RESUMEN
We have uncovered the existence of extracellular vesicle (EV)-mediated signaling between cell types within the adipose tissue (AT) proper. This phenomenon became evident in our attempts at generating an adipocyte-specific knockout of caveolin 1 (cav1) protein. Although we effectively ablated the CAV1 gene in adipocytes, cav1 protein remained abundant. With the use of newly generated mouse models, we show that neighboring endothelial cells (ECs) transfer cav1-containing EVs to adipocytes in vivo, which reciprocate by releasing EVs to ECs. AT-derived EVs contain proteins and lipids capable of modulating cellular signaling pathways. Furthermore, this mechanism facilitates transfer of plasma constituents from ECs to the adipocyte. The transfer event is physiologically regulated by fasting/refeeding and obesity, suggesting EVs participate in the tissue response to changes in the systemic nutrient state. This work offers new insights into the complex signaling mechanisms that exist among adipocytes, stromal vascular cells, and, potentially, distal organs.
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Adipocitos/metabolismo , Células Endoteliales/metabolismo , Vesículas Extracelulares/metabolismo , Ayuno/metabolismo , Transducción de Señal , Animales , Caveolina 1/genética , Caveolina 1/metabolismo , Línea Celular , Células Cultivadas , Endotelio Vascular/citología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Circular RNAs (circRNAs) are a conserved class of RNAs with diverse functions, including serving as messenger RNAs that are translated into peptides. Here we describe circular RNAs generated by human polyomaviruses (HPyVs), some of which encode variants of the previously described alternative large T antigen open reading frame (ALTO) protein. Circular ALTO RNAs (circALTOs) can be detected in virus positive Merkel cell carcinoma (VP-MCC) cell lines and tumor samples. CircALTOs are stable, predominantly located in the cytoplasm, and N6-methyladenosine (m6A) modified. The translation of MCPyV circALTOs into ALTO protein is negatively regulated by MCPyV-generated miRNAs in cultured cells. MCPyV ALTO expression increases transcription from some recombinant promoters in vitro and upregulates the expression of multiple genes previously implicated in MCPyV pathogenesis. MCPyV circALTOs are enriched in exosomes derived from VP-MCC lines and circALTO-transfected 293T cells, and purified exosomes can mediate ALTO expression and transcriptional activation in MCPyV-negative cells. The related trichodysplasia spinulosa polyomavirus (TSPyV) also expresses a circALTO that can be detected in infected tissues and produces ALTO protein in cultured cells. Thus, human polyomavirus circRNAs are expressed in human tumors and infected tissues and express proteins that have the potential to modulate the infectious and tumorigenic properties of these viruses.
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Antígenos Virales de Tumores/genética , Carcinoma de Células de Merkel/virología , Poliomavirus de Células de Merkel/genética , Infecciones por Polyomavirus/virología , ARN Circular/genética , Infecciones Tumorales por Virus/virología , Exosomas , Regulación Viral de la Expresión Génica , Células HEK293 , Humanos , MicroARNs/genética , ARN Mensajero/genética , ARN Viral/genéticaRESUMEN
Functional adipose tissue is essential for homeostatic maintenance of systemic metabolism. As such, adipose tissue dysfunction, like that seen in the obese state, directly contributes to system-wide pathological metabolism, leading to the development of type 2 diabetes and other obesity-associated comorbidities. In addition to the storage function of adipocytes, they also secrete numerous factors that robustly regulate metabolism-related pathways throughout the body. Many of these factors, in addition to other signaling proteins, RNA species and lipids, are found in extracellular vesicles (EVs) released from adipocytes. EVs are vesicles with a lipid bilayer, known to carry signaling proteins and lipids, mRNAs and miRNAs. Because of this diverse cargo, EVs can have robust and pleotropic signaling effects depending on the receiving target cells. We are only now starting to understand how adipocyte EVs can modulate metabolism within adipose tissue and beyond. Here, we highlight the current literature that demonstrates EV-mediated crosstalk between adipocytes and other tissues or distal cells. We become increasingly aware of the importance of these adipocyte-derived EV signals that establish a so far underappreciated endocrine system. Adipocyte EVs offer a new avenue for pharmacological manipulation of metabolism to treat obesity-related disease.
