, USA.

ABSTRACT

Objective: Leptin modulates food reward via central leptin receptor (LepRb) expressing neurons. Food reward requires stimulation of midbrain dopamine neurons and is modulated by central leptin action, but the exact central mechanisms remain unclear. Stimulatory and inhibitory leptin actions on dopamine neurons have been reported, e.g. by indirect actions on orexin neurons or via direct innervation of dopamine neurons in the ventral tegmental area.

Methods: We showed earlier that LepRb neurons in the lateral hypothalamus (LHA) co-express the inhibitory acting neuropeptide galanin (GAL-LepRb neurons). We studied the involvement of GAL-LepRb neurons to regulate nutrient reward in mice with selective LepRb deletion from galanin neurons (GAL-LepRb(KO) mice).

Results: We found that the rewarding value and preference for sucrose over fat was increased in GAL-LepRb(KO) mice compared to controls. LHA GAL-LepRb neurons innervate orexin neurons, but not the VTA. Further, expression of galanin and its receptor GalR1 are decreased in the LHA of GAL-LepRb(KO) mice, resulting in increased activation of orexin neurons.

Conclusion: We suggest galanin as an important mediator of leptin action to modulate nutrient reward by inhibiting orexin neurons.

No MeSH data available.


Related in: MedlinePlus