Abstract
Heat-processed diets contain high amounts of advanced glycation end products (AGEs). Here we explore the impact of an AGE-enriched diet on markers of metabolic and inflammatory disorders as well as on gut microbiota composition and plasma proteins glycosylation pattern. C57BL/6 mice were allocated into control diet (CD, n = 15) and AGE-enriched diet (AGE-D, n = 15) for 22 weeks. AGE-D was prepared replacing casein by methylglyoxal hydroimidazolone-modified casein. AGE-D evoked increased insulin and a significant reduction of GIP/GLP-1 incretins and ghrelin plasma levels, altered glucose tolerance, and impaired insulin signaling transduction in the skeletal muscle. Moreover, AGE-D modified the systemic glycosylation profile, as analyzed by lectin microarray, and increased Nε-carboxymethyllysine immunoreactivity and AGEs receptor levels in ileum and submandibular glands. These effects were associated to increased systemic levels of cytokines and impaired gut microbial composition and homeostasis. Significant correlations were recorded between changes in bacterial population and in incretins and inflammatory markers levels. Overall, our data indicates that chronic exposure to dietary AGEs lead to a significant unbalance in incretins axis, markers of metabolic inflammation, and a reshape of both the intestinal microbiota and plasma protein glycosylation profile, suggesting intriguing pathological mechanisms underlying AGEs-induced metabolic derangements.
Highlights
The progressive ageing of world population and the rapid changes in the lifestyle occurred in recent decades have contributed to the rising of chronic metabolic and inflammatory diseases [1].In particular, nowadays nutrition is considered the main beneficial or harmful tool able to either prevent or cause metabolic inflammation, which is strictly related to the pathogenesis of many chronic diseases, exerting an enormous socioeconomic impact
The significant changes recorded in the blood levels of key master hormonal regulators of metabolism were associated with local impairment of the insulin signaling pathway, which is a crucial regulator of glucose transportation, glycogen synthesis and glycolysis
Our findings are in accordance with previously in vitro studies demonstrating that cellular exposure to advanced glycation end products (AGEs) resulted in impaired secretion and activity of glucose-dependent insulinotropic polypeptide (GIP) and GLP-1, the two primary incretin hormones [24,25] and increased expression of dipeptidyl peptidase-4 (DPP-4), the main enzyme degrading incretins [26,27]
Summary
The progressive ageing of world population and the rapid changes in the lifestyle occurred in recent decades have contributed to the rising of chronic metabolic and inflammatory diseases [1].In particular, nowadays nutrition is considered the main beneficial or harmful tool able to either prevent or cause metabolic inflammation (known as “metaflammation”), which is strictly related to the pathogenesis of many chronic diseases, exerting an enormous socioeconomic impact. The progressive ageing of world population and the rapid changes in the lifestyle occurred in recent decades have contributed to the rising of chronic metabolic and inflammatory diseases [1]. A widely studied class of diet-derived substances with possible impact on inflammatory processes is the heterogeneous group of advanced glycation end products (AGEs). These highly reactive compounds are derived from a first reaction between a reducing sugar and the amino group of proteins and give rise, through a sequence of dehydration, cyclization, fragmentation, and oxidation reactions, to final AGE-modified proteins, which are non-degradable and functionally compromised [2].
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