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Diabetes Mellitus Tipo 2 , Vesículas Extracelulares , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patología , Humanos , Obesidad/metabolismoRESUMEN
Cardiac metabolic inflexibility is driven by robust up-regulation of pyruvate dehydrogenase kinase 4 (PDK4) and phosphorylation-dependent inhibition of pyruvate dehydrogenase (PDH) within a single day of feeding mice a high fat diet. In the current study, we have discovered that PDK4 is a short lived protein (t½ â¼ 1 h) and is specifically degraded by the mitochondrial protease Lon. Lon does not rapidly degrade PDK1 and -2, indicating specificity toward the PDK isoform that is a potent modulator of metabolic flexibility. Moreover, PDK4 degradation appears regulated by dissociation from the PDH complex dependent on the respiratory state and energetic substrate availability of mouse heart mitochondria. Finally, we demonstrate that pharmacologic inhibition of PDK4 promotes PDK4 degradation in vitro and in vivo These findings reveal a novel strategy to manipulate PDH activity by selectively targeting PDK4 content through dissociation and proteolysis.
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Regulación Enzimológica de la Expresión Génica , Mitocondrias Cardíacas/metabolismo , Miocitos Cardíacos/metabolismo , Proteasa La/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Complejo Piruvato Deshidrogenasa/metabolismo , Animales , Células Cultivadas , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/citología , Fosforilación , Proteasa La/genética , Proteínas Serina-Treonina Quinasas/genética , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora , Complejo Piruvato Deshidrogenasa/genéticaRESUMEN
Resistin, and its closely related homologs, the resistin-like molecules (RELMs) have been implicated in metabolic dysregulation, inflammation, and cancer. Specifically, RELMß, expressed predominantly in the goblet cells in the colon, is released both apically and basolaterally, and is hence found in both the intestinal lumen in the mucosal layer as well as in the circulation. RELMß has been linked to both the pathogenesis of colon cancer and type 2 diabetes. RELMß plays a complex role in immune system regulation, and the impact of loss of function of RELMß on colon cancer and metabolic regulation has not been fully elucidated. We therefore tested whether Retnlß (mouse ortholog of human RETNLß) null mice have an enhanced or reduced susceptibility for colon cancer as well as metabolic dysfunction. We found that the lack of RELMß leads to increased colonic expression of T helper cell type-2 cytokines and IL-17, associated with a reduced ability to maintain intestinal homeostasis. This defect leads to an enhanced susceptibility to the development of inflammation, colorectal cancer, and glucose intolerance. In conclusion, the phenotype of the Retnlß null mice unravels new aspects of inflammation-mediated diseases and strengthens the notion that a proper intestinal barrier function is essential to sustain a healthy phenotype.
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Colitis/inmunología , Neoplasias del Colon/inmunología , Hormonas Ectópicas/inmunología , Intestinos/inmunología , Animales , Colitis/genética , Neoplasias del Colon/genética , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades/inmunología , Citometría de Flujo , Hormonas Ectópicas/genética , Péptidos y Proteínas de Señalización Intercelular , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena de la Polimerasa , Linfocitos T Colaboradores-InductoresRESUMEN
Obesity enhances the risk for the development of type 2 diabetes and cardiovascular disease. Loss in insulin sensitivity and diminished ability of muscle to take up and use glucose are characteristics of type 2 diabetes. Paradoxically, regulatory mechanisms that promote utilization of fatty acids appear to initiate diet-induced insulin insensitivity. In this review, we discuss recent findings implicating increased mitochondrial production of the prooxidant H2O2 due to enhanced utilization of fatty acids, as a signal to diminish reliance on glucose and its metabolites for energy. In the short term, the ability to preferentially use fatty acids may be beneficial, promoting a metabolic shift that ensures use of available fat by skeletal muscle and heart while preventing intracellular glucose accumulation and toxicity. However, with prolonged consumption of high dietary fat and ensuing obesity, the near exclusive dependence on fatty acid oxidation for production of energy by the mitochondria drives insulin resistance, diabetes, and cardiovascular disease.
