Ghrelin is a potent orexigenic peptide hormone that acts through the growth hormone secretagogue receptor (GHSR), a G protein-coupled receptor highly expressed in the hypothalamus. In vitro studies have shown that GHSR displays a high constitutive activity, whose physiological relevance is uncertain. As GHSR gene expression in the hypothalamus is known to increase in fasting conditions, we tested the hypothesis that constitutive GHSR activity at the hypothalamic level drives the fasting-induced hyperphagia. We found that refed wild-type (WT) mice displayed a robust hyperphagia that continued for 5 days after refeeding and changed their food intake daily pattern. Fasted WT mice showed an increase in plasma ghrelin levels, as well as in GHSR expression levels and ghrelin binding sites in the hypothalamic arcuate nucleus. When fasting-refeeding responses were evaluated in ghrelin- or GHSR-deficient mice, only the latter displayed an ∼15% smaller hyperphagia, compared with WT mice. Finally, fasting-induced hyperphagia of WT mice was significantly smaller in mice centrally treated with the GHSR inverse agonist K-(D-1-Nal)-FwLL-NH2, compared with mice treated with vehicle, whereas it was unaffected in mice centrally treated with the GHSR antagonists D-Lys3-growth hormone-releasing peptide 6 or JMV2959. Taken together, genetic models and pharmacological results support the notion that constitutive GHSR activity modulates the magnitude of the compensatory hyperphagia triggered by fasting. Thus, the hypothalamic GHSR signaling system could affect the set point of daily food intake, independently of plasma ghrelin levels, in situations of negative energy balance.

Leptin resistance refers to states in which leptin fails to promote its anticipated effects, frequently coexisting with hyperleptinaemia. Leptin resistance is closely associated with obesity and also observed in physiological situations such as pregnancy and in seasonal animals. Leptin resensitisation refers to the reversion of leptin-resistant states and is associated with improvement in endocrine and metabolic disturbances commonly observed in obesity and a sustained decrease of plasma leptin levels, possibly below a critical threshold level. In obesity, leptin resensitisation can be achieved with treatments that reduce body adiposity and leptinaemia, or with some pharmacological compounds, while physiological leptin resistance reverts spontaneously. The restoration of leptin sensitivity could be a useful strategy to treat obesity, maintain weight loss and/or reduce the recidivism rate for weight regain after dieting. This review provides an update and discussion about reversion of leptin-resistant states and modulation of the molecular mechanisms involved in each situation.

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Objective The octanoylated peptide hormone ghrelin regulates appetite and glycaemic control. Des-acyl ghrelin abolishes some effects of ghrelin, but does not bind to ghrelin receptor. LEAP2 is a novel ligand for ghrelin receptor that blocks the effects of ghrelin. Some evidences show that plasma levels of these peptides are altered in adults with obesity, but their levels in childhood obesity remain poorly studied. Therefore, the objective of this study was to assess fasting plasma levels of ghrelin, des-acyl ghrelin and LEAP2 in children with normoweight, overweight/obesity and their association with different anthropometric and metabolic variables. Design A total of 42 females and 40 males, ages 3–12 years old were enrolled as a cross-sectional cohort. Results Plasma levels of des-acyl ghrelin and LEAP2 (but not ghrelin) were lower and ghrelin/des-acyl ghrelin ratio was higher in children with overweight/obesity. Des-acyl ghrelin negatively correlated with age, BMI z-score, insulin and HOMA index, and the correlations were stronger in children with overweight/obesity. LEAP2 levels negatively correlated with BMI z-score. No gender differences were found. Conclusions Our findings suggest that ghrelin tone is increased in childhood obesity, due to a decrease on plasma levels of des-acyl ghrelin and LEAP2, and that des-acyl ghrelin is associated to insulin resistance, particularly in children with overweight/obesity.