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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 project to the LC, but not the VTA. A. Overview of LHA Ad-iZ/EGFPf injections into the LHA of LepRbCre mice, the spread of infected neurons is shown in red (β-gal expression), virally infected neurons with cre-recombination are shown in green (representing LepRb neurons). B/C. EGFPf projections from LHA LepRb-cre neuron to the VTA (B.) or LC (C.). D. Overview of LHA Ad-iZ/EGFPf injections into the LHA of GalCre mice, the spread of infected neurons is shown in red (β-gal expression), virally infected neurons with cre-recombination are shown in green (representing GAL neurons). E./F. LHA GAL neurons do not project into the VTA (E.), but strongly innervate the LC (F.). G. Injection of Ad-iN/WED into the LHA of LepRbCre mice (n = 7) with infected first order neurons in yellow, co-localization of DsRed (red) and wheat germ agglutinin (WGA, green) and second order neurons in green.(WGA). H./I. Second order neurons with single WGA labeling (green) in the VTA (H.) and LC (I). J–L. Injection of Ad-iN/WED into the LHA of GalCre mice (n = 6) shows local first order neurons (yellow) and second order neurons (green) in the LHA (J.) and second order neurons in the LC (L.), but not the VTA (K.). Areas of interest are highlighted with white boxes. Gal = galanin; LepRb = long form leptin receptor; LC = locus coeruleus; VTA = ventral tegmental area; LHA = lateral hypothalamic area; Ad = adenovirus; EGFPf = farnesylated enhanced green fluorescent protein; β-gal = β-galactosidase.
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fig4: GAL-LepRb neurons project to the LC, but not the VTA. A. Overview of LHA Ad-iZ/EGFPf injections into the LHA of LepRbCre mice, the spread of infected neurons is shown in red (β-gal expression), virally infected neurons with cre-recombination are shown in green (representing LepRb neurons). B/C. EGFPf projections from LHA LepRb-cre neuron to the VTA (B.) or LC (C.). D. Overview of LHA Ad-iZ/EGFPf injections into the LHA of GalCre mice, the spread of infected neurons is shown in red (β-gal expression), virally infected neurons with cre-recombination are shown in green (representing GAL neurons). E./F. LHA GAL neurons do not project into the VTA (E.), but strongly innervate the LC (F.). G. Injection of Ad-iN/WED into the LHA of LepRbCre mice (n = 7) with infected first order neurons in yellow, co-localization of DsRed (red) and wheat germ agglutinin (WGA, green) and second order neurons in green.(WGA). H./I. Second order neurons with single WGA labeling (green) in the VTA (H.) and LC (I). J–L. Injection of Ad-iN/WED into the LHA of GalCre mice (n = 6) shows local first order neurons (yellow) and second order neurons (green) in the LHA (J.) and second order neurons in the LC (L.), but not the VTA (K.). Areas of interest are highlighted with white boxes. Gal = galanin; LepRb = long form leptin receptor; LC = locus coeruleus; VTA = ventral tegmental area; LHA = lateral hypothalamic area; Ad = adenovirus; EGFPf = farnesylated enhanced green fluorescent protein; β-gal = β-galactosidase.

Mentions: Projections of LepRb and GAL neurons were identified by injecting the adenoviral construct Ad-iZ/EGFPf [41] into the LHA of LepRbCre (n = 4) or GalCre mice (n = 3), which resulted in a cre-specific expression of a farnesylated enhanced green fluorescent protein (EGFPf) and a non-cre dependent β-galactosidase expression from all adenovirus infected cells (Figure 4A–F). The farnesylation anchors EGFPF to the cell membrane and enhances the visualization of thin axonal processes; the β-galactosidase expression is used to track the spread of overall virally infected cells. Correctly targeted Ad-iZ/EGFPf injection into the LHA of LepRbCre (Figure 4A) or GalCre mice (Figure 4D) was verified by confined EGFPf (green) and β-galactosidase (red) expression to LHA. EGFPf positive processes from LHA LepRb and GAL neurons were found locally within the LHA (Figure 4A, D, respectively). We further confirmed that LHA LepRb neurons, strongly innervate the VTA (Figure 4B, H) [41,42], but LHA GAL neurons rarely projected to the VTA (Figure 4E, K), suggesting that GAL-LepRb neurons do not innervate the VTA. Instead, both – LHA LepRb and GAL neurons – strongly innervated the locus coeruleus (LC) (Figure 4C, F, respectively), a site that had not yet been associated with leptin function.


