Hypothalamic sex-specific metabolic shift by canagliflozin during aging.

The hypothalamus undergoes significant changes with aging and plays crucial roles in age-related metabolic alterations. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are anti-diabetic agents that promote glucose excretion, and metabolic homeostasis. Recent studies have shown that a SGLT2i, Canagliflozin (Cana), can extend the median survival of genetically heterogeneous UM-HET3 male mice and improve central metabolic control via increases in hypothalamic insulin responsiveness in aged males, as well as reduced age-associated hypothalamic inflammation. We studied the long- and short-term effects of Cana on hypothalamic metabolic control in UM-HET3 mice. Starting the treatment from 7 months of age, we show that 4 weeks of Cana treatment significantly reduced body weight and fat mass in male but not female mice that was associated with enhanced glucose tolerance and insulin sensitivity observed by 12 months. Indirect calorimetry showed that Cana treatment increased energy expenditure in male, but not female mice, at 12 months of age. Long-term Cana treatment increased metabolic rates in both sexes, and markedly increasing formation of both orexigenic and anorexigenic projections to the paraventricular nucleus of the hypothalamus (PVH) mostly in females by 25 months. Hypothalamic RNA-sequencing analysis revealed increased sex-specific genes and signaling pathways related to insulin signaling, glycogen catabolic pathway, neuropeptide signaling, and mitochondrial function upregulated by Cana, with males showing a more pronounced and sustained effect on metabolic pathways at both age groups. Overall, our data provide critical evidence for sex-specific mechanisms that are affected by Cana during aging suggesting key targets of hypothalamic Cana-induced neuroprotection for metabolic control.

Intrinsic sexual dimorphism in the placenta determines the differential response to benzene exposure.

Maternal immune activation (MIA) by environmental challenges is linked to severe developmental complications, such as neurocognitive disorders, autism, and even fetal/maternal death. Benzene is a major toxic compound in air pollution that affects the mother as well as the fetus and has been associated with reproductive complications. Our objective was to elucidate whether benzene exposure during gestation triggers MIA and its impact on fetal development. We report that benzene exposure during pregnancy leads MIA associated with increased fetal resorptions, fetal growth, and abnormal placenta development. Furthermore, we demonstrate the existence of a sexual dimorphic response to benzene exposure in male and female placentas. The sexual dimorphic response is a consequence of inherent differences between male and female placenta. These data provide crucial information on the origins or sexual dimorphism and how exposure to environmental factors can have a differential impact on the development of male and female offspring.

Neuroprotective effects of Canagliflozin: Lessons from aged genetically diverse UM-HET3 mice.

The aging brain is characterized by progressive increases in neuroinflammation and central insulin resistance, which contribute to neurodegenerative diseases and cognitive impairment. Recently, the Interventions Testing Program demonstrated that the anti-diabetes drug, Canagliflozin (Cana), a sodium-glucose transporter 2 inhibitor, led to lower fasting glucose and improved glucose tolerance in both sexes, but extended median lifespan by 14% in male mice only. Here, we show that Cana treatment significantly improved central insulin sensitivity in the hypothalamus and the hippocampus of 30-month-old male mice. Aged males produce more robust neuroimmune responses than aged females. Remarkably, Cana-treated male and female mice showed significant reductions in age-associated hypothalamic gliosis with a decrease in inflammatory cytokine production by microglia. However, in the hippocampus, Cana reduced microgliosis and astrogliosis in males, but not in female mice. The decrease in microgliosis was partially correlated with reduced phosphorylation of S6 kinase in microglia of Cana-treated aged male, but not female mice. Thus, Cana treatment improved insulin responsiveness in aged male mice. Furthermore, Cana treatment improved exploratory and locomotor activity of 30-month-old male but not female mice. Taken together, we demonstrate the sex-specific neuroprotective effects of Cana treatment, suggesting its application for the potential treatment of neurodegenerative diseases.

17-α-Estradiol Has Sex-Specific Effects on Neuroinflammation That Are Partly Reversed by Gonadectomy.

17-α-Estradiol (17aE2) treatment from 4 months of age extends life span in male mice and can reduce neuroinflammatory responses in the hypothalamus of 12-month-old males. Although 17aE2 improves longevity in males, female mice are unaffected, suggesting a sexually dimorphic pattern of life-span regulation. We tested whether the sex-specific effects of 17aE2 on neuroinflammatory responses are affected by gonadal removal and whether hypothalamic changes extend to other brain regions in old age. We show that sex-specific effects of 17aE2 on age-associated gliosis are brain region specific and are partially dependent on gonadectomy. 17aE2 treatment started at 4 months of age protected 25-month-old males from hypothalamic inflammation. Castration before 17aE2 exposure reduced the effect of 17aE2 on hypothalamic astrogliosis in males. In contrast, sex-specific inhibition of microgliosis generated by 17aE2 was not significantly affected by castration. In the hippocampus, gonadectomy influenced the severity of gliosis and the responsiveness to 17aE2 in a region-dependent manner. The male-specific effects of 17aE2 correlate with increases in hypothalamic estrogen receptor alpha expression, specifically in gonadally intact males, consistent with the idea that 17aE2 might act through this receptor. Our results indicate that neuroinflammatory responses to 17aE2 are partially controlled by the presence of sex-specific gonads. Loss of gonadal function and age-associated neuroinflammation could, therefore, influence late-life health and disease onset, leading to sexual dimorphism in both aging and in response to drugs that modify the pace of aging.

