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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

Increased weight gain and late-onset obesity in KO mice. A. Schematic drawing for the generation of GalCre and KO mice. B–D. Verification of functional LepRb deletion with leptin induced pSTAT3 by immunohistochemistry in the LHA of WT (left) and KO mice (right) and cell counts for pSTAT3 positive nuclei in the LHA (C.) and NTS (D.) (n = 4–8, *pLHA < 0.01, *pNTS < 0.05). Bar size is 200 μm. E. Body weight in WT and KO mice (n = 8–11, *pt-test < 0.05). F. Body weight gain over 8 weeks. G. Increased body weight in aged KO and WT mice (n = 7, pt-test < 0.05). H. Cumulative food intake in WT and KO mice (n = 8–11). I. Metabolic rate in WT and KO mice (n = 8–11). J. Locomotor activity in WT and KO mice (n = 8–11). Gal = galanin; KO = knock out; LepRb = long form leptin receptor; LHA = lateral hypothalamic area; WT = wildtype; pSTAT3 = phosphorylated signal transducer and activator of transcription-3; NTS = nucleus of the solitary tract; fx = fornix.
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fig1: Increased weight gain and late-onset obesity in KO mice. A. Schematic drawing for the generation of GalCre and KO mice. B–D. Verification of functional LepRb deletion with leptin induced pSTAT3 by immunohistochemistry in the LHA of WT (left) and KO mice (right) and cell counts for pSTAT3 positive nuclei in the LHA (C.) and NTS (D.) (n = 4–8, *pLHA < 0.01, *pNTS < 0.05). Bar size is 200 μm. E. Body weight in WT and KO mice (n = 8–11, *pt-test < 0.05). F. Body weight gain over 8 weeks. G. Increased body weight in aged KO and WT mice (n = 7, pt-test < 0.05). H. Cumulative food intake in WT and KO mice (n = 8–11). I. Metabolic rate in WT and KO mice (n = 8–11). J. Locomotor activity in WT and KO mice (n = 8–11). Gal = galanin; KO = knock out; LepRb = long form leptin receptor; LHA = lateral hypothalamic area; WT = wildtype; pSTAT3 = phosphorylated signal transducer and activator of transcription-3; NTS = nucleus of the solitary tract; fx = fornix.

Mentions: We studied the physiological importance of leptin action in GAL neurons by generating mice with conditional LepRb deletion from GAL neurons (GAL-LepRbKO or KO mice, Figure 1A). Correct cre-expression in GalCre mice was validated in GalYFP reporter mice and compared with galanin mRNA expression from the Allen Brain Atlas (Figure S1) and immunohistochemical staining of galanin peptide (Figure S2). In earlier studies we used transgenic GaltgGFP mice to identify and characterize LHA GAL-LepRb neurons [40]. Thus, we further verified correct reporter gene expression (GFP or YFP) and distribution of GAL-LepRb neurons in GalYFP mice and Gal(-neo)YFP mice compared to GaltgGFP mice. Hypothalamic GalGFP neurons were similarly distributed in all mouse models and as described earlier GAL-LepRb neurons (neurons with GalGFP and leptin-induced phosphorylation of signal-transducer-and-activator-of-transcription-3 (pSTAT3)) were found in the LHA and the nucleus of the solitary tract (NTS; Figure S3A–C). The presence of the neo cassette had no effect on correct GAL-LepRb expression and all following experiments were conducted in GalYFP mice.


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 weight gain and late-onset obesity in KO mice. A. Schematic drawing for the generation of GalCre and KO mice. B–D. Verification of functional LepRb deletion with leptin induced pSTAT3 by immunohistochemistry in the LHA of WT (left) and KO mice (right) and cell counts for pSTAT3 positive nuclei in the LHA (C.) and NTS (D.) (n = 4–8, *pLHA < 0.01, *pNTS < 0.05). Bar size is 200 μm. E. Body weight in WT and KO mice (n = 8–11, *pt-test < 0.05). F. Body weight gain over 8 weeks. G. Increased body weight in aged KO and WT mice (n = 7, pt-test < 0.05). H. Cumulative food intake in WT and KO mice (n = 8–11). I. Metabolic rate in WT and KO mice (n = 8–11). J. Locomotor activity in WT and KO mice (n = 8–11). Gal = galanin; KO = knock out; LepRb = long form leptin receptor; LHA = lateral hypothalamic area; WT = wildtype; pSTAT3 = phosphorylated signal transducer and activator of transcription-3; NTS = nucleus of the solitary tract; fx = fornix.
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fig1: Increased weight gain and late-onset obesity in KO mice. A. Schematic drawing for the generation of GalCre and KO mice. B–D. Verification of functional LepRb deletion with leptin induced pSTAT3 by immunohistochemistry in the LHA of WT (left) and KO mice (right) and cell counts for pSTAT3 positive nuclei in the LHA (C.) and NTS (D.) (n = 4–8, *pLHA < 0.01, *pNTS < 0.05). Bar size is 200 μm. E. Body weight in WT and KO mice (n = 8–11, *pt-test < 0.05). F. Body weight gain over 8 weeks. G. Increased body weight in aged KO and WT mice (n = 7, pt-test < 0.05). H. Cumulative food intake in WT and KO mice (n = 8–11). I. Metabolic rate in WT and KO mice (n = 8–11). J. Locomotor activity in WT and KO mice (n = 8–11). Gal = galanin; KO = knock out; LepRb = long form leptin receptor; LHA = lateral hypothalamic area; WT = wildtype; pSTAT3 = phosphorylated signal transducer and activator of transcription-3; NTS = nucleus of the solitary tract; fx = fornix.
Mentions: We studied the physiological importance of leptin action in GAL neurons by generating mice with conditional LepRb deletion from GAL neurons (GAL-LepRbKO or KO mice, Figure 1A). Correct cre-expression in GalCre mice was validated in GalYFP reporter mice and compared with galanin mRNA expression from the Allen Brain Atlas (Figure S1) and immunohistochemical staining of galanin peptide (Figure S2). In earlier studies we used transgenic GaltgGFP mice to identify and characterize LHA GAL-LepRb neurons [40]. Thus, we further verified correct reporter gene expression (GFP or YFP) and distribution of GAL-LepRb neurons in GalYFP mice and Gal(-neo)YFP mice compared to GaltgGFP mice. Hypothalamic GalGFP neurons were similarly distributed in all mouse models and as described earlier GAL-LepRb neurons (neurons with GalGFP and leptin-induced phosphorylation of signal-transducer-and-activator-of-transcription-3 (pSTAT3)) were found in the LHA and the nucleus of the solitary tract (NTS; Figure S3A–C). The presence of the neo cassette had no effect on correct GAL-LepRb expression and all following experiments were conducted in GalYFP mice.

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