Biology subjects

Blumberg, B.

Publications and source records attributed to Blumberg, B..

8 recordsLinked to original sources

bioRxiv2025

Brown Adipose Tissue Dysfunction Links Obesogen Exposure to Reduced Energy Expenditure and Transgenerational Obesity

Obesity has become a global health challenge, and increasing evidence suggests that environmental obesogens contribute to its prevalence. Tributyltin (TBT) is a model obesogen known to activate PPAR{gamma} and RXR and to promote transgenerational obesity in mice, but the mechanisms linking TBT exposure to impaired energy balance remain poorly defined. Brown adipose tissue (BAT) is a central regulator of energy expenditure (EE) and basal metabolic rate (BMR) through both UCP1-dependent and UCP1-independent pathways. Here, we tested whether ancestral TBT exposure disrupts BAT function across generations. To assess whether TBT alters body composition and thermogenic capacity, we measured fat and lean mass, BAT gene expression, mitochondrial abundance, and core body temperature in F1 and F3 offspring. TBT-group males accumulated more fat mass without changes in lean mass or food intake scaled to metabolic size, indicating reduced EE/BMR. Expression of BAT lineage and oxidative genes (Zic1, Ebf2, Pgc1a, Pdk4) was suppressed in TBT-group males across generations. Ucp1 expression was unchanged at baseline but decreased after high-fat diet (HFD) challenge, whereas Ucp2 and Ucp4 were reduced even at baseline. In addition, key UCP1-independent thermogenic genes involved in creatine (Slc6a8, Ckb) and calcium (Atp2a2, Itpr) futile cycles were significantly decreased, while lipid-cycle genes (Pnpla2, Abhd5) were unaffected. Mitochondrial DNA content was largely unchanged, but core body temperature was reduced in TBT-group males prior to diet challenge, confirming impaired basal thermogenesis. These findings demonstrate that ancestral TBT exposure produces male-specific and heritable defects in BAT identity and thermogenic capacity. By suppressing both UCP1-dependent and UCP1-independent pathways without altering mitochondrial abundance, TBT-group males exhibit reduced energy expenditure and basal metabolic rate. These results identify BAT dysfunction as a mechanistic link between environmental obesogen exposure and transgenerational susceptibility to obesity.

pharmacology and toxicology↗

bioRxiv2025

The effect of cold exposure on energy expenditure of mice fed an obesogenic diet

ObjectiveCold exposure is one of the most powerful physiological stimuli for thermogenic adipose tissue activity and may positively impact metabolic homeostasis. An important gap in knowledge is whether mice with diet-induced obesity respond to cold similarly to their lean counterparts. The goal of the present study was to compare the response to cold exposure between mice fed a standard (normal-fat) diet and a higher-fat diet. MethodsMale C56BL/6J mice fed a standard diet (13.1% fat) or a higher-fat diet (21.6% fat) during adulthood and exposed to cold (4-6{degrees}C) following different approaches. Body weight, body composition, food intake, rectal temperature, energy expenditure, and respiratory exchange ratio were assessed. ResultsCold exposure significantly increased energy expenditure and limited weight gain despite elevated food intake in mice fed either a standard or a higher-fat diet, while body composition, body temperature, and respiratory exchange ratio remained stable across both dietary groups. Moreover, energy expenditure measured at 4-6 {degrees}C was comparable between mice fed standard and higher-fat diets, demonstrating that cold-induced thermogenesis may elicit a consistent metabolic response independent of dietary fat content. ConclusionsOur results demonstrated that cold exposure increased energy expenditure in both lean and obese animals, highlighting thermogenesis as a promising target for obesity treatment beyond current approaches focusing on appetite suppression. HighlightsO_LICold exposure increases energy expenditure and limits weight gain in both control diet and higher-fat diet-fed mice, despite increased food intake. C_LIO_LICore body temperature and body composition remain stable during cold exposure, regardless of dietary fat content. C_LIO_LICold-induced thermogenesis elicits a comparable metabolic response in control diet and higher-fat diet-fed mice, supporting its potential as a therapeutic strategy for obesity. C_LI

physiology↗

bioRxiv2022

miR-223 Plays A Critical Role in Obesogen-Enhanced Adipogenesis in Mesenchymal Stem Cells and in Transgenerational Obesity

