Biology subjects

Debarba, L. K.

Publications and source records attributed to Debarba, L. K..

4 recordsLinked to original sources

bioRxiv2020

Metabolic Reprogramming by In Utero Maternal Benzene Exposure

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 a 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 5 days/week (6h/day from gestational day 1 to birth) 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 six months of age, both male and female offspring displayed glucose and insulin intolerance, associated with elevated expression of hepatic gluconeogenesis and inflammatory genes. Additionally, this effect was accompanied by elevated insulin secretion and increased beta-cell mass only in male offspring. Thus, gestational benzene exposure can reprogram offspring for increased susceptibility to the metabolic imbalance in adulthood with differential sensitivity between sexes.

pharmacology and toxicology↗

bioRxiv2020

Growth hormone receptor (GHR)-expressing neurons in the hypothalamic arcuate nucleus regulate glucose metabolism and energy homeostasis

Growth hormone (GH) receptor (GHR), expressed in different brain regions, is known to participate in the regulation of whole-body energy homeostasis and glucose metabolism. However, GH activation of these GHR-expressing neurons is less studied. We have generated a novel GHR-driven Cre recombinase transgenic mouse line (GHRcre) in combination with the floxed tdTomato reporter mouse line we tracked and activated GHR-expressing neurons in different regions of the brain. We focused on neurons of the hypothalamic arcuate nucleus (ARC) where GHR was shown to elicit a negative feedback loop that regulates GH production. We found that ARCGHR+ neurons are co-localized with AgRP, GHRH, and somatostatin neurons, which were activated by GH stimulation. Using designer receptors exclusively activated by designer drugs (DREADDs) to control GHRARC neuronal activity, we revealed that activation of GHRARC neurons was sufficient in regulating distinct aspects of energy balance and glucose metabolism. Overall, our study provides a novel mouse model to study in vivo regulation and physiological function of GHR-expressing neurons in various brain regions. Furthermore, we identified for the first time specific neuronal population that responds to GH and directly linked it to metabolic responses in vivo.

neuroscience↗

bioRxiv2020

Sex hormones underlying 17a-Estradiol effects on neuroinflammation

17--estradiol (17aE2) treatment extends lifespan 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 lifespan regulation. We tested whether the sex-specific effects of 17aE2 on neuroinflammatory responses are mediated by sex hormones and whether hypothalamic changes extend to other brain regions in old age. Manipulating sex hormone levels through gonadectomy, we show that sex-specific effects of 17aE2 on age-associated gliosis are brain region-specific and are partially dependent on gonadal hormone production. 17aE2 treatment started at 4 months of age protected 25-month-old males from hypothalamic inflammation. Castration prior to 17aE2 exposure reduced the effect of 17aE2 on hypothalamic astrogliosis. By contrast, sex-specific changes in microgliosis with 17aE2 were not significantly affected by castration in males. While 17aE2 treatment had no effect of hypothalamic astrocytes or microglia in intact females, ovariectomy significantly increased the occurrence of hypothalamic gliosis evaluated in 25-month-old females, which was partially reduced by 17aE2. In the hippocampus, both male and female gonadally-derived hormones influenced the severity of gliosis and the responsiveness to 17aE2 in a regiondependent manner. The male-specific effects of 17aE2 correlate with changes in hypothalamic ER expression, highlighting a receptor through which 17aE2 could act. The results of this study demonstrate that neuroinflammatory responses to 17aE2 are partially controlled by the presence of sex-specific gonads. Interactions between sex-steroids and neuroinflammation could, therefore, influence late-life health and disease onset, leading to sexual dimorphism in aging.

neuroscience↗

bioRxiv2020

Acarbose Protects From Central and Peripheral Metabolic Imbalance Induced by Benzene Exposure

Benzene is a well-known human carcinogen that is one of the major components of air pollution. Sources of benzene in ambient air include cigarette smoke, e-cigarettes vaping and evaporation of benzene containing petrol processes. While carcinogenic effects of benzene exposure have been well studied, less is known about metabolic effects of benzene exposure. We show that chronic exposure to benzene at low levels induces severe metabolic imbalance in a sex-specific manner, which is associated with hypothalamic inflammation and endoplasmic reticulum (ER) stress. Benzene exposure rapidly activates hypothalamic ER stress and neuroinflammatory responses in male mice, while pharmacological inhibition of ER stress response by inhibiting IRE1-XBP1 pathway significantly alleviates benzene-induced glial inflammatory responses. Additionally, feeding mice with Acarbose, a clinically available anti-diabetes drug, protected against benzene induced central and peripheral metabolic imbalance. Acarbose imitates the slowing of dietary carbohydrate digestion, suggesting that choosing a diet with a low glycemic index might be a potential strategy for reducing the negative metabolic effect of chronic exposure to benzene for smokers or for people living/working in urban environments with high concentrations of exposure to automobile exhausts.

physiology↗