Biology subjects

Amato, A. A.

Publications and source records attributed to Amato, A. A..

4 recordsLinked to original sources

bioRxiv2022

Heritable changes in chromatin contacts linked to transgenerational obesity

Burgeoning evidence demonstrates that responses to environmental exposures can be transmitted to subsequent generations through the germline without DNA mutations1,2. This is controversial because underlying mechanisms remain to be identified. Therefore, understanding how effects of environmental exposures are transmitted to unexposed generations without DNA mutations is a fundamental unanswered question in biology. Here, we used an established murine model of transgenerational obesity to show that direct or ancestral exposure to the obesogen tributyltin (TBT) elicited persistent changes in topologically associating domains (TADs) in primordial germ cells (PGCs) isolated from embryos of exposed and subsequent unexposed generations. New TAD boundaries were formed within the Ide gene encoding insulin degrading enzyme in the exposed PGCs, then stably maintained in PGCs of the subsequent (unexposed) two generations. Concomitantly, Ide mRNA expression was decreased in livers of male descendants from the exposed dams. These animals were hyperinsulinemic and hyperglycemic, phenocopying Ide-deficient mice that are predisposed to adult-onset obesity. Creation of new TAD boundaries in PGCs, suppression of hepatic Ide mRNA, increased fat mass, hyperinsulinemia and hyperglycemia were male-specific. Our results provide a plausible molecular mechanism underlying transmission of the transgenerational predisposition to obesity caused by gestational exposure to an environmental obesogen. They also provide an entry point for future studies aimed at understanding how environmental exposures alter chromatin structure to influence physiology across multiple generations in mammals.

developmental biology↗

bioRxiv2022

2,4-Di-tert-butylphenol Induces Adipogenesis in Human Mesenchymal Stem Cells by Activating Retinoid X Receptors

2,4-di-tert-butylphenol (2,4-DTBP) is an important commercial antioxidant and a toxic natural secondary metabolite that has been detected in humans. However, there is scant information regarding its toxicological effects. Here we asked whether 2,4-DTBP is a potential obesogen. Using a human mesenchymal stem cell (MSC) adipogenesis assay, we found that exposure to 2,4-DTBP led to increased lipid accumulation and expression of adipogenic marker genes. Antagonist assays revealed that 2,4-DTBP increased lipid accumulation by activating the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma})-retinoid X receptor (RXR) heterodimer. 2,4-DTBP likely activated the PPAR{gamma}/RXR heterodimer by activating RXR but not directly binding to PPAR{gamma}. We confirmed that 2,4-DTBP directly bound to RXR by solving the crystal structure of this complex, then predicted and demonstrated that related compounds could also activate RXR. Our study demonstrated that 2,4-DTBP and related chemicals could act as obesogens and endocrine disruptors via RXR. These data showed that 2,4-DTBP belongs to a family of compounds whose endocrine-disrupting and obesogenic effects can be strongly modulated by their chemical composition and that structure-activity studies such as the present one could help guide the rational development of safer antioxidants. SYNOPSISLittle research exists on the effects of commercially valuable antioxidants on biological systems. This study reports that di- and tri-tert-butylphenols can act as endocrine disruptors and potential obesogens by activating nuclear hormone receptors.

pharmacology and toxicology↗

bioRxiv2022

Early exposure to high-fat diet impairs central and peripheral metabolic function: Impacts on cognition and mitochondrial function

