Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore, MD, USA.
Center on Compulsive Behaviors, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
Commun Biol. 2024 May 25;7(1):632. doi: 10.1038/s42003-024-06303-5.
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.
胃来源的激素 ghrelin 调节基本的生理功能。ghrelin 受体 (GHSR) 具有配体非依赖性作用；因此，GHSR 基因缺失可能是研究该系统在摄食行为和饮食诱导肥胖 (DIO) 中的作用的合理方法。在这里，我们研究了长期（12 个月）高脂肪 (HFD) 与常规饮食对全球 GHSR-KO 和野生型 (WT) Wistar 雄性和雌性大鼠肥胖相关指标的影响。我们的主要发现是，GHSR 基因缺失可预防 DIO，并减少雄性大鼠在 HFD 期间的食物摄入量，但对雌性大鼠则没有影响。GHSR 基因缺失可增加雄性大鼠的产热和大脑葡萄糖摄取，并以性别特异性的方式改变 HFD 对大脑葡萄糖代谢的影响，这通过小动物正电子发射断层扫描进行评估。我们使用 RNA 测序表明，GHSR-KO 大鼠棕色脂肪组织中负责脂肪氧化的基因表达上调。新型 GHSR 反向激动剂 PF-5190457 的中枢给药可减弱 ghrelin 诱导的食物摄入，但仅在雄性小鼠中，而不在雌性小鼠中。反向激动剂可减少两性的 HFD 诱导的暴食样进食。我们的结果支持 GHSR 作为肥胖症新的药物治疗的有前途的靶点。