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Metabolismo Energético/fisiología , Ácidos Grasos/metabolismo , Resistencia a la Insulina/fisiología , Mitocondrias Musculares/metabolismo , Animales , Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus/epidemiología , Glucosa/metabolismo , Humanos , Obesidad/complicaciones , Obesidad/metabolismo , Oxidación-Reducción , Factores de RiesgoRESUMEN
Recent studies have demonstrated that extracellular vesicles (EVs) serve powerful and complex functions in metabolic regulation and metabolic-associated disease, although this field of research is still in its infancy. EVs are released into the extracellular space from all cells and carry a wide range of cargo including miRNAs, mRNA, DNA, proteins, and metabolites that have robust signaling effects in receiving cells. EV production is stimulated by all major stress pathways and, as such, has a role in both restoring homeostasis during stress and perpetuating disease. In metabolic regulation, the dominant stress signal is a lack of energy due to either nutrient deficits or damaged mitochondria from nutrient excess. This stress signal is termed "energetic stress," which triggers a robust and evolutionarily conserved response that engages major cellular stress pathways, the ER unfolded protein response, the hypoxia response, the antioxidant response, and autophagy. This article proposes the model that energetic stress is the dominant stimulator of EV release with a focus on metabolically important cells such as hepatocytes, adipocytes, myocytes, and pancreatic ß-cells. Furthermore, this article will discuss how the cargo in stress-stimulated EVs regulates metabolism in receiving cells in both beneficial and detrimental ways. © 2023 American Physiological Society. Compr Physiol 13:5051-5068, 2023.
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Vesículas Extracelulares , Enfermedades Metabólicas , MicroARNs , Humanos , Vesículas Extracelulares/metabolismo , Enfermedades Metabólicas/metabolismo , Transducción de Señal , Comunicación CelularRESUMEN
Extracellular vesicles (EVs) produced by adipocytes and other adipose tissue (AT) cells are present in the space between cells in the tissue and in circulation. These EVs have been shown to robustly signal between cells in the tissue and in distal organs. AT has unique biophysical properties that require an optimized EV isolation protocol that ensures an uncontaminated EV isolate. This protocol can be used to isolate and characterize the total, heterogeneous population of EVs from the AT.
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Tejido Adiposo , Vesículas Extracelulares , AdipocitosRESUMEN
The disease progression of the metabolic syndrome is associated with prolonged hyperlipidemia and insulin resistance, eventually giving rise to impaired insulin secretion, often concomitant with hypoadiponectinemia. As an adipose tissue derived hormone, adiponectin is beneficial for insulin secretion and ß cell health and differentiation. However, the down-stream pathway of adiponectin in the pancreatic islets has not been studied extensively. Here, along with the overall reduction of endocrine pancreatic function in islets from adiponectin KO mice, we examine PPARα and HNF4α as additional down-regulated transcription factors during a prolonged metabolic challenge. To elucidate the function of ß cell-specific PPARα and HNF4α expression, we developed doxycycline inducible pancreatic ß cell-specific PPARα (ß-PPARα) and HNF4α (ß-HNF4α) overexpression mice. ß-PPARα mice exhibited improved protection from lipotoxicity, but elevated ß-oxidative damage in the islets, and also displayed lowered phospholipid levels and impaired glucose-stimulated insulin secretion. ß-HNF4α mice showed a more severe phenotype when compared to ß-PPARα mice, characterized by lower body weight, small islet mass and impaired insulin secretion. RNA-sequencing of the islets of these models highlights overlapping yet unique roles of ß-PPARα and ß-HNF4α. Given that ß-HNF4α potently induces PPARα expression, we define a novel adiponectin-HNF4α-PPARα cascade. We further analyzed downstream genes consistently regulated by this axis. Among them, the islet amyloid polypeptide (IAPP) gene is an important target and accumulates in adiponectin KO mice. We propose a new mechanism of IAPP aggregation in type 2 diabetes through reduced adiponectin action.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Animales , Ratones , Adiponectina/genética , Adiponectina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismoRESUMEN
Extracellular vesicles (EVs) are small, lipid-bilayer-bound particles released by cells that can contain important bioactive molecules, including lipids, RNAs, and proteins. Once released in the extracellular environment, EVs can act as messengers locally as well as to distant tissues to coordinate tissue homeostasis and systemic responses. There is a growing interest in not only understanding the physiology of EVs as signaling particles but also leveraging them as minimally invasive diagnostic and prognostic biomarkers (e.g., they can be found in biofluids) and drug-delivery vehicles. On October 30-November 2, 2022, researchers in the EV field convened for the Keystone symposium "Exosomes, Microvesicles, and Other Extracellular Vesicles" to discuss developing standardized language and methodology, new data on the basic biology of EVs and potential clinical utility, as well as novel technologies to isolate and characterize EVs.
