Ghrelin-responsive mediobasal hypothalamic neurons mediate exercise-associated food intake and exercise endurance
Omprakash Singh, … , Luis Leon Mercado, Jeffrey M. Zigman
Omprakash Singh, … , Luis Leon Mercado, Jeffrey M. Zigman
Published November 14, 2023
Citation Information: JCI Insight. 2023;8(24):e172549. https://doi.org/10.1172/jci.insight.172549.
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Research Article Metabolism Neuroscience

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

Abstract

Previous studies have implicated the orexigenic hormone ghrelin as a mediator of exercise endurance and the feeding response postexercise. Specifically, plasma ghrelin levels nearly double in mice when they are subjected to an hour-long bout of high-intensity interval exercise (HIIE) using treadmills. Also, growth hormone secretagogue receptor–null (GHSR-null) mice exhibit decreased food intake following HIIE and diminished running distance (time until exhaustion) during a longer, stepwise exercise endurance protocol. To investigate whether ghrelin-responsive mediobasal hypothalamus (MBH) neurons mediate these effects, we stereotaxically delivered the inhibitory designer receptor exclusively activated by designer drugs 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) 1) suppressed food intake following HIIE, 2) reduced maximum running distance and raised blood glucose and blood lactate levels during an exercise endurance protocol, 3) reduced food intake following ghrelin administration, and 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.

Authors

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 Leon Mercado, Jeffrey M. Zigman

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Figure 7

Inhibition of GHSR-expressing MBH neurons reduces food intake and MBH c-Fos induction in response to administered ghrelin.

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Inhibition of GHSR-expressing MBH neurons reduces food intake and MBH c-...
(A) Schematic of the experimental design. (B and C) Effects of administration of CNO (0.3 mg/kg BW, i.p.) in hM4Di-injected Ghsr-IRES-Cre “hits” versus “misses” on (B) food intake and (C) c-Fos induction within the ARC measured 2 hours following delivery of ghrelin (1 mg/kg BW s.c.). (D–G) Fluorescence images of coronal brain sections showing c-Fos immunoreactivity (green) and mCherry expression (red) in the MBH of a representative hM4Di-injected “hit” (D and E) and a representative hM4Di-injected “miss” (F and G) sacrificed 2 hours following ghrelin delivery. DAPI counterstaining is shown in blue. Scale bar in G = 50 μm and applies to panels D–G. Approximate distance of the coronal section from bregma (“B”) is indicated in the lower left corner of panels. n = 16 “hits” and n = 11 “misses” were used for food intake measurements. n = 5 “hits” and n = 5 “misses” were used for quantification of c-Fos induction. (B and C) Unpaired Student’s t test (2 tailed). **P < 0.01, ****P < 0.0001.