Brain Peptides and Obesity: Pharmacologic Treatment

Abstract

Obesity results from an imbalance between nutrient ingestion and metabolism, with more calories being ingested than utilized. The brain plays an important role in coordinating these complex behavioral and physiological functions, operating through multiple neurochemical systems with distinct properties. This review focuses on two hypothalamic peptide systems, neuropeptide Y (NPY) and galanin (GAL), that illustrate how the brain operates through different mechanisms to control the body's nutrient stores, in different states or conditions. These peptides have different behavioral and physiological effects and are, themselves, differentially responsive to feedback signals from circulating steroids, peptides, and nutrients. They can be distinguished by their relation to natural feeding patterns and endogenous hormones and by their specificity of action in relation to natural biological rhythms. The neuroanatomical substrates involved in these actions of NPY and GAL are also distinct. The neurocircuit mediating NPY's actions originates in the arcuate nucleus and terminates in the medial portion of the paraventricular nucleus; the GAL‐containing neurons, in contrast, are concentrated in the lateral portion of the paraventricular nucleus, in addition to the medial preoptic area, which contribute to local GAL innervation as well as projections to the median eminence. Regarding their distinct functions, the evidence suggests that the NPY system is more closely related to patterns of carbohydrate ingestion and carbohydrate utilization, channeling nutrients towards the synthesis of fat. It is most strongly activated at the start of the active feeding cycle or after weaning, in close association with the adrenal steroid, corticosterone. The GAL system, in contrast, is more closely associated with patterns of fat consumption and signals related to fat oxidation. This peptide system is most active during the middle of the feeding cycle or immediately after puberty, in close association with the gonadal steroids. The gene expression and synthesis of these peptides in their respective neuronal cell groups is inhibited by circulating insulin and altered by dietary nutrients. Disturbances in sensitivity to insulin and steroid feedback regulation in the brain are believed to be involved in producing abnormal patterns of peptide function that result in overeating and body weight gain.