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Micropartículas Derivadas de Células , Exosomas , Vesículas Extracelulares , Humanos , Exosomas/metabolismo , Vesículas Extracelulares/metabolismo , Micropartículas Derivadas de Células/metabolismo , ARN/metabolismoRESUMEN
Extracellular vesicles (EVs), exosomes and microvesicles, is a burgeoning field of biological and biomedical research that may change our understanding of cell communication in plants and animals while holding great promise for the diagnosis of disease and the development of therapeutics. However, the challenge remains to develop a general hypothesis about the role of EVs in physiological homeostasis and pathobiology across kingdoms. While they can act systemically, EVs are often seen to operate locally within a microenvironment. This microenvironment is built as a collection of microunits comprised of cells that interact with each other via EV exchange, EV signaling, EV seeding, and EV disposal. We propose that microunits are part of a larger matrix at the tissue level that collectively communicates with the surrounding environment, including other end-organ systems. Herein, we offer a working model that encompasses the various facets of EV function in the context of the cell biology and physiology of multicellular organisms.
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Iron is essential to many fundamental biological processes, but its cellular compartmentalization and concentration must be tightly controlled. Although iron overload can contribute to obesity-associated metabolic deterioration, the subcellular localization and accumulation of iron in adipose tissue macrophages is largely unknown. Here, we show that macrophage mitochondrial iron levels control systemic metabolism in male mice by altering adipocyte iron concentrations. Using various transgenic mouse models to manipulate the macrophage mitochondrial matrix iron content in an inducible fashion, we demonstrate that lowering macrophage mitochondrial matrix iron increases numbers of M2-like macrophages in adipose tissue, lowers iron levels in adipocytes, attenuates inflammation and protects from high-fat-diet-induced metabolic deterioration. Conversely, elevating macrophage mitochondrial matrix iron increases M1-like macrophages and iron levels in adipocytes, exacerbates inflammation and worsens high-fat-diet-induced metabolic dysfunction. These phenotypes are robustly reproduced by transplantation of a small amount of fat from transgenic to wild-type mice. Taken together, we identify macrophage mitochondrial iron levels as a crucial determinant of systemic metabolic homeostasis in mice.
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Tejido Adiposo , Hierro , Masculino , Ratones , Animales , Hierro/metabolismo , Tejido Adiposo/metabolismo , Macrófagos/metabolismo , Adipocitos/metabolismo , Inflamación/metabolismoRESUMEN
Caveolin-1 (cav1) is an important structural and signaling component of plasma membrane invaginations called caveolae and is abundant in adipocytes. As previously reported, adipocyte-specific ablation of the cav1 gene (ad-cav1 knockout [KO] mouse) does not result in elimination of the protein, as cav1 protein traffics to adipocytes from neighboring endothelial cells. However, this mouse is a functional KO because adipocyte caveolar structures are depleted. Compared with controls, ad-cav1KO mice on a high-fat diet (HFD) display improved whole-body glucose clearance despite complete loss of glucose-stimulated insulin secretion, blunted insulin-stimulated AKT activation in metabolic tissues, and partial lipodystrophy. The cause is increased insulin-independent glucose uptake by white adipose tissue (AT) and reduced hepatic gluconeogenesis. Furthermore, HFD-fed ad-cav1KO mice display significant AT inflammation, fibrosis, mitochondrial dysfunction, and dysregulated lipid metabolism. The glucose clearance phenotype of the ad-cav1KO mice is at least partially mediated by AT small extracellular vesicles (AT-sEVs). Injection of control mice with AT-sEVs from ad-cav1KO mice phenocopies ad-cav1KO characteristics. Interestingly, AT-sEVs from ad-cav1KO mice propagate the phenotype of the AT to the liver. These data indicate that ad-cav1 is essential for healthy adaptation of the AT to overnutrition and prevents aberrant propagation of negative phenotypes to other organs by EVs.
