Catch-up fat in male adults induces low testosterone and consequently promotes metabolic abnormalities and cognitive impairment

Background Catch-up fat in adults (CUFA) caused by rapid nutrition promotion after undernutrition plays an important role in the epidemic of insulin resistance (IR)-related diseases in developing societies. Insulin resistance is considered to be closely associated with reduced testosterone levels and cognitive function. However, the effects of CUFA on testosterone levels and cognitive function are unclear in males. Objectives To investigate the changes in testosterone levels and cognitive function in CUFA in male humans and rats, and explore their probable relationship and mechanisms in rats. Materials and methods The blood testosterone levels, fasting glucose, and blood insulin (FINS) were measured in subpopulation 1 (27 CUFA individuals, 61 controls without CUFA) aged 40-50 years to show the characteristics of sex hormone levels and the metabolic status in CUFA men. Cognitive Flexibility Inventory was conducted in subpopulation 2 (54 CUFA individuals, 214 controls) over 20 years to investigate the associations between sex hormone levels, cognitive function, and CUFA. Male rats (n = 27) were randomly allocated to the NC group (normal chow controls), RN group (CUFA, refeeding after caloric restriction), and RT group (RN with testosterone intramuscular injected while refeeding). The blood testosterone levels, intraperitoneal insulin tolerance test (IPITT), and FINS were measured, and the attentional set-shifting task test (ASST) for the assessment of cognitive function was performed in these animals. Insulin signaling pathway, N-methyl-d-aspartate receptors subtype 2A (NR2A) and 2B (NR2B) expression levels were determined in the rat cerebral cortex. Results The total testosterone levels decreased (medium [inter-quartile ranges], 13.43 [9.87-18.96] vs. 15.58 [13.37-24.96], p = 0.036), and HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) elevated (1.61 [1.08-2.33] vs. 1.24 [0.87-1.87], P = 0.037) in CUFA men in subpopulation 1. Additionally, cognitive impairment was observed in CUFA men in subpopulation 2. Moreover, our results indicated decreases in total and free testosterone levels, elevations in visceral lipid accumulation, FINS, HOMA-IR, blood glucose, and the area under the curve after IPITT, increases in the number of trials required to achieve the criterion of the first reversal of discrimination (R1) in ASST, and downregulation of IRS-1 mRNA expression, AKT phosphorylation, and the NR2A and NR2B expression in brain tissue in male CUFA rats. Notably, testosterone supplementation improved visceral lipid accumulation and IR-related metabolic disorders, cognitive dysfunction, decreases in IRS-1 mRNA expression, Akt phosphorylation, and NR2A and NR2B expression in brain tissue in male CUFA rodents. Discussion and Conclusion CUFA was characterized by reduced testosterone levels, metabolic abnormalities, and cognitive dysfunction in males, and testosterone supplementation attenuated these changes, as well as the alteration in insulin signaling and NR2A and NR2B expression in male CUFA rodents. Herein, we tentatively put forward that CUFA in males induces low testosterone, consequently promoting metabolic abnormalities and cognitive impairment probably mediated by defects in insulin signaling and NR2A, NR2B pathway in brain tissue.