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1.
bioRxiv ; 2024 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-39314496

RESUMEN

Gene therapy with Adeno-Associated Viral (AAV) vectors requires knowledge of their tropism within the body. Here we analyze the tropism of ten naturally occurring AAV serotypes (AAV3B, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh8, AAVrh10 and AAVrh74) following systemic delivery into male and female mice. A transgene expressing ZsGreen and Cre recombinase was used to identify transduction in a cell-dependent manner based on fluorescence. Cre-driven activation of tdTomato fluorescence offered superior sensitivity for transduced cells. All serotypes except AAV3B and AAV4 had high liver tropism. Fluorescence activation revealed transduction of unexpected tissues, including adrenals, testes and ovaries. Rare transduced cells within tissues were also readily visualized. Biodistribution of AAV genomes correlated with fluorescence, except in immune tissues. AAV4 was found to have a pan-endothelial tropism while also targeting pancreatic beta cells. This public resource enables selection of the best AAV serotypes for basic science and preclinical applications in mice.

2.
Trends Endocrinol Metab ; 35(9): 809-820, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38749883

RESUMEN

Body composition impacts female fertility and there are established relationships between adipose tissue and the reproductive system. Maintaining functional adipose tissue is vital for meeting the energetic demands during the reproductive process, from ovulation to delivery and lactation. White adipose tissue (WAT) shows plastic responses to daily physiology and secretes diverse adipokines that affect the hypothalamic-pituitary-ovarian axis, but many other interorgan interactions remain to be determined. This review summarizes the current state of research on the dialogue between WAT and the female reproductive system, focusing on the impact of this crosstalk on ovarian and endometrial factors essential for fecundity.


Asunto(s)
Tejido Adiposo Blanco , Metabolismo Energético , Reproducción , Humanos , Femenino , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/fisiología , Animales , Metabolismo Energético/fisiología , Reproducción/fisiología , Ovario/fisiología , Ovario/metabolismo
3.
Immunol Rev ; 324(1): 11-24, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38683173

RESUMEN

White adipose tissue (WAT) is a vital endocrine organ that regulates energy balance and metabolic homeostasis. In addition to fat cells, WAT harbors macrophages with distinct phenotypes that play crucial roles in immunity and metabolism. Nutrient demands cause macrophages to accumulate in WAT niches, where they remodel the microenvironment and produce beneficial or detrimental effects on systemic metabolism. Given the abundance of macrophages in WAT, this review summarizes the heterogeneity of WAT macrophages in physiological and pathological conditions, including their alterations in quantity, phenotypes, characteristics, and functions during WAT growth and development, as well as healthy or unhealthy expansion. We will discuss the interactions of macrophages with other cell partners in WAT including adipose stem cells, adipocytes, and T cells in the context of various microenvironment niches in lean or obese condition. Finally, we highlight how adipose tissue macrophages merge immunity and metabolic changes to govern energy balance for the organism.


Asunto(s)
Tejido Adiposo Blanco , Metabolismo Energético , Macrófagos , Obesidad , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/inmunología , Animales , Obesidad/inmunología , Obesidad/metabolismo , Adipocitos/metabolismo , Adipocitos/inmunología , Homeostasis
4.
Diabetes ; 73(5): 701-712, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38320268

RESUMEN

Bile acids (BAs) are pleiotropic regulators of metabolism. Elevated levels of hepatic and circulating BAs improve energy metabolism in peripheral organs, but the precise mechanisms underlying the metabolic benefits and harm still need to be fully understood. In the current study, we identified orosomucoid 2 (ORM2) as a liver-secreted hormone (i.e., hepatokine) induced by BAs and investigated its role in BA-induced metabolic improvements in mouse models of diet-induced obesity. Contrary to our expectation, under a high-fat diet (HFD), our Orm2 knockout (Orm2-KO) exhibited a lean phenotype compared with C57BL/6J control, partly due to the increased energy expenditure. However, when challenged with a HFD supplemented with cholic acid, Orm2-KO eliminated the antiobesity effect of BAs, indicating that ORM2 governs BA-induced metabolic improvements. Moreover, hepatic ORM2 overexpression partially replicated BA effects by enhancing insulin sensitivity. Mechanistically, ORM2 suppressed interferon-γ/STAT1 activities in inguinal white adipose tissue depots, forming the basis for anti-inflammatory effects of BAs and improving glucose homeostasis. In conclusion, our study provides new insights into the molecular mechanisms of BA-induced liver-adipose cross talk through ORM2 induction.


