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 3

Inhibition of GHSR-expressing MBH neurons attenuates food intake after HIIE.

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Inhibition of GHSR-expressing MBH neurons attenuates food intake after H...
(A) Schematic of coronal brain section demonstrates the sites of injection of AAV-hSyn-DIO-hM4D(Gi)-mCherry virus (hM4Di) within the MBH of Ghsr-IRES-Cre mice. (B) Schematic of the experimental design. (C–H) Representative coronal brain sections from Ghsr-IRES-Cre mice injected with the virus, demonstrating Cre-dependent mCherry expression in the MBH (red) or the lack thereof. DAPI (blue) is used as counterstaining. Approximate distances of each coronal section from bregma (“B”) are indicated in the lower left corner of each panel. (C–E) The top row displays brain sections from a representative mouse classified as a “hit” as a result of a correctly targeted MBH. (F–H) The bottom row displays brain sections from a representative mouse classified as a “miss” as a result of incorrect targeting of the virus. Scale bar = 100 μm in C–H. (I–L) Effects of administration of CNO (0.3 mg/kg BW, i.p.) versus saline in “hits” on (I) food intake, (J) blood glucose, (K) blood lactate, and (L) and body weight. (M–P) Effects of administration of CNO (0.3 mg/kg BW, i.p.) versus saline in “misses” on (M) food intake, (N) blood glucose, (O) blood lactate, and (P) and body weight. n = 16 “hits” and n = 11 “misses.” (I and M) Repeated measures 2-way ANOVA followed by Holm-Šidák post hoc multiple comparisons test. (J–L and N–P) Paired Student’s t test (2 tailed). *P < 0.05.