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Ghrelin receptor in agouti‐related peptide neurones regulates metabolic adaptation to calorie restriction
Author(s) -
Wu ChiaShan,
Bongmba Odelia Y. N.,
Lee Jong Han,
Tuchaai Ellie,
Zhou Yu,
Li DePei,
Xue Bingzhong,
Chen Zheng,
Sun Yuxiang
Publication year - 2019
Publication title -
journal of neuroendocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.062
H-Index - 116
eISSN - 1365-2826
pISSN - 0953-8194
DOI - 10.1111/jne.12763
Subject(s) - ghrelin , endocrinology , medicine , orexigenic , biology , hypothalamus , calorie restriction , appetite , growth hormone secretagogue receptor , receptor , hormone , neuropeptide y receptor , neuropeptide
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 (Ag RP ) 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 Ag RP 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;Ghsr f/f ) to investigate the role of GHS ‐R in hypothalamic Ag RP 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;Ghsr f/f mice exhibited reductions in body weight, fat mass and blood glucose. Metabolic profiling of these CR ‐fed AgRP‐Cre;Ghsr f/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;Ghsr f/f mice exhibited a decreased counter‐regulatory response, showing impaired hepatic glucose production. Lastly, hypothalamic gene expression in AgRP‐Cre;Ghsr f/f mice revealed increased Ag RP expression and a decreased expression of genes in β‐oxidation pathways. In summary, our data suggest that GHS ‐R in Ag RP neurones is a key component of the neurocircuitry involved in metabolic adaptation to calorie restriction.