Constitutive GHSR activity in the brain, not plasma ghrelin, drives high-fat binge eating in mice.
Background
The growth hormone secretagogue receptor (GHSR) is a key player in appetite and food-related behaviors, including binge eating. It is activated by the hormone ghrelin, but also exhibits significant ligand-independent, or constitutive, activity. Another endogenous ligand, liver-expressed antimicrobial peptide 2 (LEAP2), can block both ghrelin-evoked and constitutive GHSR signaling. Previous research showed that GHSR-deficient mice have a reduced tendency for binge-like high-fat intake. However, the specific contribution of the receptor's constitutive (ligand-independent) signaling pathway to this behavior, distinct from the influence of circulating ghrelin and LEAP2, remained unclear. This study aims to isolate and understand the role of this baseline receptor activity in driving high-fat binge eating.
Study Design
This study used a 4-day binge-like eating protocol in mice. The model involved providing daily, time-limited access to a high-fat (HF) diet to induce binge eating behavior. Researchers measured plasma levels of ghrelin and LEAP2. They then performed systemic and central (brain) administrations of various compounds to probe the GHSR pathway. Interventions included the agonist ghrelin, the antagonist/inverse agonist LEAP2, the ghrelin-evoked activity blocker [D-Lys3]-GHRP-6, another blocker JMV2959, and the constitutive activity blocker K-(D-1-Nal)-FwLL-NH2. The primary endpoint was the change in high-fat food intake during the binge sessions.
Results
The 4-day binge-like eating protocol did not alter plasma levels of either ghrelin or LEAP2 in the mice. Systemic administration of ghrelin or LEAP2 also failed to change high-fat food intake under these experimental conditions. Critically, central administration of compounds that block ghrelin-evoked GHSR activity, specifically [D-Lys3]-GHRP-6 and JMV2959, did not modify binge-like high-fat intake. In stark contrast, central administration of compounds that block the constitutive, ligand-independent activity of GHSR produced a significant effect.
Central administration of LEAP2 or K-(D-1-Nal)-FwLL-NH2, both of which reduce constitutive
GHSRactivity, successfully reduced binge-like high-fat food intake.
These results collectively indicate that it is the baseline, constitutive signaling of GHSR within the brain, rather than fluctuations in peripheral ghrelin or LEAP2, that drives this specific binge-eating behavior.
Key Findings
- Central administration of the ghrelin-evoked GHSR activity blocker [D-Lys3]-GHRP-6 did not modify binge-like high-fat intake.
- Central administration of LEAP2, a blocker of constitutive GHSR activity, reduced binge-like high-fat intake.
- Central administration of another constitutive GHSR activity blocker, K-(D-1-Nal)-FwLL-NH2, also reduced binge-like high-fat intake.
- Plasma levels of ghrelin and LEAP2 were not modified by a 4-day binge-like eating protocol in mice.
- Systemic administration of ghrelin or LEAP2 did not alter high-fat intake in this model.
Why It Matters
This research reframes the therapeutic approach to binge eating by shifting focus from blocking circulating hunger hormones like ghrelin to modulating the intrinsic activity of the GHSR in the brain. For those exploring GHSR modulators, it suggests that compounds acting as inverse agonists (which reduce constitutive activity) may be more effective for curbing high-fat binge urges than simple antagonists that only block ghrelin's effects. Targeting the brain's baseline GHSR activity could be a more direct and effective strategy for managing binge eating disorders. This is an early-stage animal study, so clinical translation is distant. However, it provides a crucial mechanistic insight that could guide the development of new classes of drugs designed to specifically dampen this receptor's ligand-independent signaling for appetite control.
