Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet

The Graphical Abstract for this study. Image copyright: Nature Communications Biology

Featured Paper of the Month – December 2024

Published in Nature Communications Biology by András H Lékó, Adriana Gregory-Flores and Lorenzo Leggio et al. of the NIDA IRP Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section.

Summary

The stomach-derived ‘hunger hormone’ ghrelin plays an important role in metabolism, reward, and food intake. Serum ghrelin levels fluctuate along with feeding states, increasing during fasting and decreasing during satiety. The orexigenic and obesity-promoting effects of ghrelin are mediated by the growth hormone secretagogue receptor (GHSR; the ghrelin receptor), which is localized widely in the body, including the central nervous system and adipose tissue. High-fat diets can induce weight gain and obesity in rodents and humans. Here, we investigated whether the deletion of the GHSR gene (GHSR-KO) in rats can prevent or attenuate weight gain caused by a high-fat diet. Our main findings were that the GHSR gene deletion protected against obesity and decreased food intake in male but not female rats. GHSR gene deletion increased thermogenesis and brain glucose uptake and metabolism in a sex-specific manner. Using a pharmacological approach, we found that the inverse agonist/competitive antagonist PF-5190457 attenuated ghrelin-induced food intake in male but not in female mice. Our results support GHSR as a promising target for new pharmacotherapies for obesity; the sexual dimorphism highlighted in this study needs to be considered during medication development.

Image copyright: Nature Communications Biology

Publication Information

Lékó, András H; Gregory-Flores, Adriana; Marchette, Renata C N; Gomez, Juan L; Vendruscolo, Janaina C M; Repunte-Canonigo, Vez; Choung, Vicky; Deschaine, Sara L; Whiting, Kimberly E; Jackson, Shelley N; Cornejo, Maria Paula; Perello, Mario; You, Zhi-Bing; Eckhaus, Michael; Rasineni, Karuna; Janda, Kim D; Zorman, Barry; Sumazin, Pavel; Koob, George F; Michaelides, Michael; Sanna, Pietro P; Vendruscolo, Leandro F; Leggio, Lorenzo

Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet Journal Article

In: Commun Biol, vol. 7, no. 1, pp. 632, 2024, ISSN: 2399-3642.

Abstract | Links

@article{pmid38796563,

title = {Genetic or pharmacological GHSR blockade has sexually dimorphic effects in rodents on a high-fat diet},

author = {András H Lékó and Adriana Gregory-Flores and Renata C N Marchette and Juan L Gomez and Janaina C M Vendruscolo and Vez Repunte-Canonigo and Vicky Choung and Sara L Deschaine and Kimberly E Whiting and Shelley N Jackson and Maria Paula Cornejo and Mario Perello and Zhi-Bing You and Michael Eckhaus and Karuna Rasineni and Kim D Janda and Barry Zorman and Pavel Sumazin and George F Koob and Michael Michaelides and Pietro P Sanna and Leandro F Vendruscolo and Lorenzo Leggio},

doi = {10.1038/s42003-024-06303-5},

issn = {2399-3642},

year  = {2024},

date = {2024-05-01},

urldate = {2024-05-01},

journal = {Commun Biol},

volume = {7},

number = {1},

pages = {632},

abstract = {The stomach-derived hormone ghrelin regulates essential physiological functions. The ghrelin receptor (GHSR) has ligand-independent actions; therefore, GHSR gene deletion may be a reasonable approach to investigate the role of this system in feeding behaviors and diet-induced obesity (DIO). Here, we investigate the effects of a long-term (12-month) high-fat (HFD) versus regular diet on obesity-related measures in global GHSR-KO and wild-type (WT) Wistar male and female rats. Our main findings are that the GHSR gene deletion protects against DIO and decreases food intake during HFD in male but not in female rats. GHSR gene deletion increases thermogenesis and brain glucose uptake in male rats and modifies the effects of HFD on brain glucose metabolism in a sex-specific manner, as assessed with small animal positron emission tomography. We use RNA-sequencing to show that GHSR-KO rats have upregulated expression of genes responsible for fat oxidation in brown adipose tissue. Central administration of a novel GHSR inverse agonist, PF-5190457, attenuates ghrelin-induced food intake, but only in male, not in female mice. HFD-induced binge-like eating is reduced by inverse agonism in both sexes. Our results support GHSR as a promising target for new pharmacotherapies for obesity.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}