Ghrelin and energy balance: focus on current controversies

Ghrelin is an enteric peptide that is the only known circulating appetite stimulant. This feature of the hormone has garnered widespread attention, as reflected by more than 1000 scientific papers featuring ghrelin that have been published since the first reports of its orexigenic actions, approximately four years ago. In this review, we discuss data that support roles for ghrelin in the short-term regulation of pre-meal hunger and meal initiation, functioning as a unique orexigenic counterpart to short-acting gastrointestinal satiation factors, such as cholecystokinin (CCK). We also highlight evidence indicating that ghrelin satisfies recognized criteria to be viewed as a participant in long-term body-weight regulation--a potential anabolic counterpart to the traditional adiposity hormones, leptin and insulin. We then discuss the following controversial questions in ghrelin research and offer our opinions regarding these debates. (1) Is ghrelin synthesized within the brain? (2) How does ghrelin increase food intake? (3) Does des-acyl ghrelin have a physiologic function? (4) Are there receptors for ghrelin other than GHS-R1a? (5) Does ghrelin regulate insulin secretion? (6) Does ghrelin regulate gastrointestinal motility? (7) Can ghrelin or ghrelin-receptor agonists be used to treat wasting conditions? Finally, we offer a speculative model of ghrelin as a thrifty gene product that evolved to help animals consume and store fat well, thereby increasing their chances of survival during times of famine. We suggest that ghrelin is a "saginary" hormone, from the Latin, saginare, which means, "to fatten".