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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.


Increased activation of orexin neurons in KO mice. A–B. Immunohistochemical staining for cFos (red) and orexin (green). The fornix (fx) is shown as a landmark for the location within the LHA. C. Percentage of orexin neurons that co-express cFos, in comparison to the total number of cFos/orexin neurons (D.) and total number of orexin neurons (E.). F. Quantification of LHA orexin mRNA and its receptors OX1 and OX2 (n = 10–13; *pt-test < 0.02). G. Immunohistochemical staining for orexin (red) and GalR1 (green). H. Schematic summary of distinct LHA LepRb neurons and their projections. KO = knock out; GalR1 = galanin receptor 1; LHA = lateral hypothalamic area; OX1 and OX2 = orexin receptor 1 and 2.
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fig6: Increased activation of orexin neurons in KO mice. A–B. Immunohistochemical staining for cFos (red) and orexin (green). The fornix (fx) is shown as a landmark for the location within the LHA. C. Percentage of orexin neurons that co-express cFos, in comparison to the total number of cFos/orexin neurons (D.) and total number of orexin neurons (E.). F. Quantification of LHA orexin mRNA and its receptors OX1 and OX2 (n = 10–13; *pt-test < 0.02). G. Immunohistochemical staining for orexin (red) and GalR1 (green). H. Schematic summary of distinct LHA LepRb neurons and their projections. KO = knock out; GalR1 = galanin receptor 1; LHA = lateral hypothalamic area; OX1 and OX2 = orexin receptor 1 and 2.

Mentions: LHA Gal and GalR1 expression was decreased in KO mice (Figure 2A, B) and GAL acts via GalR1 to potently inhibit neuronal excitation in many neuronal systems, including the hypothalamus [4,19,20]. We hypothesized that GAL may mediate the inhibitory actions of leptin on orexin neurons. Therefore, we predicted an increased activation of orexin neurons in KO mice. We analyzed KO and WT brains for basal levels of cFos (as a surrogate for neuronal activation) in orexin neurons and indeed found increased cFos/orexin co-localization, which was most prominent in the rostral portion of orexin/hypocretin neurons (Figure 6A–E, n = 5, pANOVA < 0.003,*pHolm-Sidak < 0.05). This was due to an increased number of cFos/ox neurons (Figure 6D), while the total number of orexin neurons was unchanged between groups (Figure 6E). Enhanced cFos expression was restricted to the LHA, while other adjacent sites, e.g. the DMH, showed similar cFos expression (Figure S8). Further, orexin gene expression was similar in KO and WT mice (Figure 6F). However, the gene expression of LHA orexin receptor Ox2, but not Ox1, was significantly decreased (Figure 6F, *pt-test < 0.02), indicating that within the LHA Ox1 signaling would be preferentially enhanced. We further determined that orexin neurons were co-labeled with GalR1 (Figure 6G), demonstrating that orexin neurons have the molecular capability to respond to GAL (Figure 6H).


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)

Increased activation of orexin neurons in KO mice. A–B. Immunohistochemical staining for cFos (red) and orexin (green). The fornix (fx) is shown as a landmark for the location within the LHA. C. Percentage of orexin neurons that co-express cFos, in comparison to the total number of cFos/orexin neurons (D.) and total number of orexin neurons (E.). F. Quantification of LHA orexin mRNA and its receptors OX1 and OX2 (n = 10–13; *pt-test < 0.02). G. Immunohistochemical staining for orexin (red) and GalR1 (green). H. Schematic summary of distinct LHA LepRb neurons and their projections. KO = knock out; GalR1 = galanin receptor 1; LHA = lateral hypothalamic area; OX1 and OX2 = orexin receptor 1 and 2.
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fig6: Increased activation of orexin neurons in KO mice. A–B. Immunohistochemical staining for cFos (red) and orexin (green). The fornix (fx) is shown as a landmark for the location within the LHA. C. Percentage of orexin neurons that co-express cFos, in comparison to the total number of cFos/orexin neurons (D.) and total number of orexin neurons (E.). F. Quantification of LHA orexin mRNA and its receptors OX1 and OX2 (n = 10–13; *pt-test < 0.02). G. Immunohistochemical staining for orexin (red) and GalR1 (green). H. Schematic summary of distinct LHA LepRb neurons and their projections. KO = knock out; GalR1 = galanin receptor 1; LHA = lateral hypothalamic area; OX1 and OX2 = orexin receptor 1 and 2.
Mentions: LHA Gal and GalR1 expression was decreased in KO mice (Figure 2A, B) and GAL acts via GalR1 to potently inhibit neuronal excitation in many neuronal systems, including the hypothalamus [4,19,20]. We hypothesized that GAL may mediate the inhibitory actions of leptin on orexin neurons. Therefore, we predicted an increased activation of orexin neurons in KO mice. We analyzed KO and WT brains for basal levels of cFos (as a surrogate for neuronal activation) in orexin neurons and indeed found increased cFos/orexin co-localization, which was most prominent in the rostral portion of orexin/hypocretin neurons (Figure 6A–E, n = 5, pANOVA < 0.003,*pHolm-Sidak < 0.05). This was due to an increased number of cFos/ox neurons (Figure 6D), while the total number of orexin neurons was unchanged between groups (Figure 6E). Enhanced cFos expression was restricted to the LHA, while other adjacent sites, e.g. the DMH, showed similar cFos expression (Figure S8). Further, orexin gene expression was similar in KO and WT mice (Figure 6F). However, the gene expression of LHA orexin receptor Ox2, but not Ox1, was significantly decreased (Figure 6F, *pt-test < 0.02), indicating that within the LHA Ox1 signaling would be preferentially enhanced. We further determined that orexin neurons were co-labeled with GalR1 (Figure 6G), demonstrating that orexin neurons have the molecular capability to respond to GAL (Figure 6H).

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.