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Caveolina 1 , Vesículas Extracelulares , Insulina , Animales , Ratones , Adipocitos/metabolismo , Caveolina 1/genética , Caveolina 1/metabolismo , Dieta Alta en Grasa , Células Endoteliales/metabolismo , Vesículas Extracelulares/metabolismo , Glucosa/metabolismo , Insulina/metabolismo , Insulina Regular Humana , Ratones NoqueadosRESUMEN
Obesity is associated with increased cancer incidence and progression. However, the relationship between adiposity and cancer remains poorly understood at the mechanistic level. Here, we report that adipocytes from tumor-invasive mammary fat undergo de-differentiation to fibroblast-like precursor cells during tumor progression and integrate into the tumor microenvironment. Single-cell sequencing reveals that these de-differentiated adipocytes lose their original identities and transform into multiple cell types, including myofibroblast- and macrophage-like cells, with their characteristic features involved in immune response, inflammation, and extracellular matrix remodeling. The de-differentiated cells are metabolically distinct from tumor-associated fibroblasts but exhibit comparable effects on tumor cell proliferation. Inducing de-differentiation by Xbp1s overexpression promotes tumor progression despite lower adiposity. In contrast, promoting lipid-storage capacity in adipocytes through MitoNEET overexpression curbs tumor growth despite greater adiposity. Collectively, the metabolic interplay between tumor cells and adipocytes induces adipocyte mesenchymal transition and contributes to reconfigure the stroma into a more tumor-friendly microenvironment.
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Neoplasias de la Mama , Neoplasias Mamarias Animales , Adipocitos/metabolismo , Animales , Neoplasias de la Mama/patología , Matriz Extracelular/metabolismo , Femenino , Humanos , Neoplasias Mamarias Animales/patología , Microambiente TumoralRESUMEN
Adipocytes transfer mitochondria to macrophages in white and brown adipose tissues to maintain metabolic homeostasis. In obesity, adipocyte-to-macrophage mitochondria transfer is impaired, and instead, adipocytes release mitochondria into the blood to induce a protective antioxidant response in the heart. We found that adipocyte-to-macrophage mitochondria transfer in white adipose tissue is inhibited in murine obesity elicited by a lard-based high-fat diet, but not a hydrogenated-coconut-oil-based high-fat diet, aging, or a corn-starch diet. The long-chain fatty acids enriched in lard suppress mitochondria capture by macrophages, diverting adipocyte-derived mitochondria into the blood for delivery to other organs, such as the heart. The depletion of macrophages rapidly increased the number of adipocyte-derived mitochondria in the blood. These findings suggest that dietary lipids regulate mitochondria uptake by macrophages locally in white adipose tissue to determine whether adipocyte-derived mitochondria are released into systemic circulation to support the metabolic adaptation of distant organs in response to nutrient stress.
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Tejido Adiposo Blanco , Antioxidantes , Adipocitos/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Antioxidantes/metabolismo , Dieta Alta en Grasa , Ácidos Grasos/metabolismo , Macrófagos/metabolismo , Ratones , Mitocondrias/metabolismo , Obesidad/metabolismo , Almidón/metabolismoRESUMEN
The adipose tissue stroma is a rich source of molecularly distinct stem and progenitor cell populations with diverse functions in metabolic regulation, adipogenesis, and inflammation. The ontology of these populations and the mechanisms that govern their behaviors in response to stimuli, such as overfeeding, however, are unclear. Here, we show that the developmental fates and functional properties of adipose platelet-derived growth factor receptor beta (PDGFRß)+ progenitor subpopulations are tightly regulated by mitochondrial metabolism. Reducing the mitochondrial ß-oxidative capacity of PDGFRß+ cells via inducible expression of MitoNEET drives a pro-inflammatory phenotype in adipose progenitors and alters lineage commitment. Furthermore, disrupting mitochondrial function in PDGFRß+ cells rapidly induces alterations in immune cell composition in lean mice and impacts expansion of adipose tissue in diet-induced obesity. The adverse effects on adipose tissue remodeling can be reversed by restoring mitochondrial activity in progenitors, suggesting therapeutic potential for targeting energy metabolism in these cells.
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Adipogénesis , Tejido Adiposo Blanco , Tejido Adiposo/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Proteínas de Unión a Hierro/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Mitocondrias , Células Madre/metabolismoRESUMEN
Adipocytes undergo intense energetic stress in obesity resulting in loss of mitochondrial mass and function. We have found that adipocytes respond to mitochondrial stress by rapidly and robustly releasing small extracellular vesicles (sEVs). These sEVs contain respiration-competent, but oxidatively damaged mitochondrial particles, which enter circulation and are taken up by cardiomyocytes, where they trigger a burst of ROS. The result is compensatory antioxidant signaling in the heart that protects cardiomyocytes from acute oxidative stress, consistent with a preconditioning paradigm. As such, a single injection of sEVs from energetically stressed adipocytes limits cardiac ischemia/reperfusion injury in mice. This study provides the first description of functional mitochondrial transfer between tissues and the first vertebrate example of "inter-organ mitohormesis." Thus, these seemingly toxic adipocyte sEVs may provide a physiological avenue of potent cardio-protection against the inevitable lipotoxic or ischemic stresses elicited by obesity.
