Neuropeptidergic Control of Feeding: Focus on the Galanin Family of Peptides

Abstract

Obesity/overweight are important health problems due to metabolic complications. Dysregulation of peptides exerting orexigenic/anorexigenic effects must be investigated in-depth to understand the mechanisms involved in feeding behaviour. One of the most important and studied orexigenic peptides is galanin (GAL). The aim of this review is to update the mechanisms of action and physiological roles played by the GAL family of peptides (GAL, GAL-like peptide, GAL message-associated peptide, alarin) in the control of food intake and to review the involvement of these peptides in metabolic diseases and food intake disorders in experimental animal models and humans. The interaction between GAL and NPY in feeding and energy metabolism, the relationships between GAL and other substances involved in food intake mechanisms, the potential pharmacological strategies to treat food intake disorders and obesity and the possible clinical applications will be mentioned and discussed. Some research lines are suggested to be developed in the future, such as studies focused on GAL receptor/neuropeptide Y Y₁ receptor interactions in hypothalamic and extra-hypothalamic nuclei and sexual differences regarding the expression of GAL in feeding behaviour. It is also important to study the possible GAL resistance in obese individuals to better understand the molecular mechanisms by which GAL regulates insulin/glucose metabolism. GAL does not exert a pivotal role in weight regulation and food intake, but this role is crucial in fat intake and also exerts an important action by regulating the activity of other key compounds under conditions of stress/altered diet.

Keywords: GAL message-associated peptide; GAL receptor; GAL-like peptide; alarin; celastrol; daidzein; obesity; orexigenic peptides; spexin.

Figure 1

General overview of the most important interactions between the hypothalamic nuclei involved in the control of food intake. The most studied neurochemical substances related to these mechanisms are included in the corresponding hypothalamic nucleus. Green arrows (right side of the figure) represent activation; red arrows (left side of the figure) represent inhibition. Connections of the Arc with other extrahypothalamic areas implicated in the control of feeding behavior are represented by a discontinuous arrow. Abbreviations: α-MSH: alpha-melanocyte stimulating hormone; 3V: third ventricle; Arc: arcuate hypothalamic nucleus; BNST: bed nucleus of the stria terminalis; CART: cocaine- and amphetamine-regulated transcript peptide; CeAmg: central nucleus of the amygdala; Enk: enkephalin; GABA: gamma-aminobutyric acid; GAL: galanin; GALP: galanin-like peptide; GHRF: growth hormone releasing factor; Glut: glutamate; LH: lateral hypothalamus; MCH: melanin-concentrating hormone; NPY/AgRP: neuropeptide Y/agouti-related protein neurons; PAG: periaqueductal gray matter; PBN: parabrachial nucleus; POMC: pro-opio-melanocortin; PVH: paraventricular hypothalamic nucleus.

Figure 2

Paraventricular hypothalamic nucleus (PVH): neural pathway and changes in the nucleus after different situations (left side). PVH plays a crucial role in modulating feeding mechanisms. ↑: increase; ↓: decrease; +: activation; -: inhibition; ?: action to be demonstrated. GABA: gamma-aminobutyric acid; GAL: galanin; MAPKs: mitogen-activated protein kinases; NPY: neuropeptide Y.

Figure 3

Paraventricular hypothalamic nucleus: physiological effects promoted by different substances when they were administered into the nucleus (left side). Some positive/inverse relationships are also shown (right side). ↑: increase; ↓: decrease. GAL: galanin; PVH: paraventricular hypothalamic nucleus.

Figure 4

Extended perifornical area: neural pathway and neuroactive substances involved. Leptin inhibits the activity of neurons containing orexin. This inhibition is mediated by GAL after binding to the GAL receptor 1 expressed in neurons with orexin; however, high palatable foods block the inhibitory action of leptin on orexin neurons and stimulate the activity of the latter neurons. ↑: increase; +: activation (orexigenic action); -: inhibition (anorexigenic action). GAL: galanin; GAL receptor 2 agonists restore the ability of leptin to restrain palatable food eating. CART: cocaine- and amphetamine-regulated transcript peptide; MCH: melanin-concentrating hormone; NT: neurotensin.

Figure 5

Effects of celastrol. ↑: increase; ↓: decrease. CREB: cAMP response element-binding protein; GAL: galanin; MAPK: mitogen-activated protein kinase; PGC-1α: peroxisome proliferator-activated receptor γ co-activator.

Figure 6

Molecular interactions between GAL and other substances. General interactions (i.e., hypothalamus) are indicated, and more specific actions are signaled separately. Actions mediated specifically by GAL are represented by blue arrows. ↑: increase; ↓: decrease; +: activation; -: inhibition. Acb: accumbens nucleus; b-end: beta-endorphin; CeAmg: central nucleus of the amygdala; DA: dopamine; Enk: enkephalin; GAL: galanin; GH: growth hormone; IL-1β: interleukin 1-beta; NE: norepinephrine; PVH: paraventricular hypothalamic nucleus; TNFα: tumor necrosis factor-alpha.

Figure 7

GAL receptor–NPY receptor interaction (arcuate nucleus): antagonistic GAL receptor modulation of NPY Y₁ receptor mechanisms. GAL (threshold dose; no effect on food intake when administered alone) blocks food consumption mediated by NPY Y₁ receptor agonists. GAL, after binding to its receptor, decreases NPY Y₁ receptor agonist affinity and signalling; this was counteracted by the GAL receptor antagonist M-35. The administration of GAL (a dose that promotes food ingestion) or NPY Y₁ receptor agonist increased the expression of c-fos, but the co-administration of both compounds decreased this expression. GAL^* (threshold dose); ↑: increase; ↓: decrease; X (inhibition). GAL: galanin; NPY: neuropeptide Y.