Asunto(s)
Ácidos y Sales Biliares , Orosomucoide , Ratones , Animales , Ácidos y Sales Biliares/metabolismo , Orosomucoide/metabolismo , Orosomucoide/farmacología , Ratones Endogámicos C57BL , Obesidad/genética , Obesidad/metabolismo , Hígado/metabolismo , Dieta Alta en Grasa/efectos adversos
5.
Res Sq ; 2024 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-38260478

RESUMEN

N-acetylaspartate (NAA), the brain's second most abundant metabolite, provides essential substrates for myelination through its hydrolysis. However, activities and physiological roles of NAA in other tissues remain unknown. Here, we show aspartoacylase (ASPA) expression in white adipose tissue (WAT) governs systemic NAA levels for postprandial body temperature regulation. Proteomics and mass spectrometry revealed NAA accumulation in WAT of Aspa knockout mice stimulated the pentose phosphate pathway and pyrimidine production. Stable isotope tracing confirmed higher incorporation of glucose-derived carbon into pyrimidine metabolites in Aspa knockout cells. Additionally, serum NAA positively correlates with the pyrimidine intermediate orotidine and this relationship predicted lower body mass index in humans. Using whole-body and tissue-specific knockout mouse models, we demonstrate that fat cells provided plasma NAA and suppressed postprandial body temperature elevation. Furthermore, exogenous NAA supplementation reduced body temperature. Our study unveils WAT-derived NAA as an endocrine regulator of postprandial body temperature and physiological homeostasis.

6.
Endocr Rev ; 45(2): 190-209, 2024 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-37556371

RESUMEN

Over the past 4 decades, the clinical care of people living with HIV (PLWH) evolved from treatment of acute opportunistic infections to the management of chronic, noncommunicable comorbidities. Concurrently, our understanding of adipose tissue function matured to acknowledge its important endocrine contributions to energy balance. PLWH experience changes in the mass and composition of adipose tissue depots before and after initiating antiretroviral therapy, including regional loss (lipoatrophy), gain (lipohypertrophy), or mixed lipodystrophy. These conditions may coexist with generalized obesity in PLWH and reflect disturbances of energy balance regulation caused by HIV persistence and antiretroviral therapy drugs. Adipocyte hypertrophy characterizes visceral and subcutaneous adipose tissue depot expansion, as well as ectopic lipid deposition that occurs diffusely in the liver, skeletal muscle, and heart. PLWH with excess visceral adipose tissue exhibit adipokine dysregulation coupled with increased insulin resistance, heightening their risk for cardiovascular disease above that of the HIV-negative population. However, conventional therapies are ineffective for the management of cardiometabolic risk in this patient population. Although the knowledge of complex cardiometabolic comorbidities in PLWH continues to expand, significant knowledge gaps remain. Ongoing studies aimed at understanding interorgan communication and energy balance provide insights into metabolic observations in PLWH and reveal potential therapeutic targets. Our review focuses on current knowledge and recent advances in HIV-associated adipose tissue dysfunction, highlights emerging adipokine paradigms, and describes critical mechanistic and clinical insights.


Asunto(s)
Enfermedades Cardiovasculares , Infecciones por VIH , Humanos , Grasa Subcutánea/metabolismo , Tejido Adiposo/metabolismo , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Obesidad/complicaciones , Obesidad/metabolismo , Adipoquinas/metabolismo , Adipoquinas/uso terapéutico , Enfermedades Cardiovasculares/metabolismo
7.
Development ; 150(17)2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37676777

RESUMEN

Meiotically competent oocytes in mammals undergo cyclic development during folliculogenesis. Oocytes within ovarian follicles are transcriptionally active, producing and storing transcripts required for oocyte growth, somatic cell communication and early embryogenesis. Transcription ceases as oocytes transition from growth to maturation and does not resume until zygotic genome activation. Although SUMOylation, a post-translational modification, plays multifaceted roles in transcriptional regulation, its involvement during oocyte development remains poorly understood. In this study, we generated an oocyte-specific knockout of Ube2i, encoding the SUMO E2 enzyme UBE2I, using Zp3-cre+ to determine how loss of oocyte SUMOylation during folliculogenesis affects oocyte development. Ube2i Zp3-cre+ female knockout mice were sterile, with oocyte defects in meiotic competence, spindle architecture and chromosome alignment, and a premature arrest in metaphase I. Additionally, fully grown Ube2i Zp3-cre+ oocytes exhibited sustained transcriptional activity but downregulated maternal effect genes and prematurely activated genes and retrotransposons typically associated with zygotic genome activation. These findings demonstrate that UBE2I is required for the acquisition of key hallmarks of oocyte development during folliculogenesis, and highlight UBE2I as a previously unreported orchestrator of transcriptional regulation in mouse oocytes.


