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.

Prenatal benzene exposure in mice alters offspring hypothalamic development predisposing to metabolic disease in later life.

Maternal exposure to environmental contaminants during pregnancy poses a significant threat to a developing fetus, as these substances can easily cross the placenta and disrupt the neurodevelopment of offspring. Specifically, the hypothalamus is essential in the regulation of metabolism, notably during critical windows of development. An abnormal hormonal and inflammatory milieu during development can trigger persistent changes in the function of hypothalamic circuits, leading to long-lasting effects on the body's energy homeostasis and metabolism. We recently demonstrated that gestational exposure to clinically relevant levels of benzene induces severe metabolic dysregulation in the offspring. Given the central role of the hypothalamus in metabolic control, we hypothesized that prenatal exposure to benzene impacts hypothalamic development, contributing to the adverse metabolic effects in the offspring. C57BL/6JB dams were exposed to benzene at 50 ppm in the inhalation chambers exclusively during pregnancy (from E0.5 to E19). Transcriptomic analysis of the exposed offspring at postnatal day 21 (P21) revealed hypothalamic changes in genes related to metabolic regulation, inflammation, and neurodevelopment exclusively in males. Moreover, the hypothalamus of prenatally benzene-exposed male offspring displayed alterations in orexigenic and anorexigenic projections, impairments in leptin signaling, and increased microgliosis. Additional exposure to benzene during lactation did not promote further microgliosis or astrogliosis in the offspring, while the high-fat diet (HFD) challenge in adulthood exacerbated glucose metabolism and hypothalamic inflammation in benzene-exposed offspring of both sexes. These findings reveal the persistent adverse effects of prenatal benzene exposure on hypothalamic circuits and neuroinflammation, predisposing the offspring to long-lasting metabolic health conditions.

Prenatal benzene exposure alters offspring hypothalamic development predisposing to metabolic disease in later life.

The hypothalamus is essential in the regulation of metabolism, notably during critical windows of development. An abnormal hormonal and inflammatory milieu during development can trigger persistent changes in the function of hypothalamic circuits, leading to long-lasting effects on the body’s energy homeostasis and metabolism. We recently demonstrated that gestational exposure to benzene at smoking levels induces severe metabolic dysregulation in the offspring. Given the central role of the hypothalamus in metabolic control, we hypothesized that prenatal exposure to benzene impacts hypothalamic development, contributing to the adverse metabolic effects in the offspring. C57BL/6JB dams were exposed to benzene in the inhalation chambers exclusively during pregnancy (from E0.5 to E19). The transcriptome analysis of the offspring hypothalamus at postnatal day 21 (P21) revealed changes in genes related to metabolic regulation, inflammation, and neurodevelopment exclusively in benzene-exposed male offspring. Moreover, the hypothalamus of prenatally benzene-exposed male offspring displayed alterations in orexigenic and anorexigenic projections, impairments in leptin signaling, and increased microgliosis. Additional exposure to benzene during lactation did not promote further microgliosis or astrogliosis in the offspring, while the high-fat diet (HFD) challenge in adulthood exacerbated glucose metabolism and hypothalamic inflammation in benzene-exposed offspring of both sexes. These findings reveal the persistent impact of prenatal benzene exposure on hypothalamic circuits and neuroinflammation, predisposing the offspring to long-lasting metabolic health conditions.

Growth hormone receptor (GHR) in AgRP neurons regulates thermogenesis in a sex-specific manner.

Evidence for hypothalamic regulation of energy homeostasis and thermoregulation in brown adipose tissue (BAT) during aging has been well recognized, yet the central molecular mediators involved in this process are poorly understood. The arcuate hypothalamus, orexigenic agouti-related peptide (AgRP) neurons control nutrient intake, energy homeostasis, and BAT thermogenesis. To determine the roles of growth hormone receptor (GHR) signaling in the AgRP neurons, we used mice with the AgRP-specific GHR deletion (AgRPΔGHR). We found that female AgRPΔGHR mice were resistant to temperature adaptation, and their body core temperature remained significantly lower when held at 10 °C, 22 °C, or 30 °C, compared to control mice. Low body core temperature in female AgRPΔGHR mice has been associated with significant reductions in Ucp1 and Pgc1α expression in the BAT. Further, neuronal activity in AgRP in response to cold exposure was blunted in AgRPΔGHR female mice, while the number of Fos+ AgRP neurons was increased in female controls exposed to cold. Global transcriptome from BAT identified increased the expression of genes related to immune responses and chemokine activity and decreased the expression of genes involved in triglyceride synthesis and metabolic pathways in AgRPΔGHR female mice. Importantly, these were the same genes that are downregulated by thermoneutrality in control mice but not in the AgRPΔGHR animals. Collectively, these data demonstrate a novel sex-specific role for GHR signaling in AgRP neurons in thermal regulation, which might be particularly relevant during aging.

Prenatal Pollutant Exposures and Hypothalamic Development: Early Life Disruption of Metabolic Programming.

Environmental contaminants in ambient air pollution pose a serious risk to long-term metabolic health. Strong evidence shows that prenatal exposure to pollutants can significantly increase the risk of Type II Diabetes (T2DM) in children and all ethnicities, even without the prevalence of obesity. The central nervous system (CNS) is critical in regulating whole-body metabolism. Within the CNS, the hypothalamus lies at the intersection of the neuroendocrine and autonomic systems and is primarily responsible for the regulation of energy homeostasis and satiety signals. The hypothalamus is particularly sensitive to insults during early neurodevelopmental periods and may be susceptible to alterations in the formation of neural metabolic circuitry. Although the precise molecular mechanism is not yet defined, alterations in hypothalamic developmental circuits may represent a leading cause of impaired metabolic programming. In this review, we present the current knowledge on the links between prenatal pollutant exposure and the hypothalamic programming of metabolism.

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.