Featured ArticlesVolume 22 | April 2019
|Silver nanoparticles inhibit beige fat function and promote adiposityNanoparticles, ultrafine particles of 1 to 100 nm in size, show unique optical, electrical, or thermal properties. The recent decade has seen an exponential growth in the fabrication of nanoparticles, commonly termed as engineered nanoparticles (ENPs). Silver nanoparticles (AgNPs) are among the most widely used ENPs. However, concerns have been raised about their safety and potential influence on human health. The potential contribution of AgNPs specifically to obesity as well as the underlying mechanism have not yet been addressed. Yue, Zhao, Wang, et al. studied the in vitro effects of AgNPs on beige adipocyte differentiation and function, as well as their in vivo influence on beige fat and metabolic parameters of mice on a high fat diet. Their results show that AgNPs suppress beige adipocyte development and function. This suggests that environmental exposure with AgNPs may contribute to the obesity epidemic.|
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Objective: Obesity is a complex chronic disease of high prevalence worldwide. Multiple factors play integral roles in obesity development, with rising interest focusing on the contribution of environmental pollutants frequent in modern society. Silver nanoparticles (AgNPs) are widely used for bactericidal purpose in various applications in daily life. However, their potential toxicity and contribution to the obesity epidemic are not clear.
Methods: Beige adipocytes are newly discovered adipocytes characterized by high thermogenic and energy dissipating capacity upon activation and the “browning” process. In the present study, we assess the impact of AgNPs exposure on beige adipocytes differentiation and functionality both in vitro and in vivo. We also systematically investigate the influence of AgNPs on adiposity and metabolic performance in mice, as well as the possible underlying molecular mechanism.
Results: The results showed that, independent of particle size, AgNPs inhibit the adipogenic, mitochondrial, and thermogenic gene programs of beige adipocytes, thus suppressing their differentiation ability, mitochondrial activity, and thermogenic response. Importantly, exposure to AgNPs in mice suppresses browning gene programs in subcutaneous fat, leading to decreased energy expenditure and increased adiposity in mice. Mechanistically, we found that AgNPs increase reactive oxidative species (ROS) levels and specifically activate MAPK-ERK signaling in beige adipocytes. The negative impacts of AgNPs on beige adipocytes can be ameliorated by antioxidant or ERK inhibitor FR180204 treatment.
Conclusions: Taken together, these results revealed an unexpected role of AgNPs in promoting adiposity through the inhibition of beige adipocyte differentiation and functionality, possibly by disrupting ROS homeostasis and ERK phosphorylation. Future assessments on the health risk of AgNPs applications and their safe dosages are warranted.[Hide abstract]
|Analysis of white and brown adipose tissue by shotgun lipidomicsThe two main forms of adipose tissue (AT) are white adipose tissue (WAT), which functions primarily as an energy reservoir, and brown adipose tissue (BAT), which contributes to thermoregulation. AT lipidomics analyses have reported differences between BAT and WAT and demonstrated remodeling upon exercise or cold exposure. However, these studies applied generic methods of lipid extraction and measurement rather than techniques tailored to these tissues. Grzybek, Palladini, et al. present a shotgun lipidomics method for the analysis for ATs with an unprecedented coverage of more than 300 lipid species. With their method, they not only observe clear differences between BAT and WAT lipidomes, but also amongst WAT subtypes, i.e. gonadal and inguinal subcutaneous ATs.|
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Objective: Shotgun lipidomics enables an extensive analysis of lipids from tissues and fluids. Each specimen requires appropriate extraction and processing procedures to ensure good coverage and reproducible quantification of the lipidome. Adipose tissue (AT) has become a research focus with regard to its involvement in obesity-related pathologies. However, the quantification of the AT lipidome is particularly challenging due to the predominance of triacylglycerides, which elicit high ion suppression of the remaining lipid classes.
Methods: We present a new and validated method for shotgun lipidomics of AT, which tailors the lipid extraction procedure to the target specimen and features high reproducibility with a linear dynamic range of at least 4 orders of magnitude for all lipid classes.
Results: Utilizing this method, we observed tissue-specific and diet-related differences in three AT types (brown, gonadal, inguinal subcutaneous) from lean and obese mice. Brown AT exhibited a distinct lipidomic profile with the greatest lipid class diversity and responded to high-fat diet by altering its lipid composition, which shifted towards that of white AT. Moreover, diet-induced obesity promoted an overall remodeling of the lipidome, where all three AT types featured a significant increase in longer and more unsaturated triacylglyceride and phospholipid species.
