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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #367645
Title: Ghrelin receptor in agouti-related peptide neurones regulates metabolic adaptation to calorie restriction

Author
item WU, CHIA-SHAN - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item BONGMBA, ODELIA - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item LEE, JONG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item TUCHAAI, ELLIE - WEST TEXAS A & M UNIVERSITY
item ZHOU, YU - QINGDAO UNIVERSITY
item LI, DE-PEI - UNIVERSITY OF MISSOURI
item XUE, BINGZHONG - GEORGIA STATE UNIVERSITY
item CHEN, ZHENG - UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER
item SUN, YUXIANG - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)

Submitted to: Journal of Neuroendocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/25/2019
Publication Date: 7/22/2019
Citation: Wu, C., Bongmba, O.Y., Lee, J.H., Tuchaai, E., Zhou, Y., Li, D., Xue, B., Chen, Z., Sun, Y. 2019. Ghrelin receptor in agouti-related peptide neurones regulates metabolic adaptation to calorie restriction. Journal of Neuroendocrinology. e12763. https://doi.org/10.1111/jne.12763.
DOI: https://doi.org/10.1111/jne.12763

Interpretive Summary: Hormone ghrelin signals the brain to increase food intake and promote obesity. Ample evidences reveal that ghrelin has important role in energy surplus state obesity, but its role in energy deficit state such as calorie restriction (CR) is less clear. Ghrelin functions are mediated through it receptor, named GHS-R). In the present study, we generated a mouse model with GHS-R delated in specific region of the brain. To investigate the role of GHS-R in CR, we subjected the mice to a mild 40% CR. The CR-fed mice exhibited reductions in body weight, body fat and blood glucose, but increased physical activity. This study supports that ghrelin signaling is also important in adaptation of energy deficiency, which may have important implications in weight loss and obesity control.

Technical Abstract: Ghrelin is a gut hormone that signals to the hypothalamus to stimulate growth hormone release, increase food intake and promote fat deposition. The ghrelin receptor, also known as growth hormone secretagogue receptor (GHS-R), is highly expressed in the brain, with the highest expression in agouti-related peptide (AgRP) neurones in the hypothalamus. Compelling evidence indicates that ghrelin serves as a survival hormone with respect to maintaining blood glucose and body weight during nutritional deficiencies. Recent studies have demonstrated that AgRP neurones are involved in metabolic and behavioural adaptation to an energy deficit to improve survival. In the present study, we used a neuronal subtype-specific GHS-R knockout mouse (AgRP-Cre;Ghsrf/f ) to investigate the role of GHS-R in hypothalamic AgRP neurones in metabolic and behavioural adaptation to hypocaloric restricted feeding. We subjected the mice to a restricted feeding regimen of 40% mild calorie restriction (CR), with one-quarter of food allotment given in the beginning of the light cycle and three-quarters given at the beginning of the dark cycle, to mimic normal mouse intake pattern. The CR-fed AgRP-Cre;Ghsrf/f mice exhibited reductions in body weight, fat mass and blood glucose. Metabolic profiling of these CR-fed AgRP-Cre;Ghsrf/f mice showed a trend toward reduced basal metabolic rate, significantly reduced core body temperature and a decreased expression of thermogenic genes in brown adipose tissue. This suggests a metabolic reset to a lower threshold. Significantly increased physical activity, a trend toward increased food anticipatory behaviour and altered fuel preferences were also observed in these mice. In addition, these CR-fed AgRP-Cre;Ghsrf/f mice exhibited a decreased counter-regulatory response, showing impaired hepatic glucose production. Lastly, hypothalamic gene expression in AgRP-Cre;Ghsrf/f mice revealed increased AgRP expression and a decreased expression of genes in ß-oxidation pathways. In summary, our data suggest that GHS-R in AgRP neurones is a key component of the neurocircuitry involved in metabolic adaptation to calorie restriction.