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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.


Altered nutrient reward in KO mice. Gene expression in WT and KO mice (n = 10–13) for LHA galanin (A., *pt-test < 0.01) and LHA galanin receptors (GalR1-3, B., *pt-test < 0.05). C. Cumulative Intralipid (IL) intake in KO and WT mice, 1 h/day access to 10% Intralipid over 10 days (n = 5; pANOVA < 0.001; *pHolm-Sidak < 0.05–0.001). D. Cumulative sucrose (S) and Intralipid intake KO and WT mice, 1 h/day access to a-choice of 10% Intralipid and 25% sucrose solutions (both 1 kcal/ml) over 10 days (n = 5–7; pANOVA < 0.0001; *pHolm-Sidak < 0.05–0.001). E. Total sucrose and Intralipid intake over 10 days in KO mice, while WT mice (n = 5–7, pANOVA < 0.001; * pHolm-Sidak < 0.01). F. Daily intake of sucrose and Intralipid during the first 4 days shows that sucrose preference is prevalent on day 1 in naïve KO mice (pANOVA < 0.05; *pHolm-Sidak < 0.02). WT = wildtype; KO = knock out, LHA = lateral hypothalamic area.
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fig2: Altered nutrient reward in KO mice. Gene expression in WT and KO mice (n = 10–13) for LHA galanin (A., *pt-test < 0.01) and LHA galanin receptors (GalR1-3, B., *pt-test < 0.05). C. Cumulative Intralipid (IL) intake in KO and WT mice, 1 h/day access to 10% Intralipid over 10 days (n = 5; pANOVA < 0.001; *pHolm-Sidak < 0.05–0.001). D. Cumulative sucrose (S) and Intralipid intake KO and WT mice, 1 h/day access to a-choice of 10% Intralipid and 25% sucrose solutions (both 1 kcal/ml) over 10 days (n = 5–7; pANOVA < 0.0001; *pHolm-Sidak < 0.05–0.001). E. Total sucrose and Intralipid intake over 10 days in KO mice, while WT mice (n = 5–7, pANOVA < 0.001; * pHolm-Sidak < 0.01). F. Daily intake of sucrose and Intralipid during the first 4 days shows that sucrose preference is prevalent on day 1 in naïve KO mice (pANOVA < 0.05; *pHolm-Sidak < 0.02). WT = wildtype; KO = knock out, LHA = lateral hypothalamic area.

Mentions: Earlier data indicated that leptin induced LHA Gal gene expression [40]. Consistent with this, KO mice showed a 60% decrease in LHA Gal gene expression (Figure 2A, pt-test < 0.01). Furthermore, GalR1 expression, was significantly decreased by 30% (Figure 2B, pt-test < 0.05), while GalR2 and GalR3 expression remained unchanged within the LHA (Figure 2B).


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)

Altered nutrient reward in KO mice. Gene expression in WT and KO mice (n = 10–13) for LHA galanin (A., *pt-test < 0.01) and LHA galanin receptors (GalR1-3, B., *pt-test < 0.05). C. Cumulative Intralipid (IL) intake in KO and WT mice, 1 h/day access to 10% Intralipid over 10 days (n = 5; pANOVA < 0.001; *pHolm-Sidak < 0.05–0.001). D. Cumulative sucrose (S) and Intralipid intake KO and WT mice, 1 h/day access to a-choice of 10% Intralipid and 25% sucrose solutions (both 1 kcal/ml) over 10 days (n = 5–7; pANOVA < 0.0001; *pHolm-Sidak < 0.05–0.001). E. Total sucrose and Intralipid intake over 10 days in KO mice, while WT mice (n = 5–7, pANOVA < 0.001; * pHolm-Sidak < 0.01). F. Daily intake of sucrose and Intralipid during the first 4 days shows that sucrose preference is prevalent on day 1 in naïve KO mice (pANOVA < 0.05; *pHolm-Sidak < 0.02). WT = wildtype; KO = knock out, LHA = lateral hypothalamic area.
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fig2: Altered nutrient reward in KO mice. Gene expression in WT and KO mice (n = 10–13) for LHA galanin (A., *pt-test < 0.01) and LHA galanin receptors (GalR1-3, B., *pt-test < 0.05). C. Cumulative Intralipid (IL) intake in KO and WT mice, 1 h/day access to 10% Intralipid over 10 days (n = 5; pANOVA < 0.001; *pHolm-Sidak < 0.05–0.001). D. Cumulative sucrose (S) and Intralipid intake KO and WT mice, 1 h/day access to a-choice of 10% Intralipid and 25% sucrose solutions (both 1 kcal/ml) over 10 days (n = 5–7; pANOVA < 0.0001; *pHolm-Sidak < 0.05–0.001). E. Total sucrose and Intralipid intake over 10 days in KO mice, while WT mice (n = 5–7, pANOVA < 0.001; * pHolm-Sidak < 0.01). F. Daily intake of sucrose and Intralipid during the first 4 days shows that sucrose preference is prevalent on day 1 in naïve KO mice (pANOVA < 0.05; *pHolm-Sidak < 0.02). WT = wildtype; KO = knock out, LHA = lateral hypothalamic area.
Mentions: Earlier data indicated that leptin induced LHA Gal gene expression [40]. Consistent with this, KO mice showed a 60% decrease in LHA Gal gene expression (Figure 2A, pt-test < 0.01). Furthermore, GalR1 expression, was significantly decreased by 30% (Figure 2B, pt-test < 0.05), while GalR2 and GalR3 expression remained unchanged within the LHA (Figure 2B).

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.