Lean mean fat reducing "ghrelin" machine: Hypothalamic ghrelin and ghrelin receptors as therapeutic targets in obesity

Obesity has reached epidemic proportions not only in Western societies but also in the developing world. Current pharmacological treatments for obesity are either lacking in efficacy and/or are burdened with adverse side effects. Thus, novel strategies are required. A better understanding of the intricate molecular pathways controlling energy homeostasis may lead to novel therapeutic intervention. The circulating hormone, ghrelin represents a major target in the molecular signalling regulating food intake, appetite and energy expenditure and its circulating levels often display aberrant signalling in obesity. Ghrelin exerts its central orexigenic action mainly in the hypothalamus and in particular in the arcuate nucleus via activation of specific G-protein coupled receptors (GHS-R). In this review we describe current pharmacological models of how ghrelin regulates food intake and how manipulating ghrelin signalling may give novel insight into developing better and more selective anti-obesity drugs. Accumulating data suggests multiple ghrelin variants and additional receptors exist to play a role in energy metabolism and these may well play an important role in obesity. In addition, the recent findings of hypothalamic GHS-R crosstalk and heterodimerisation may add to the understanding of the complexity of bodyweight regulation.