Conclusions: The here presented method facilitates reproducible systematic lipidomic profiling of AT and could be integrated with further –omics approaches used in (pre-) clinical research, in order to advance the understanding of the molecular metabolic dynamics involved in the pathogenesis of obesity-associated disorders.[Hide abstract]
|Membrane metallo-endopeptidase regulates inflammatory response and insulin signaling Membrane metallo-endopeptidase (MME) is a membrane-bound protein with an extracellular protease domain. Ramirez et al. show that MME has distinct roles in white preadipocytes. MME can target a broad class of inflammatory cytokines, thus its high expression in subcutaneous preadipocytes may serve to decrease inflammatory responses. MME can also regulate receptor trafficking, suggesting a cellular role in insulin signaling.|
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Objective: Accumulation of visceral white adipose tissue (WAT) associates with insulin resistance, adipose tissue inflammation, and metabolic syndrome, whereas accumulation of subcutaneous WAT may be protective. We aimed to identify molecular mechanisms that might provide mechanistic insights underlying the phenotypic differences in these tissues. Membrane Metallo-Endopeptidase (MME/Neprislyin) is an extracellular, membrane-bound protease enriched in subcutaneous WAT that can target degradation of a variety of peptides, including insulin, IL6, and β-amyloids. We hypothesized that MME contributes to adipose depot-specific metabolic properties.
Methods: We performed RNA sequencing on human subcutaneous and visceral preadipocytes and array gene expression profiling in murine subcutaneous and visceral preadipocytes. We conducted several insulin signaling and inflammatory response experiments on different cellular states of MME expression.
Results: MME in white preadipocytes is expressed at a higher level in subcutaneous compared to visceral WAT and favors insulin signaling and a low inflammatory response. Thus, knockdown of MME in subcutaneous preadipocytes increased the inflammatory response to substance P and amyloid β aggregates. This associated with increased basal insulin signaling and decreased insulin-stimulated signaling. Moreover, MME differentially regulates the internalization and turnover of the α/β subunits of the insulin receptor.
Conclusions: MME is a novel regulator of the insulin receptor in adipose tissue. Given the clinical significance of both chronic inflammation and insulin sensitivity in metabolic disease, these results show a potentially new target to increase insulin sensitivity and decrease inflammatory susceptibility.[Hide abstract]
|The BAT glucagon receptor is functional but not essential for control of energy homeostasisThe principal biological role of pancreatic glucagon is the maintenance of euglycemia through its control of hepatic glucose production. However, the glucagon receptor is not only expressed in hepatocytes but also in brown adipose tissue (BAT) and other tissues. Beaudry et al. examined the importance of the BAT glucagon receptor for glucagon-stimulated energy expenditure in mice. They show that, although the BAT glucagon receptor is functional, it is not essential for glucagon-stimulated increase in energy expenditure or the adaptive metabolic responses to high fat diet feeding or prolonged cold exposure.|
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Objective: Administration of glucagon (GCG) or GCG-containing co-agonists reduces body weight and increases energy expenditure. These actions appear to be transduced by multiple direct and indirect GCG receptor (GCGR)-dependent mechanisms. Although the canonical GCGR is expressed in brown adipose tissue (BAT) the importance of BAT GCGR activity for the physiological control of body weight, or the response to GCG agonism, has not been defined.
Methods: We studied the mechanisms linking GCG action to acute increases in oxygen consumption using wildtype (WT), Ucp1−/− and Fgf21−/− mice. The importance of basal GCGR expression within the Myf5+ domain for control of body weight, adiposity, glucose and lipid metabolism, food intake, and energy expenditure was examined in GcgrBAT−/− mice housed at room temperature or 4 °C, fed a regular chow diet (RCD) or after a prolonged exposure to high fat diet (HFD).
Results: Acute GCG administration induced lipolysis and increased the expression of thermogenic genes in BAT cells, whereas knockdown of Gcgr reduced expression of genes related to thermogenesis. GCG increased energy expenditure (measured by oxygen consumption) both in vivo in WT mice and ex vivo in BAT and liver explants. GCG also increased acute energy expenditure in Ucp1−/− mice, but these actions were partially blunted in Ffg21−/− mice. However, acute GCG administration also robustly increased oxygen consumption in GcgrBAT−/− mice. Moreover, body weight, glycemia, lipid metabolism, body temperature, food intake, activity, energy expenditure and adipose tissue gene expression profiles were normal in GcgrBAT−/− mice, either on RCD or HFD, whether studied at room temperature, or chronically housed at 4 °C.