In Utero Maternal Benzene Exposure Predisposes to the Metabolic Imbalance in the Offspring.

Environmental chemicals play a significant role in the development of metabolic disorders, especially when exposure occurs early in life. We have recently demonstrated that benzene exposure, at concentrations relevant to cigarette smoke, induces a severe metabolic imbalance in a sex-specific manner affecting male but not female mice. However, the roles of benzene in the development of aberrant metabolic outcomes following gestational exposure, remain largely unexplored. In this study, we exposed pregnant C57BL/6JB dams to benzene at 50 ppm or filtered air for 6 h/day from gestational day 0.5 (GD0.5) through GD21 and studied male and female offspring metabolic phenotypes in their adult life. While no changes in body weight or body composition were observed between groups, 4-month-old male and female offspring exhibited reduced parameters of energy homeostasis (VO2, VCO2, and heat production). However, only male offspring from benzene-exposed dams were glucose intolerant and insulin resistant at this age. By 6 months of age, both male and female offspring exhibited marked glucose intolerance however, only male offspring developed severe insulin resistance. This effect was accompanied by elevated insulin secretion and increased beta-cell mass only in male offspring. In support, Homeostatic Model Assessment for Insulin Resistance, the index of insulin resistance was elevated only in male but not in female offspring. Regardless, both male and female offspring exhibited a considerable increase in hepatic gene expression associated with inflammation and endoplasmic reticulum stress. Thus, gestational benzene exposure can predispose offspring to increased susceptibility to the metabolic imbalance in adulthood with differential sensitivity between sexes.

Sex differences in body composition, metabolism-related hormones, and energy homeostasis during aging in Wistar rats.

Aging affects the body composition and balance of energy metabolism. Here, we collected in a single work several physiological parameters to show how aging and sex differences can influence energy homeostasis. Body mass index (BMI), Lee index, glucose tolerance, glycemia, and lipidogram in fasting were measured in male and female Wistar rats at the ages of 2, 6, 9, 12, and 18 months. We also measured the lipid profile, free fatty acids, glycerol, glycemia, leptin, adiponectin, insulin, corticosterone (CORT), prolactin (PRL), thyroid stimulated hormone, and triiodothyronine (T3) in 3- and 18-month-old rats of both sexes, fed ad libitum. Animals were classified as obese beginning at 2 months in males and 6 months in females. Aged male rats showed hyperglycemia and glucose intolerance compared to young males and old females. In the ad libitum condition, the 18-month males presented higher serum levels of triglycerides, total cholesterol, and free fatty acids than females. The 18-month-old females had higher PRL and CORT concentration than males, but insulin and T3 were higher in 18-month-old males than females. Our work demonstrated that aging processes on energy metabolism in rats is sex specific, with a better lipid profile and glucose tolerance in aged females.

Sex- and age-dependent differences in the hormone and drinking responses to water deprivation.

Maintenance of the volume and osmolality of body fluids is important, and the adaptive responses recruited to protect against osmotic stress are crucial for survival. The objective of this work was to compare the responses that occur in aging male and female rats during water deprivation. For this purpose, groups of male and female Wistar rats aged 3 mo (adults) or 18 mo (old) were submitted to water deprivation (WD) for 48 h. The water and sodium (0.15 M NaCl) intake, plasma concentrations of oxytocin (OT), arginine vasopressin (AVP), corticosterone (CORT), atrial natriuretic peptide (ANP), and angiotensin II (ANG II) were determined in hydrated and water-deprived animals. In response to WD, old male and female rats drank less water and saline than adults, and both adult and old females drank more water and saline than respective males. Dehydrated old animals displayed lower ANG II plasma concentration and CORT response compared with the respective normohydrated rats. Dehydrated adult males had higher plasma ANP and AVP as well as lower CORT concentrations than dehydrated adult females. Moreover, plasma OT and CORT levels of old female rats were higher than those in the dehydrated old male rats. Relative expression of ANG II type 1 receptor mRNA was decreased in the subfornical organ of adult and old male rats as well as adult female rats in response to WD. In conclusion, the study elucidated the effect of sex and age on responses induced by WD, altering the degree of dehydration induced by 48 h of WD.