Decreased ghrelin levels: the cause of obesity and weight regain?

Ghrelin is a circulating orexigenic hormone which is implicated in both the short-term control of food intake at single meals and in long-term body weight regulation. Due to the potent orexigenic action of this hormone, it would be expected that obese subjects would show elevated ghrelin levels that could contribute to pathogenesis of obesity. However, it was observed that ghrelin is downregulated in human obesity and fasting plasma ghrelin concentrations were negatively correlated with body weight, percentage body fat, BMI and fat mass, as well as with leptin and insulin [1]. This downregulation was proposed to represent a physiological adaptation to the positive energy balance associated with obesity [1]. In the same line of obesity, our research group recently found that baseline plasma ghrelin levels could explain the variability in body weight regain after an energy restriction treatment. Thus, after a weight reduction induced by an 8-week balanced hypocaloric diet, subjects who regained at least 10% of the lost weight 6 months later appeared to have lower fasting plasma ghrelin levels at all times during the study than those that maintained body weight. These finding was accompanied by higher fasting plasma leptin levels in the weight regain group compared with the maintained group of patients [2]. These counterintuitive findings of ghrelin and leptin suggest that weight regain may be associated with some central or peripheral resistance to both hormones, in the same way as obesity [2]. Indeed, a recent study demonstrated that obesity causes central ghrelin resistance in hypothalamic neuropeptide Y and agouti-related peptide circuits [3]. It was postulated that the hypothalamus senses excessive positive energy balance or calorie intake and responds by suppressing the neuroendocrine ghrelin axis by reducing the acylated and des-acylated forms of plasma ghrelin, suppressing the ghrelin and Goat mRNA in the stomach and the growth hormone secretagogue receptor mRNA levels in the hypothalamus of diet-induced obesity mice compared with controls [3]. These results, together with a previous study demonstrating that ghrelin increases UCP2, suggest that the primary role of ghrelin is to prevent starvation rather than promote obesity since UCP2 enhances peripheral fat oxidation and as a result prevents excessive fat deposition [4]. Besides being an important hormone that promotes food intake, ghrelin has potent lipogenic action [5] and preproghrelinderived peptides have a role in adipogenesis through an autocrine/paracrine mechanism [6]. However, these actions appear to be mediated mainly in the absence of UCP2. The acute actions of ghrelin on food intake require uncoupling protein UCP2 for a complete food intake response and chronic ghrelin treatment either via osmotic minipumps or daily intraperitoneal injections, which favor lipogenesis and induce more potentiated body weight gain in UCP2-knockout mice than in UCP2 wild-type mice [4]. Expert Rev. Endocrinol. Metab. 7(2), 127–129 (2012)