Ghrelin-responsive mediobasal hypothalamic neurons mediate exercise-associated food intake and exercise endurance

Omprakash Singh; Sean B. Ogden; Salil Varshney; Kripa Shankar; Deepali Gupta; Subhojit Paul; Sherri Osborne-Lawrence; Corine P. Richard; Nathan P. Metzger; Connor Lawrence; Luis León-Mercado; Jeffrey M. Zigman

doi:10.1172/jci.insight.172549

Ghrelin-responsive mediobasal hypothalamic neurons mediate exercise-associated food intake and exercise endurance

Omprakash Singh,¹ Sean B. Ogden,¹ Salil Varshney,¹ Kripa Shankar,¹ Deepali Gupta,¹ Subhojit Paul,¹ Sherri Osborne-Lawrence,² Corine P. Richard,¹ Nathan P. Metzger,¹ Connor Lawrence,¹ Luis León-Mercado,¹ and Jeffrey M. Zigman¹

Published November 14, 2023 - More info

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Abstract

Previous studies have implicated the orexigenic hormone ghrelin as a mediator of exercise endurance and the feeding response post-exercise. Specifically, plasma ghrelin levels nearly double in mice when they are submitted to an hour-long bout of high-intensity interval exercise (HIIE) using treadmills. Also, GHSR (ghrelin receptor)-null mice exhibit decreased food intake following HIIE and a diminished running distance (time until exhaustion) during a longer, step-wise exercise endurance protocol. To investigate whether ghrelin-responsive mediobasal hypothalamus (MBH) neurons mediate these effects, we stereotaxically delivered the inhibitory DREADD virus AAV2-hSyn-DIO-hM4(Gi)-mCherry to the MBH of Ghsr-IRES-Cre mice, which express Cre-recombinase directed by the Ghsr promoter. We found that chemogenetic inhibition of GHSR-expressing MBH neurons [upon delivery of clozapine-N-oxide (CNO)] 1) suppressed food intake following HIIE by 31.3%, 2) reduced maximum running distance by 20.7%-22.7% and raised blood glucose and blood lactate levels by 18.4%-51.5% and 24.6%-39.2%, respectively, during an exercise endurance protocol, 3) reduced food intake following ghrelin administration by 57.2%, but 4) did not affect glucose tolerance. Further, HIIE increased MBH Ghsr expression. These results indicate that activation of ghrelin-responsive MBH neurons is required for the normal feeding response to HIIE and the usual amount of running exhibited during an exercise endurance protocol.

Ghrelin-responsive mediobasal hypothalamic neurons mediate exercise-associated food intake and exercise endurance

Omprakash Singh,¹ Sean B. Ogden,¹ Salil Varshney,¹ Kripa Shankar,¹ Deepali Gupta,¹ Subhojit Paul,¹ Sherri Osborne-Lawrence,² Corine P. Richard,¹ Nathan P. Metzger,¹ Connor Lawrence,¹ Luis León-Mercado,¹ and Jeffrey M. Zigman¹

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Ghrelin-responsive mediobasal hypothalamic neurons mediate exercise-associated food intake and exercise endurance

Omprakash Singh,1 Sean B. Ogden,1 Salil Varshney,1 Kripa Shankar,1 Deepali Gupta,1 Subhojit Paul,1 Sherri Osborne-Lawrence,2 Corine P. Richard,1 Nathan P. Metzger,1 Connor Lawrence,1 Luis León-Mercado,1 and Jeffrey M. Zigman1

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Omprakash Singh,¹ Sean B. Ogden,¹ Salil Varshney,¹ Kripa Shankar,¹ Deepali Gupta,¹ Subhojit Paul,¹ Sherri Osborne-Lawrence,² Corine P. Richard,¹ Nathan P. Metzger,¹ Connor Lawrence,¹ Luis León-Mercado,¹ and Jeffrey M. Zigman¹