Conclusions: Exogenous GCG increases oxygen consumption in mice, also evident both in liver and BAT explants ex vivo, through UCP1-independent, FGF21-dependent pathways. Nevertheless, GCGR signaling within BAT is not physiologically essential for control of body weight, whole body energy expenditure, glucose homeostasis, or the adaptive metabolic response to cold or prolonged exposure to an energy dense diet.[Hide abstract]
|Pnpla3 silencing ameliorates NASH and fibrosis in Pnpla3 I148M knock-in miceNonalcoholic fatty liver disease (NAFLD) is becoming the leading cause of chronic liver disease worldwide. The progression of NAFLD has a strong genetic component. A polymorphism in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene resultig in a change from isoleucine (I) to methionine (M) at position 148 of the protein exerts the largest effect on NAFLD progression identified to date. Lindén and colleagues show that Pnpla3 silencing exerts a beneficial effect on liver fat accumulation, inflammation, and fibrosis that is more pronounced in the presence of the Pnpla3 I148M mutation.
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Objective: Nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of advanced chronic liver disease. The progression of NAFLD, including nonalcoholic steatohepatitis (NASH), has a strong genetic component, and the most robust contributor is the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 encoding the 148M protein sequence variant. We hypothesized that suppressing the expression of the PNPLA3 148M mutant protein would exert a beneficial effect on the entire spectrum of NAFLD.
Methods: We examined the effects of liver-targeted GalNAc3-conjugated antisense oligonucleotide (ASO)-mediated silencing of Pnpla3 in a knock-in mouse model in which we introduced the human PNPLA3 I148M mutation.
Results: ASO-mediated silencing of Pnpla3 reduced liver steatosis (p = 0.038) in homozygous Pnpla3 148M/M knock-in mutant mice but not in wild-type littermates fed a steatogenic high-sucrose diet. In mice fed a NASH-inducing diet, ASO-mediated silencing of Pnpla3 reduced liver steatosis score and NAFLD activity score independent of the Pnpla3 genotype, while reductions in liver inflammation score (p = 0.018) and fibrosis stage (p = 0.031) were observed only in the Pnpla3 knock-in 148M/M mutant mice. These responses were accompanied by reduced liver levels of Mcp1 (p = 0.026) and Timp2 (p = 0.007) specifically in the mutant knock-in mice. This may reduce levels of chemokine attracting inflammatory cells and increase the collagenolytic activity during tissue regeneration.
Conclusion: This study provides the first evidence that a Pnpla3 ASO therapy can improve all features of NAFLD, including liver fibrosis, and suppress the expression of a strong innate genetic risk factor, Pnpla3 148M, which may open up a precision medicine approach in NASH.[Hide abstract]
|Activation of hepatic ER-α increases energy expenditure by stimulating FGF21 productionEstrogens help maintain energy homeostasis in both male and female rodents and humans. After menopause, estrogen-deficient women are predisposed to metabolic dysfunction. Fibroblast growth factor 21 (FGF21), a hormone mainly produced by the liver during fasting, shows multiple beneficial effects in obese and diabetic individuals. Allard et al. show that in female mice, treatment with exogenous estrogen acting on the hepatocyte estrogen receptor-α increases serum FGF21 concentrations. In these mice, exogenous estrogen stimulates energy expenditure at least partially via FGF21. However, these results were not reproduced in an observational cohort of menopausal women who received estrogen therapy.|
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Objective: The endogenous estrogen 17β-estradiol (E2) promotes metabolic homeostasis in premenopausal women. In a mouse model of post-menopausal metabolic syndrome, we reported that estrogens increased energy expenditure, thus preventing estrogen deficiency-induced adiposity. Estrogens' prevention of fat accumulation was associated with increased serum concentrations of fibroblast growth factor 21 (FGF21), suggesting that FGF21 participates in estrogens' promotion of energy expenditure.
Methods: We studied the effect of E2 on FGF21 production and the role of FGF21 in E2 stimulation of energy expenditure and prevention of adiposity, using female estrogen receptor (ER)- and FGF21-deficient mice fed a normal chow and a cohort of ovariectomized women from the French E3N prospective cohort study.
