Involvement of the Receptor for Advanced Glycation End Products (RAGE) in high fat-high sugar diet-induced anhedonia in rats.

Abstract

Clinical and basic science investigation indicates a link between insulin resistance and anhedonia. Previous results of this laboratory point to impaired nucleus accumbens (NAc) insulin signaling as an underpinning of diet-induced anhedonia, based on use of a glucose lick microstructure assay. The present study evaluated whether advanced glycation end products (AGEs) and their receptor (RAGE), known to mediate obesogenic diet-induced inflammation and pathological metabolic conditions, are involved in this behavioral change. Six weeks maintenance of male and female rats on a high fat-high sugar liquid diet (chocolate Ensure) increased body weight gain, and markedly increased circulating insulin and leptin, but induced anhedonia (decreased first minute lick rate and lick burst size) in males only. In these subjects, anhedonia correlated with plasma concentrations of insulin. Although the diet did not alter plasma or NAc AGEs, or the expression of RAGE in the NAc, marginally significant correlations were seen between anhedonia and plasma content of several AGEs and NAc RAGE. Importantly, a small molecule RAGE antagonist, RAGE229, administered twice daily by oral gavage, prevented diet-induced anhedonia. This beneficial effect was associated with improved adipose function, reflected in the adiponectin/leptin ratio, and increased pCREB/total CREB in the NAc, and a shift in the pCREB correlation with pThr34-DARPP-32 from near-zero to strongly positive, such that both phospho-proteins correlated with the rescued hedonic response. This set of findings suggests that the receptor/signaling pathway and cell type underlying the RAGE229-mediated increase in pCREB may mediate anhedonia and its prevention. The possible role of adipose tissue as a locus of diet-induced RAGE signaling, and source of circulating factors that target NAc to modify hedonic reactivity are discussed.

• Authors: Kenneth D Carr, Sydney P Weiner, Carolina Vasquez, Ann Marie Schmidt
• Journal: Physiology & behavior (Physiol Behav) Vol. 271 Pg. 114337 (11 01 2023) ISSN: 1873-507X [Electronic] United States
• PMID: 37625475 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2023 Elsevier Inc. All rights reserved.

Chemical References

• Glycation End Products, Advanced
• Insulin
• Leptin
• Receptor for Advanced Glycation End Products
• Sugars
• Ager protein, rat

Topics

• Animals
• Female
• Humans
• Male
• Rats
• Adipose Tissue (metabolism)
• Anhedonia
• Diet, High-Fat (adverse effects)
• Glycation End Products, Advanced (metabolism)
• Insulin
• Leptin (metabolism)
• Receptor for Advanced Glycation End Products (metabolism)
• Sugars (metabolism)