The impact of overnutrition early in life is not restricted to the onset of cardiovascular and metabolic diseases, but also affects critical brain functions related to cognition. This study aimed to evaluate the relationship between peripheral metabolic and bioenergetic changes induced by high-fat diet (HFD) and their impact on hippocampal cognitive functions in juvenile mice. To this purpose, three-week-old male C57BL/6 mice received a HFD or control diet for seven weeks, associated with two low doses of streptozotocin (STZ) or vehicle, to accelerate the metabolic dysfunction. HFD induced metabolic changes in mice, particularly related to glucose metabolism, in spite of the absence of obesity and changes in lipid profile. HFD exposure starting from weaning impaired recognition and spatial memories in mice, without inducing a depressive-like behavior. Increased immunoreactivity for GFAP and a trend towards a decrease in NeuN staining were verified in the hippocampus of HFD-fed mice. HFD caused a bioenergetic impairment in the hippocampus, characterized by a decrease in both O2 consumption related to ATP production and in the maximum respiratory capacity. The thermogenic capacity of brown adipose tissue was impaired by HFD, here verified through the absence of a decrease in O2 consumption after UCP-1 inhibition and increase in the reserve respiratory capacity. Impaired mitochondria function was also observed in the liver of HFD mice, while no changes were verified in O2 consumption in the heart of juvenile mice. These results indicate that the introduction of a HFD early in life has a detrimental impact on bioenergetic and mitochondrial function of tissues with metabolic and thermogenic activities, which is likely related to hippocampal metabolic changes and cognitive impairment. HighlightsO_LIHFD introduced early in life impacts mitochondrial function C_LIO_LIDietary shift early in life leads hippocampal dysfunction C_LIO_LIEarly life HFD exposure disrupts BAT thermogenic acitivity C_LIO_LIHFD-induced hippocampal and BAT mitochondrial dysfunction impacts cognition C_LI

neuroscience↗

bioRxiv2021

Selective Modulator of Nuclear Receptor PPARy with Reduced Adipogenic Potential Ameliorates Experimental Nephrotic Syndrome

BackgroundGlomerular disease, often manifesting as nephrotic syndrome (NS) with high proteinuria, can be refractory to standard treatment and is typically associated with hypoalbuminemia, hypercholesterolemia and hypercoagulopathy. We hypothesized that the nuclear receptor PPAR{gamma} can be selectively modulated using a novel partial agonist, GQ-16, to gain therapeutic advantage over traditional PPAR{gamma} agonists (e.g. thiazolidinediones) for the treatment of glomerular disease. MethodsNephropathy was induced with puromycin amino-nucleoside (PAN) in Wistar rats and treated with Pioglitazone (Pio) or GQ-16. Plasma, serum, and urine chemistries were performed, and kidneys, glomeruli, liver, and white adipose tissue (WAT) were harvested. Lipid accumulation and adipogenic gene expression were measured in adipocytes. ResultsPAN-induced proteinuria was significantly reduced with Pio to 64% of PAN-value. It was reduced robustly with GQ-16 to 81% of PAN, which was comparable to controls. While both GQ-16 and Pio restored glomerular Nphs1 and hepatic Pcsk9 expression and reduced hypercholesterolemia, GQ-16 also restored glomerular Nrf2, and reduced hypoalbuminemia and hypercoagulopathy. Furthermore, RNA-seq analysis identified both common and distinct restored glomerular genes downstream of Pio and GQ-16. Pio but not GQ-16 significantly induced aP2 (fatty acid binding protein) in adipocytes and in WAT. Pio induced more lipid accumulation than GQ-16 in differentiated adipocytes. Both, Pio and GQ-16 induced insulin sensitizing adipokines in WAT with varying degrees. ConclusionsSelective modulation of PPAR{gamma} by a partial agonist, GQ-16, is more advantageous than pioglitazone in reducing proteinuria and NS associated co-morbidities, while reducing the adipogenic side-effects conferred by traditional PPAR{gamma} full agonists. Translational StatementThe authors have previously reported that type-II diabetes drugs, thiazolidinediones (PPAR{gamma} agonists), also provide beneficial effects in reducing podocyte and glomerular injury. However, these drugs are associated with adverse effects such as weight gain, and their effects on glomerular disease-associated features are largely unexplored. Their current findings demonstrate that PPAR{gamma} can be selectively modulated by its partial agonist, GQ-16, which reduces proteinuria and improves nephrotic syndrome (NS) with reduced side-effects typically conferred by thiazolidinediones. These findings not only deepen our molecular understanding of the role of PPAR{gamma} in glomerular disease and underscore the potential for partial agonists of PPAR{gamma}, such as GQ-16 as a treatment modality for NS, but also lend the possibility of its potential benefits in diabetic nephropathy.

molecular biology↗