Results: E2 acting on the hepatocyte ERα increases hepatic expression and production of FGF21 in female mice. In vivo activation of ERα increases the transcription of Fgf21 via an estrogen response element outside the promoter of Fgf21. Treatment with E2 increases oxygen consumption and energy expenditure and prevents whole body fat accumulation in ovariectomized female WT mice. The effect of E2 on energy expenditure is not observed in FGF21-deficient mice. While E2 treatment still prevents fat accumulation in FGF21-deficient mice, this effect is decreased compared to WT mice. In an observational cohort of ovariectomized women, E2 treatment was associated with lower serum FGF21 concentrations, which may reflect a healthier metabolic profile.
Conclusion: In female mice, E2 action on the hepatocyte ERα increases Fgf21 transcription and FGF21 production, thus promoting energy expenditure and partially decreasing fat accumulation.[Hide abstract]
|Functional peroxisomes are required for β-cell integrity in micePeroxisomes are still enigmatic organelles six decades after their discovery. Their importance for pancreatic β-cell function remains largely unexplored. Baboota, Shinde, and colleagues assessed the abundance of peroxisomes in the endocrine pancreas and used an in vivo loss-of-function approach to investigate the role of peroxisomes in pancreatic β-cells. They provide evidence that peroxisomal metabolism plays an essential role in the preservation of β-cell integrity. This suggests that enhancing peroxisome activity is a potential avenue to support β-cell function in metabolic stress conditions.|
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Objective: Peroxisomes play a crucial role in lipid and reactive oxygen species metabolism, but their importance for pancreatic β-cell functioning is presently unknown. To examine the contribution of peroxisomal metabolism to β-cell homeostasis in mice, we inactivated PEX5, the import receptor for peroxisomal matrix proteins, in an inducible and β-cell restricted manner (Rip-Pex5−/− mice).
Methods: After tamoxifen-induced recombination of the Pex5 gene at the age of 6 weeks, mice were fed either normal chow or a high-fat diet for 12 weeks and were subsequently phenotyped.
Results: Increased levels of very long chain fatty acids and reduced levels of plasmalogens in islets confirmed impairment of peroxisomal fatty acid oxidation and ether lipid synthesis, respectively. The Rip-Pex5−/− mice fed on either diet exhibited glucose intolerance associated with impaired insulin secretion. Ultrastructural and biochemical analysis revealed a decrease in the density of mature insulin granules and total pancreatic insulin content, which was further accompanied by mitochondrial disruptions, reduced complex I activity and massive vacuole overload in β-cells. RNAseq analysis suggested that cell death pathways were affected in islets from HFD-fed Rip-Pex5−/− mice. Consistent with this change we observed increased β-cell apoptosis in islets and a decrease in β-cell mass.
Conclusions: Our data indicate that normal peroxisome metabolism in β-cells is crucial to preserve their structure and function.[Hide abstract]
|miR-132-3p is a positive regulator of alpha-cell mass miRNAs are small non-coding RNAs that regulate the expression of target genes by inhibiting translation or by inducing mRNA degradation. Several studies have illustrated the importance of miRNAs in glucose homeostasis. Dusaulcy et al. hypothesized that miRNAs are involved in alpha-cell molecular and functional alterations or adaptations in type 2 diabetes. They identified 16 miRNAs in alpha-cells and 28 in beta-cells differentially regulated according to diet. The most highly differentially regulated miRNA in alpha-cells from hyperglycemic mice, miR-132-3p, was found to be involved in alpha-cell proliferation and survival.|
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Objective: Diabetes is a complex disease implicating several organs and cell types. Within the islets, dysregulation occurs in both alpha- and beta-cells, leading to defects of insulin secretion and increased glucagon secretion. Dysregulation of alpha-cells is associated with transcriptome changes. We hypothesized that microRNAs (miRNAs) which are negative regulators of mRNA stability and translation could be involved in alpha-cell alterations or adaptations during type 2 diabetes.
Methods: miRNA microarray analyses were performed on pure alpha- and beta-cells from high-fat diet fed obese hyperglycemic mice and low-fat diet fed controls. Then, the most regulated miRNA was overexpressed or inhibited in primary culture of mouse and human alpha-cells to determine its molecular and functional impact.
Results: 16 miRNAs were significantly regulated in alpha-cells of obese hyperglycemic mice and 28 in beta-cells. miR-132-3p had the strongest regulation level in alpha-cells, where it was downregulated, while we observed an opposite upregulation in beta-cells. In vitro experiments showed that miR-132-3p, which is inversely regulated by somatostatin and cAMP, is a positive modulator of alpha-cell proliferation and implicated in their resistance to apoptosis. These effects are associated with the regulation of a series of genes, including proliferation and stress markers Mki67 and Bbc3 in mouse and human alpha-cells, potentially involved in miR-132-3p functions.
