Genetic or Pharmacological GHSR Blockade Has Sexually Dimorphic Effects in Rodents on a High-fat Diet

Overview

Journal Res Sq

Date 2023 Oct 27

PMID 37886546

Authors

Lorenzo Leggio

Andras Leko

Adriana Gregory-Flores

Renata Marchette

Juan Gomez

Janaina Vendruscolo

Vez Repunte-Canonigo

Vicky Chuong

Sara Deschaine

Kimberly Whiting

Shelley Jackson

Maria Cornejo

Mario Perello

Zhi-Bing You

Michael Eckhaus

Kim Janda

Barry Zorman

Pavel Sumazin

George Koob

Michael Michaelides

Pietro Paolo Sanna

Leandro Vendruscolo

Affiliations

Soon will be listed here.

Abstract

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

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