Asunto(s)
Ensamble y Desensamble de Cromatina , Sumoilación , Femenino , Animales , Ratones , Ensamble y Desensamble de Cromatina/genética , Oocitos , Folículo Ovárico , Cigoto , Mamíferos
8.
Biol Sex Differ ; 14(1): 50, 2023 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-37553579

RESUMEN

BACKGROUND: Bronchopulmonary dysplasia (BPD) is characterized by an arrest in lung development and is a leading cause of morbidity in premature neonates. It has been well documented that BPD disproportionally affects males compared to females, but the molecular mechanisms behind this sex-dependent bias remain unclear. Female mice show greater preservation of alveolarization and angiogenesis when exposed to hyperoxia, accompanied by increased miR-30a expression. In this investigation, we tested the hypothesis that loss of miR-30a would result in male and female mice experiencing similar impairments in alveolarization and angiogenesis under hyperoxic conditions. METHODS: Wild-type and miR-30a-/- neonatal mice were exposed to hyperoxia [95% FiO2, postnatal day [PND1-5] or room air before being euthanized on PND21. Alveolarization, pulmonary microvascular development, differences in lung transcriptome, and miR-30a expression were assessed in lungs from WT and miR-30a-/- mice of either sex. Blood transcriptomic signatures from preterm newborns (with and without BPD) were correlated with WT and miR-30a-/- male and female lung transcriptome data. RESULTS: Significantly, the sex-specific differences observed in WT mice were abrogated in the miR-30a-/- mice upon exposure to hyperoxia. The loss of miR-30a expression eliminated the protective effect in females, suggesting that miR-30a plays an essential role in regulating alveolarization and angiogenesis. Transcriptome analysis by whole lung RNA-Seq revealed a significant response in the miR-30a-/- female hyperoxia-exposed lung, with enrichment of pathways related to cell cycle and neuroactive ligand-receptor interaction. Gene expression signature in the miR-30a-/- female lung associated with human BPD blood transcriptomes. Finally, we showed the spatial localization of miR-30a transcripts in the bronchiolar epithelium. CONCLUSIONS: miR-30a could be one of the biological factors mediating the resilience of the female preterm lung to neonatal hyperoxic lung injury. A better understanding of the effects of miR-30a on pulmonary angiogenesis and alveolarization may lead to novel therapeutics for treating BPD.


Bronchopulmonary dysplasia (BPD) is a lung condition that affects babies born prematurely, causing problems with their lung development. Interestingly, BPD tends to affect boys more than girls, but we do not fully understand why. To investigate this, we conducted a study using mice. Female mice had better lung development and blood vessel formation when exposed to high oxygen levels. We found higher expression of a molecule called miR-30a in the female mice and seemed to be protective. So, we wanted to see if removing miR-30a would have the same effect on both male and female mice. To test this, we exposed newborn mice without miR-30a and normal mice to high oxygen levels or regular room air. Interestingly, the differences between normal males and females were no longer present in the mice without miR-30a. This suggested that miR-30a plays an important role in lung development. We also identified that the female mice without miR-30a, when exposed to high oxygen, had the greatest number of genes affected, and these gene changes were like those seen in blood samples from premature babies with BPD. Finally, we report that miR-30a was in a specific part of the lung called the bronchiolar epithelium. Overall, this study suggests that miR-30a is crucial in protecting premature lungs from damage caused by high oxygen levels. By understanding how miR-30a affects lung development, we may be able to develop new treatments for BPD in the future.


