Interplay Between Galanin and Leptin in the Hypothalamic Control of Feeding via Corticotropin-Releasing Hormone and Neuropeptide Y

Abstract

Over long periods, feeding and metabolism are tightly regulated at the central level. The total amount of nutrients ingested is thought to result from a delicate balance between orexigenic and anorexigenic factors expressed and secreted by specialized hypothalamic neuronal populations. We have developed a system of perifused hypothalamic neurons to characterize the relationships existing between the orexigenic peptide galanin and two other physiological modulators of feeding: neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH). We demonstrated that galanin stimulates CRH and NPY secretion from hypothalamic neurons in a dose-dependent manner. Exposure to leptin for 24 h before galanin stimulation decreased NPY secretion by 30%, leaving the responsiveness of CRH neurons intact. These results suggest that CRH and NPY neurons participate to the intrahypothalamic signaling pathway of galanin, an observation that can explain the lower potency of galanin to stimulate food intake in vivo compared with NPY. The differential effects exerted by leptin on CRH and NPY suggest that there exists a subset of NPY neurons that are exquisitely sensitive to marked variations in leptin levels, and that the CRH neurons are less responsive to increases in leptin concentrations. Diabetes 50:2666 -2672, 2001 R ecent evidence suggests that the central nervous system plays a key role in controlling food intake and metabolic adaptations (1). A delicate interplay seems to exist between the activities of highly specialized neuronal subpopulations involved in the regulation of feeding and energy storage, or of satiety and energy expenditure. Overall, these regulations, operating at the level of the central nervous system, achieve the tight control of energy balance observed in mammals (2). The neurons involved are mainly located within the hypothalamus, where they serve as central integrators of peripheral metabolic signals. One important function of leptin (3) seems to be informing these neurons about levels of energy stored in the body (4). Changes in circulating leptin levels can therefore trigger an appropriate response of the central nervous system to modulate food intake and metabolism according to the total amount of body fat (5) as well as the variations of energy balance (6).However, the relations between the different hypothalamic neuronal subpopulations seem to be extremely complex (1). The systems involved are redundant, and thus they are most difficult to individualize in vivo. Neuropeptide Y (NPY) and galanin can both elicit strong feeding behavior when injected centrally (7-10) and are expressed in hypothalamic areas associated with feeding and metabolic regulations (10 -12). NPY is one of the most abundant peptides of the hypothalamus (11) and remains among the most potent orexigenic factors (13). In addition, it has also been implicated in the control of neuroendocrine adaptations to fasting or unfavorable metabolic conditions (14,15). Like NPY, galanin plays a physiologically important role in the regulation of ne...

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