Conclusions: Downregulation of miR-132-3p in alpha-cells of obese diabetic mice may constitute a compensatory mechanism contributing to keep glucagon-producing cell number constant in diabetes.[Hide abstract]
|Synbiotic-driven improvement of metabolic disturbances is associated with changes in the gut microbiome The gut microbiota are thought to play a key role in the regulation of host metabolism. Modulation of the gut microbiome may have beneficial effects on metabolism in obese individuals. Ke et al. tested interventions that modulate the gut microbiome and found that a combination of living bacteria and substances that promote their growth, called a synbiotic, improved metabolic disturbances in diet-induced obese mice. This was associated with changes in the gut microbiome which they characterized using a multi-omics approach.
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Objective: The gut microbiota is an important influencing factor of metabolic health. Although dietary interventions with probiotics, prebiotics, and synbiotics can be effective means to regulate obesity and associated comorbidities, the underlying shifts in gut microbial communities, especially at the functional level, have not been characterized in great details. In this study, we sought to investigate the effects of synbiotics on the regulation of gut microbiota and the alleviation of high-fat diet (HFD)-induced metabolic disorders in mice.
Methods: Specific pathogen-free (SPF) male C57BL/6J mice were fed diets with either 10% (normal diet, ND) or 60% (high-fat diet, HFD) of total calories from fat (lard). Dietary interventions in the HFD-fed mice included (i) probiotic (Bifidobacterium animalis subsp. lactis and Lactobacillus paracasei subsp. paracasei DSM 46331), (ii) prebiotic (oat β-glucan), and (iii) synbiotic (a mixture of i and ii) treatments for 12 weeks. Besides detailed characterization of host metabolic parameters, a multi-omics approach was used to systematically profile the microbial signatures at both the phylogenetic and functional levels using 16S rRNA gene sequencing, metaproteomics and targeted metabolomics analysis.
Results: The synbiotic intervention significantly reduced body weight gain and alleviated features of metabolic complications. At the phylogenetic level, the synbiotic treatment significantly reversed HFD-induced changes in microbial populations, both in terms of richness and the relative abundance of specific taxa. Potentially important species such as Faecalibaculum rodentium and Alistipes putredinis that might mediate the beneficial effects of the synbiotic were identified. At the functional level, short-chain fatty acid and bile acid profiles revealed that all dietary interventions significantly restored cecal levels of acetate, propionate, and butyrate, while the synbiotic treatment reduced the bile acid pools most efficiently. Metaproteomics revealed that the effects of the synbiotic intervention might be mediated through metabolic pathways involved in carbohydrate, amino acid, and energy metabolisms.
Conclusions: Our results suggested that dietary intervention using the novel synbiotic can alleviate HFD-induced weight gain and restore gut microbial ecosystem homeostasis phylogenetically and functionally.[Hide abstract]
|Repeated cold exposures protect a mouse model of Alzheimer’s disease against cold-induced tau phosphorylationAlzheimer’s disease (AD) is a neurodegenerative disease characterized by disrupted cognitive functions and is diagnosed neuropathologically by the presence of tau-laden neurofibrillary tangles. Animal studies suggest that thermoregulatory deficits contribute to AD pathogenesis. Tournissac and colleagues corrected thermoregulatory impairments through brown adipose tissue stimulation by repeated cold exposures in a mouse model of AD. Indeed, they found improved glucose metabolism and protection against cold-induced tau phosphorylation in their model.|
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Objective: Old age is associated with a rise in the incidence of Alzheimer's disease (AD) but also with thermoregulatory deficits. Indicative of a link between the two, hypothermia induces tau hyperphosphorylation. The 3xTg-AD mouse model not only develops tau and amyloid pathologies in the brain but also metabolic and thermoregulatory deficits. Brown adipose tissue (BAT) is the main thermogenic driver in mammals, and its stimulation counteracts metabolic deficits in rodents and humans. We thus investigated whether BAT stimulation impedes AD neuropathology.
Methods: 15-month-old 3xTg-AD mice were subjected to repeated short cold exposures (RSCE), consisting of 4-hour sessions of cold exposure (4 °C), five times per week for four weeks, compared to animals kept at housing temperature.