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Adipocitos , Vesículas Extracelulares , Adipocitos/metabolismo , Animales , Vesículas Extracelulares/metabolismo , Ratones , Mitocondrias/metabolismo , Mitocondrias Cardíacas , Miocitos Cardíacos/metabolismo , Estrés OxidativoRESUMEN
Iron overload is positively associated with diabetes risk. However, the role of iron in adipose tissue remains incompletely understood. Here, we report that transferrin-receptor-1-mediated iron uptake is differentially required for distinct subtypes of adipocytes. Notably, adipocyte-specific transferrin receptor 1 deficiency substantially protects mice from high-fat-diet-induced metabolic disorders. Mechanistically, low cellular iron levels have a positive impact on the health of the white adipose tissue and can restrict lipid absorption from the intestine through modulation of vesicular transport in enterocytes following high-fat diet feeding. Specific reduction of adipocyte iron by AAV-mediated overexpression of the iron exporter Ferroportin1 in adult mice effectively mimics these protective effects. In summary, our studies highlight an important role of adipocyte iron in the maintenance of systemic metabolism through an adipocyte-enterocyte axis, offering an additional level of control over caloric influx into the system after feeding by regulating intestinal lipid absorption.
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Adipocitos , Tejido Adiposo , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Animales , Dieta Alta en Grasa , Hierro/metabolismo , Lípidos , Ratones , Obesidad/metabolismoRESUMEN
Plasma hyaluronan (HA) increases systemically in type 2 diabetes (T2D) and the HA synthesis inhibitor, 4-Methylumbelliferone, has been proposed to treat the disease. However, HA is also implicated in normal physiology. Therefore, we generated a Hyaluronan Synthase 2 transgenic mouse line, driven by a tet-response element promoter to understand the role of HA in systemic metabolism. To our surprise, adipocyte-specific overproduction of HA leads to smaller adipocytes and protects mice from high-fat-high-sucrose-diet-induced obesity and glucose intolerance. Adipocytes also have more free glycerol that can be released upon beta3 adrenergic stimulation. Improvements in glucose tolerance were not linked to increased plasma HA. Instead, an HA-driven systemic substrate redistribution and adipose tissue-liver crosstalk contributes to the systemic glucose improvements. In summary, we demonstrate an unexpected improvement in glucose metabolism as a consequence of HA overproduction in adipose tissue, which argues against the use of systemic HA synthesis inhibitors to treat obesity and T2D.
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Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Dioxoles/farmacología , Glucosa/metabolismo , Ácido Hialurónico/metabolismo , Lipólisis/efectos de los fármacos , Adipocitos/citología , Tejido Adiposo/citología , Animales , Células Cultivadas , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa/efectos adversos , Femenino , Intolerancia a la Glucosa/metabolismo , Homeostasis , Humanos , Hipoglucemiantes/farmacología , Masculino , Ratones , Ratones Transgénicos , Obesidad/etiología , Obesidad/metabolismoRESUMEN
Obesity-associated type 2 diabetes mellitus (T2DM) entails insulin resistance and loss of ß-cell mass. Adipose tissue mitochondrial dysfunction is emerging as a key component in the etiology of T2DM. Identifying approaches to preserve mitochondrial function, adipose tissue integrity, and ß-cell mass during obesity is a major challenge. Mitochondrial ferritin (FtMT) is a mitochondrial matrix protein that chelates iron. We sought to determine whether perturbation of adipocyte mitochondria influences energy metabolism during obesity. We used an adipocyte-specific doxycycline-inducible mouse model of FtMT overexpression (FtMT-Adip mice). During a dietary challenge, FtMT-Adip mice are leaner but exhibit glucose intolerance, low adiponectin levels, increased reactive oxygen species damage, and elevated GDF15 and FGF21 levels, indicating metabolically dysfunctional fat. Paradoxically, despite harboring highly dysfunctional fat, transgenic mice display massive ß-cell hyperplasia, reflecting a beneficial mitochondria-induced fat-to-pancreas interorgan signaling axis. This identifies the unique and critical impact that adipocyte mitochondrial dysfunction has on increasing ß-cell mass during obesity-related insulin resistance.