Exposure of pregnant F0 mouse dams to the obesogen tributyltin (TBT) predisposes unexposed male descendants to obesity and diverts mesenchymal stem cells (MSCs) toward the adipocytic lineage. TBT also promotes adipogenic commitment and differentiation of MSCs, in vitro. We sought to identify TBT-induced factors predisposing MSCs toward the adipocytic fate. We exposed mouse MSCs to TBT, the PPAR{gamma}-selective agonist rosiglitazone or the RXR-selective agonist LG-100268 and determined their transcriptomal profiles to determine candidate microRNAs (miR) regulating adipogenic commitment and differentiation. Of the top 10 candidate microRNAs predicted by Ingenuity Pathway Analysis, miR-21, miR-33 and miR-223 were expressed in a manner consistent with an ability to differentially regulate target genes during adipogenesis. After 24 hours exposure to 50 nM TBT, miR-223 levels in MSCs were increased and expression of its target genes ZEB1, NFIB, and FOXP1 was decreased. Both ROSI and TBT increased miR-223 levels, and this induction was inhibited by the PPAR{gamma} antagonist T0070907 but not by the RXR antagonists HX531 or UVI3003, placing miR-223 downstream of PPAR{gamma}. Chromatin immunoprecipitation confirmed TBT-induced binding of PPAR{gamma} to regulatory elements in the miR-223 promoter. miR-223 levels were elevated in white adipose tissue of F2 and F3 male descendants of pregnant F0 mouse dams exposed to 50 nM TBT throughout gestation. miR-223 levels were further induced in males fed with an increased fat diet. We infer that TBT induced miR-223 expression and increased adipogenesis in MSCs through the PPAR{gamma} pathway and that transgenerationally increased expression of miR-223 plays an important role in the development of obesity caused by TBT exposure.

developmental biology↗

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↗

bioRxiv2021

Revisiting the Use of Structural Similarity Index in Hi-C

Identification of dynamic changes in chromatin conformation is a fundamental task in genetics. In 2020, Galan et al.1 presented CHESS (Comparison of Hi-C Experiments using Structural Similarity), a novel computational algorithm designed for systematic identification of structural differences in chromatin-contact maps. Using CHESS, the same group recently reported that chromatin organization is largely maintained across tissues during dorsoventral patterning of fruit fly embryos despite tissue-specific chromatin states and gene expression2. However, here we show that the primary outputs of CHESS-namely, the structural similarity index (SSIM) profiles-are nearly identical regardless of the input matrices, even when query and reference reads were shuffled to destroy any significant differences. This issue stems from the dominance of the regional counting noise arising from stochastic sampling in chromatin-contact maps, reflecting a fundamentally incorrect assumption of the CHESS algorithm. Therefore, biological interpretation of SSIM profiles generated by CHESS requires considerable caution.

bioinformatics↗

bioRxiv2021

Tributyltin exposure leads to increased adiposity and reduced abundance of leptogenic bacteria in the zebrafish intestine

The chemical obesogen tributyltin (TBT) is known to promote fat storage in adipose tissue through direct action on vertebrate cells. TBT also has direct toxic effects on microorganisms, raising the possibility that TBT may also promote fat storage in vertebrates by altering their microbiota. Here we show that exposure of conventionally-reared post-embryonic zebrafish to TBT results in increased adiposity, reduced body size, and altered intestinal microbiota composition including reduced relative abundance of Plesiomonas bacteria. To test if those microbiota alterations affected host adiposity, we exposed conventionally-reared zebrafish to intestinal bacterial strains representative of TBT-altered taxa. We found that introduction of a Plesiomonas strain into conventionally-reared zebrafish was sufficient to reduce adiposity and alter intestinal microbiota composition. Using new long-term gnotobiotic zebrafish husbandry methods, we found that colonization of germ-free zebrafish with Plesiomonas was sufficient to reduce host adiposity. Together these results show the leptogenic activity of Plesiomonas on zebrafish hosts, indicating that the ability of TBT to increase adiposity in vivo may be due in part to TBT-mediated modification of the abundance of leptogenic bacteria like Plesiomonas. These findings underscore how complex reciprocal interactions between animals and their microbial and chemical environments can influence energy balance and metabolic health. IMPORTANCEObesogens are environmental chemicals that promote fat storage and are generally thought to exert this effect directly on animal cells. Using zebrafish, we show that the obesogen tributyltin can also promote fat storage by acting upon intestinal microbiota via reduction of bacteria that are sufficient to reduce fat storage.

microbiology↗

bioRxiv2017

Ancestral perinatal obesogen exposure results in a transgenerational thrifty phenotype in mice

Ancestral environmental exposures to non-mutagenic agents can exert effects in unexposed descendants. This transgenerational inheritance has significant implications for understanding disease etiology. The obesogen hypothesis proposes that exposure to obesogenic chemicals can lead to increased adiposity, in vivo. Here we show that exposure of F0 mice to the obesogen tributyltin (TBT) throughout pregnancy and lactation predisposes unexposed F4 male descendants to obesity when dietary fat is increased. Analyses of body fat, plasma hormone levels, and visceral white adipose tissue DNA methylome and transcriptome collectively indicate that the F4 obesity is consistent with a leptin resistant, \"thrifty phenotype\". Ancestral TBT exposure induces global changes in DNA methylation together with altered expression of metabolism-relevant genes when the F4 animals were exposed to dietary challenges. Analysis of chromatin accessibility in F3 and F4 sperm reveal significant differences between control and TBT groups and significant similarities between F3 and F4 TBT groups that overlap with areas of differential methylation in F4 adipose tissue. Taken together, our data suggest that ancestral TBT exposure induces changes in higher order chromatin organization transmissible through meiosis and mitosis.\n\nNon-technical summaryAncestral obesogen exposure in mice causes obesity in untreated F4 male descendants by inducing heritable changes in genome architecture that predispose these animals to become obese when dietary fat is increased modestly. This result is consistent with these animals having a leptin-resistant, \"thrifty\" phenotype

developmental biology↗