Results: First, we confirmed that 3xTg-AD RSCE-trained mice exhibited BAT thermogenesis and improved glucose tolerance. RSCE-trained mice were completely resistant to tau hyperphosphorylation in the hippocampus induced by a 24-hour cold challenge. Finally, RSCE increased plasma levels of fibroblast growth factor 21 (FGF21), a batokine, which inversely correlated with hippocampal tau phosphorylation.
Conclusions: Overall, BAT stimulation through RSCE improved metabolic deficits and completely blocked cold-induced tau hyperphosphorylation in the 3xTg-AD mouse model of AD neuropathology. These results suggest that improving thermogenesis could exert a therapeutic effect in AD.[Hide abstract]
|Roles for STAT proteins in leptin actionLeptin, a peptide hormone produced by white adipose tissue in proportion to energy stores, plays a central role in the control of feeding and energy balance. Leptin acts via its receptor to activate several members of the signal transducer and activator of transcription (STAT) transcription factor family. Pan, Allison, and colleagues investigated the roles of STAT1, STAT3 and STAT5 in response to leptin. Although leptin receptor activates STAT1, STAT3, and STAT5 in cultured cells, their findings reveal no role for STAT1 or STAT5 in leptin action in vivo.
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Objective: Leptin acts via its receptor LepRb on specialized neurons in the brain to modulate food intake, energy expenditure, and body weight. LepRb activates signal transducers and activators of transcription (STATs, including STAT1, STAT3, and STAT5) to control gene expression.
Methods: Because STAT3 is crucial for physiologic leptin action, we used TRAP-seq to examine gene expression in LepRb neurons of mice ablated for Stat3 in LepRb neurons (Stat3LepRbKO mice), revealing the STAT3-dependent transcriptional targets of leptin. To understand roles for STAT proteins in leptin action, we also ablated STAT1 or STAT5 from LepRb neurons and expressed a constitutively-active STAT3 (CASTAT3) in LepRb neurons.
Results: While we also found increased Stat1 expression and STAT1-mediated transcription of leptin-regulated genes in Stat3LepRbKO mice, ablating Stat1 in LepRb neurons failed to alter energy balance (even on the Stat3LepRbKO background); ablating Stat5 in LepRb neurons also failed to alter energy balance. Importantly, expression of a constitutively-active STAT3 (CASTAT3) in LepRb neurons decreased food intake and body weight and improved metabolic parameters in leptin-deficient (ob/ob) mice, as well as in wild-type animals.
Conclusions: Thus, STAT3 represents the unique STAT protein required for leptin action and STAT3 suffices to mediate important components of leptin action in the absence of other LepRb signals.[Hide abstract]
|WWOX ablation in skeletal muscles alters glucose metabolismWWOX is a tumor suppressor that is commonly lost in several human malignancies. Several reports have implicated WWOX function in cellular metabolism. Abu-Remaileh et al. screened for the metabolic function of WWOX using engineered mouse models in which the murine Wwox gene was specifically deleted in the main metabolic peripheral organs including liver, adipose tissue, and skeletal muscle. They found that only mice with skeletal muscle-specific ablation of Wwox develop a phenotype resembling metabolic syndrome, as manifested by hyperglycemia, obesity, and dyslipidemia.
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Objective: WWOX, a well-established tumor suppressor, is frequently lost in cancer and plays important roles in DNA damage response and cellular metabolism.
Methods: We re-analyzed several genome-wide association studies (GWAS) using the Type 2 Diabetes Knowledge Portal website to uncover WWOX's association with metabolic syndrome (MetS). Using several engineered mouse models, we studied the effect of somatic WWOX loss on glucose homeostasis.
Results: Several WWOX variants were found to be strongly associated with MetS disorders. In mouse models, somatic ablation of Wwox in skeletal muscle (WwoxΔSKM) results in weight gain, glucose intolerance, and insulin resistance. Furthermore, WwoxΔSKM mice display reduced amounts of slow-twitch fibers, decreased mitochondrial quantity and activity, and lower glucose oxidation levels. Mechanistically, we found that WWOX physically interacts with the cellular energy sensor AMP-activated protein kinase (AMPK) and that its loss is associated with impaired activation of AMPK, and with significant accumulation of the hypoxia inducible factor 1 alpha (HIF1α) in SKM.
Conclusions: Our studies uncover an unforeseen role of the tumor suppressor WWOX in whole-body glucose homeostasis and highlight the intimate relationship between cancer progression and metabolic disorders, particularly obesity and type-2 diabetes.[Hide abstract]