Impact of diet-induced obesity in male mouse reproductive system: The role of advanced glycation end product–receptor for advanced glycation end product axis

Abstract

Obesity represents a route to broad physiological dysfunction affecting major organs including male urogenital system. Hyperglycemia, hyperlipidemia, and oxidative stress associated with obesity augment the formation of reactive metabolic by-products, namely advanced glycation end products (AGEs), leading to increased tissue deposition and damage. The exogenous intake and the endogenous accumulation of AGEs contribute to metabolic and reproductive abnormalities in both women and men. The present study assessed the effects of a diet high in saturated fatty acids (SAFA) on the lipid and metabolic profile (AGE levels, oxidative stress) as well as pathogenic (AGE, receptor for AGEs [RAGE] expression, apoptosis) and morphometric parameters of male reproductive system in vivo. Effects of switching to a diet rich in monounsaturated fatty acids (MUFA) or equal in the proportion MUFA to SAFA were further investigated. SAFA-fed animals were characterized by increased serum lipid concentrations (p < .05) compared to controls, but AGEs and peroxide levels were not significantly different across the different experimental groups. Elevated AGE deposition was detected for the first time in germ cells with a higher staining intensity in animals on the SAFA diet, compared to MUFA or MUFA-SAFA-fed animals or the control samples (p = .018). In Leydig cells, AGE localization was higher in the entire cohort of high-fat-fed animals compared to controls (p < .05). High-fat-fed mice displayed enhanced apoptosis compared to controls (p < .005). Furthermore, prostatic tissue demonstrated reduction in epithelial folding, an effect which was significantly reversed after MUFA diet administration. Our findings provide the basis for further investigation of AGE-RAGE axis in testicular and prostatic disturbances associated with diet-induced obesity. Simple dietetic intervention has beneficial effects on metabolic dysfunction of reproductive system before overt manifestations, indicating glycation as a promising therapeutic target.

Dietary Options for Rodents in the Study of Obesity

“…In other words, the main contributor to the development of obesity is the profile of fatty acids in the diet rather than the energy content of the ingested fats [73][74][75]. This is important in the selection of a type of HFD, since the composition of dietary fatty acids can affect the results [76,77]. Most of the HFDs used in DIO studies contain high amounts of saturated and/or trans fats.…”

Advanced glycation end products inhibit testosterone secretion by rat Leydig cells by inducing oxidative stress and endoplasmic reticulum stress

“…AGEs are a heterogeneous class of compounds formed by the non-enzymatic glycation of proteins, which is accelerated in diabetes as a result of hyperglycaemia and oxidative stress. The receptor for AGEs (RAGE) exists in the testes, epididymides and sperm (19,20). N'-carboxymethyl-lysine, a prominent AGE, accumulates in the reproductive tract of patients with diabetes (21), as well as in animal models of both diabetes (22) and metabolic syndrome (23).…”

Advanced Glycation End Products and Risks for Chronic Diseases: Intervening Through Lifestyle Modification

“…While most of these empirical studies do not address a cause-and-effect relationship between AGEs and a disease condition, there are observations supporting altered physiologic responses following administration of exogenous AGEs, foods rich in AGEs, or perturbation of their endogenous levels. [116][117][118][119][120][121][122][123][124][125][126][127][128] Some examples of such observations from animal and human studies include reproductive abnormalities and prostatic disorders in mice, 116 induction of inflammatory mediators, 116,117 promotion of insulin resistance in mice following oral administration of AGEs, 119 acute state of impaired endothelial function, 120 acute impairment of vascular function after a high AGEs meal, 121 enhancement of low-density lipoprotein (LDL)-induced vascular toxicity by high AGEs diet, 122 increased proteinuria, 123,124 and increase in lung level of high mobility group box protein 1 (HMGB1). HMGB1 is a nuclear protein that acts like an agonist for RAGE.…”