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 project to the LC, but not the VTA. A. Overview of LHA Ad-iZ/EGFPf injections into the LHA of LepRbCre mice, the spread of infected neurons is shown in red (β-gal expression), virally infected neurons with cre-recombination are shown in green (representing LepRb neurons). B/C. EGFPf projections from LHA LepRb-cre neuron to the VTA (B.) or LC (C.). D. Overview of LHA Ad-iZ/EGFPf injections into the LHA of GalCre mice, the spread of infected neurons is shown in red (β-gal expression), virally infected neurons with cre-recombination are shown in green (representing GAL neurons). E./F. LHA GAL neurons do not project into the VTA (E.), but strongly innervate the LC (F.). G. Injection of Ad-iN/WED into the LHA of LepRbCre mice (n = 7) with infected first order neurons in yellow, co-localization of DsRed (red) and wheat germ agglutinin (WGA, green) and second order neurons in green.(WGA). H./I. Second order neurons with single WGA labeling (green) in the VTA (H.) and LC (I). J–L. Injection of Ad-iN/WED into the LHA of GalCre mice (n = 6) shows local first order neurons (yellow) and second order neurons (green) in the LHA (J.) and second order neurons in the LC (L.), but not the VTA (K.). Areas of interest are highlighted with white boxes. Gal = galanin; LepRb = long form leptin receptor; LC = locus coeruleus; VTA = ventral tegmental area; LHA = lateral hypothalamic area; Ad = adenovirus; EGFPf = farnesylated enhanced green fluorescent protein; β-gal = β-galactosidase.
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fig4: GAL-LepRb neurons project to the LC, but not the VTA. A. Overview of LHA Ad-iZ/EGFPf injections into the LHA of LepRbCre mice, the spread of infected neurons is shown in red (β-gal expression), virally infected neurons with cre-recombination are shown in green (representing LepRb neurons). B/C. EGFPf projections from LHA LepRb-cre neuron to the VTA (B.) or LC (C.). D. Overview of LHA Ad-iZ/EGFPf injections into the LHA of GalCre mice, the spread of infected neurons is shown in red (β-gal expression), virally infected neurons with cre-recombination are shown in green (representing GAL neurons). E./F. LHA GAL neurons do not project into the VTA (E.), but strongly innervate the LC (F.). G. Injection of Ad-iN/WED into the LHA of LepRbCre mice (n = 7) with infected first order neurons in yellow, co-localization of DsRed (red) and wheat germ agglutinin (WGA, green) and second order neurons in green.(WGA). H./I. Second order neurons with single WGA labeling (green) in the VTA (H.) and LC (I). J–L. Injection of Ad-iN/WED into the LHA of GalCre mice (n = 6) shows local first order neurons (yellow) and second order neurons (green) in the LHA (J.) and second order neurons in the LC (L.), but not the VTA (K.). Areas of interest are highlighted with white boxes. Gal = galanin; LepRb = long form leptin receptor; LC = locus coeruleus; VTA = ventral tegmental area; LHA = lateral hypothalamic area; Ad = adenovirus; EGFPf = farnesylated enhanced green fluorescent protein; β-gal = β-galactosidase.
Mentions: Projections of LepRb and GAL neurons were identified by injecting the adenoviral construct Ad-iZ/EGFPf [41] into the LHA of LepRbCre (n = 4) or GalCre mice (n = 3), which resulted in a cre-specific expression of a farnesylated enhanced green fluorescent protein (EGFPf) and a non-cre dependent β-galactosidase expression from all adenovirus infected cells (Figure 4A–F). The farnesylation anchors EGFPF to the cell membrane and enhances the visualization of thin axonal processes; the β-galactosidase expression is used to track the spread of overall virally infected cells. Correctly targeted Ad-iZ/EGFPf injection into the LHA of LepRbCre (Figure 4A) or GalCre mice (Figure 4D) was verified by confined EGFPf (green) and β-galactosidase (red) expression to LHA. EGFPf positive processes from LHA LepRb and GAL neurons were found locally within the LHA (Figure 4A, D, respectively). We further confirmed that LHA LepRb neurons, strongly innervate the VTA (Figure 4B, H) [41,42], but LHA GAL neurons rarely projected to the VTA (Figure 4E, K), suggesting that GAL-LepRb neurons do not innervate the VTA. Instead, both – LHA LepRb and GAL neurons – strongly innervated the locus coeruleus (LC) (Figure 4C, F, respectively), a site that had not yet been associated with leptin function.

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