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Division of Endocrinology, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285
Address all correspondence and requests for reprints to: Mark L. Heiman, Lilly Corporate Center, DC 0545, Eli Lilly and Company, Indianapolis, Indiana 46285. E-mail: Heiman_Mark_L{at}lilly.com.
A spontaneous mutation of the obese (ob) gene presented an obese mouse (ob/ob) phenotype that served as the impetus for cloning that gene and predicting its secreted protein sequence (1). That hormone, later named leptin, is primarily produced by adipose tissue and secreted into blood in proportion to adipose tissue mass (1, 2), except in rare cases of leptin deficiency (3). Leptin signals via a class 1 cytokine receptor that is mapped to various regions of the brain (4). It is suggested by many that leptin provides signals of the level of fuel supply available to the hypothalamic energy homeostatic circuitry systems, thereby regulating energy intake and expenditure, reproduction, and immune system functions in rodents and man (5, 6, 7). However, the precise neurophysiological pathways that leptin uses to regulate these diverse biological functions remain largely unknown.
One area that is best studied is leptin regulation of energy intake, body weight, and body composition. Leptin replacement in the ob/ob mouse induces a maximal hypophagia within 1 wk that is sustained throughout replacement therapy (5). Furthermore, such treatment induces a continual loss in body weight despite no further decrease in caloric intake. The same dose administered to a wild-type mouse also reduces food intake and body weight for 1 wk, but then food intake returns to that of ad libitum vehicle-treated mice, whereas body weight loss remains constantly reduced (5). One of the reasons that chronic administration of leptin to ob/ob, or C57BL/6J, mice either continues to stimulate weight loss or maintains weight loss when the rate of food intake is either reduced or returns to that of vehicle-treated mice, respectively, is that leptin also activates the sympathetic nervous system (SNS), resulting in increased thermogenesis and energy expenditure.
Galanin is a 29- to 30-amino-acid peptide that exhibits widespread distribution in the central nervous system. Receptors for galanin are of the G protein-coupled class, forming three distinct subtypes, GalR1, GalR2, and GalR3, that share an overlapping yet distinct distribution. Galanin-expressing neurons and galanin receptors are anatomically positioned in the hypothalamic circuitry to influence energy balance (reviewed in Ref. 8). Indeed, hypothalamic galanin neurons express leptin receptors. Central administration of galanin to experimental animals stimulates food intake (9), suggesting counterregulatory actions on energy balance to that of leptin. Other studies suggest that galanin preferentially increases consumption of dietary fat (10), although increases in mixed macronutrient diets also occur (11). Although these data indicate that galanin regulates acute energy balance, other findings argue against galanin regulation of long-term energy balance. Repeated administration of galanin does not produce sustained hyperphagia or significant changes in body weight (12). Moreover, transgenic mice that do not express galanin (13), or that overexpress galanin (14), do not display a lean or obese phenotype. In addition, GalR1 knockout mice do not display any alteration in body weight or composition, although anxiety (15), hyperalgesia (16), and seizures (17) are reported. Therefore, the role of leptin-responsive galanin neurons in the long-term regulation of energy balance remains equivocal.
Recently, a 60-amino-acid peptide structurally related to galanin, galanin-like peptide (GALP), was isolated from porcine hypothalamus (18). Although galanin exhibits similar potency at GalR1 and GalR2 receptors, GALP has approximately 180 times higher agonist potency for the GalR2 receptor when compared with GalR1. Interestingly, GalR2 expression is reported in the CNS and in the periphery (reviewed in Ref. 8), offering speculation as to potential peripheral sites of GALP activity or for additional hypothalamic GALP receptors. Similar to proopiomelanocortin (POMC) and unlike galanin, GALP expression appears to be negatively regulated by fasting and in the leptin-deficient ob/ob mouse, which can be rescued with leptin treatment (19, 20). Indeed, GALP neurons express the leptin receptor, and neuronal expression of GALP is stimulated by leptin (reviewed in Ref. 8). Consistent with leptin-like actions, central GALP administration appears to reduce energy intake and increase energy expenditure (21, 22). Additionally, intracerebroventricular administration of GALP stimulates LH-releasing hormone and LH secretion in rodents (22, 23), suggesting that GALP, like leptin, may serve to relay energy reserve information to the reproductive axis. Thus, the role of GALP in regulating energy balance and reproduction appears distinct from galanin and may be a component of the leptin-stimulated neuronal circuitry regulating food intake and reproduction.
Experiments designed and performed by Hansen et al. (published in this issue; see Ref. 24) sufficiently tested the hypothesis that GALP neurons relay information obtained from changes in circulating leptin levels to hypothalamic mechanisms regulating food intake and energy expenditure. The group used ob/ob mice to eliminate such signaling and administered GALP centrally. They provide data obtained from chronic GALP administration that remarkably resembles outcomes resulting from leptin replacement therapy for ob/ob mice. Hansen, Krasnow, and colleagues demonstrate that GALP reduces caloric intake and body weight during the first week of treatment. Moreover, like the response of wild-type mice after the initial treatment week, anorexia wanes and food intake returns to that of a vehicle group, whereas weight loss is maintained. Therefore, this group investigated whether central administration of GALP would activate the SNS. They provide data describing up-regulation of uncoupling protein-I mRNA as well as uncoupling protein-I protein levels in brown adipose tissue. Unlike exogenous peripheral administration of leptin that stimulates POMC/cocaine- and amphetamine-regulated transcript neurons, centrally applied GALP reduced the number of neurons expressing POMC mRNA. This may be a consequence of leptin-independent compensatory mechanisms responding to hypophagia, increased thermogenesis, and (or) weight loss that undoubtedly will be investigated further.
The continuum of pioneering data from Robert Steiner’s laboroatory, studying both galanin and GALP neuroendocrinology, is paramount to understanding links between energy stores and hypothalamic mechanisms regulating energy balance and reproduction. The work of Hansen, Krasnov, and colleagues (24) is a very important new installment because it suggests that GALP provides a link between leptin and the SNS participating in the regulation of energy expenditure and, thus, is another component of the energy homeostatic circuitry. We now await this group’s or others’ efforts to engineer a GALP, GalR2, and GalR3 knockout mice to determine how much of the ob/ob mouse phenotype will be recapitulated. We also look forward to learning whether GALP signals within the hypothalamus solely via one of the known galanin receptors or through a yet-undefined GALP receptor.
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Received August 21, 2003.
Accepted for publication August 22, 2003.
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  J. L. Trevaskis and A. A. Butler Double Leptin and Melanocortin-4 Receptor Gene Mutations Have an Additive Effect on Fat Mass and Are Associated with Reduced Effects of Leptin on Weight Loss and Food Intake Endocrinology, October 1, 2005; 146(10): 4257 - 4265. [Abstract] [Full Text] [PDF]
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