Asunto(s)
Displasia Broncopulmonar , Hiperoxia , Lesión Pulmonar , MicroARNs , Animales , Femenino , Masculino , Ratones , Animales Recién Nacidos , Displasia Broncopulmonar/genética , Displasia Broncopulmonar/metabolismo , Hiperoxia/complicaciones , Hiperoxia/metabolismo , Pulmón/metabolismo , Lesión Pulmonar/genética , Lesión Pulmonar/complicaciones , Lesión Pulmonar/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Factores Sexuales
9.
Elife ; 122023 Jul 07.
Artículo en Inglés | MEDLINE | ID: mdl-37417957

RESUMEN

Flavin adenine dinucleotide (FAD) interacts with flavoproteins to mediate oxidation-reduction reactions required for cellular energy demands. Not surprisingly, mutations that alter FAD binding to flavoproteins cause rare inborn errors of metabolism (IEMs) that disrupt liver function and render fasting intolerance, hepatic steatosis, and lipodystrophy. In our study, depleting FAD pools in mice with a vitamin B2-deficient diet (B2D) caused phenotypes associated with organic acidemias and other IEMs, including reduced body weight, hypoglycemia, and fatty liver disease. Integrated discovery approaches revealed B2D tempered fasting activation of target genes for the nuclear receptor PPARα, including those required for gluconeogenesis. We also found PPARα knockdown in the liver recapitulated B2D effects on glucose excursion and fatty liver disease in mice. Finally, treatment with the PPARα agonist fenofibrate activated the integrated stress response and refilled amino acid substrates to rescue fasting glucose availability and overcome B2D phenotypes. These findings identify metabolic responses to FAD availability and nominate strategies for the management of organic acidemias and other rare IEMs.


Asunto(s)
Glucosa , Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Glucosa/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Flavina-Adenina Dinucleótido/metabolismo , Ácidos Grasos/metabolismo , Hígado/metabolismo , Ayuno/metabolismo , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Oxidación-Reducción , Flavoproteínas/metabolismo
10.
Mol Metab ; 72: 101717, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37004989

RESUMEN

OBJECTIVE: Mitophagy removes damaged mitochondria to maintain cellular homeostasis. Aryl hydrocarbon receptor (AhR) expression in the liver plays a crucial role in supporting normal liver functions, but its impact on mitochondrial function is unclear. Here, we identified a new role of AhR in the regulation of mitophagy to control hepatic energy homeostasis. METHODS: In this study, we utilized primary hepatocytes from AhR knockout (KO) mice and AhR knockdown AML12 hepatocytes. An endogenous AhR ligand, kynurenine (Kyn), was used to activate AhR in AML12 hepatocytes. Mitochondrial function and mitophagy process were comprehensively assessed by MitoSOX and mt-Keima fluorescence imaging, Seahorse XF-based oxygen consumption rate measurement, and Mitoplate S-1 mitochondrial substrate utilization analysis. RESULTS: Transcriptomic analysis indicated that mitochondria-related gene sets were dysregulated in AhR KO liver. In both primary mouse hepatocytes and AML12 hepatocyte cell lines, AhR inhibition strongly suppressed mitochondrial respiration rate and substrate utilization. AhR inhibition also blunted the fasting response of several essential autophagy genes and the mitophagy process. We further identified BCL2 interacting protein 3 (BNIP3), a mitophagy receptor that senses nutrient stress, as an AhR target gene. AhR is directly recruited to the Bnip3 genomic locus, and Bnip3 transcription was enhanced by AhR endogenous ligand treatment in wild-type liver and abolished entirely in AhR KO liver. Mechanistically, overexpression of Bnip3 in AhR knockdown cells mitigated the production of mitochondrial reactive oxygen species (ROS) and restored functional mitophagy. CONCLUSIONS: AhR regulation of the mitophagy receptor BNIP3 coordinates hepatic mitochondrial function. Loss of AhR induces mitochondrial ROS production and impairs mitochondrial respiration. These findings provide new insight into how endogenous AhR governs hepatic mitochondrial homeostasis.


Asunto(s)
Mitocondrias , Receptores de Hidrocarburo de Aril , Ratones , Animales , Especies Reactivas de Oxígeno/metabolismo , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Ligandos , Mitocondrias/metabolismo , Hígado/metabolismo , Ratones Noqueados , Homeostasis
11.
Nat Med ; 28(12): 2537-2546, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36536256

RESUMEN

Serotonin reuptake inhibitors and receptor agonists are used to treat obesity, anxiety and depression. Here we studied the role of the serotonin 2C receptor (5-HT2CR) in weight regulation and behavior. Using exome sequencing of 2,548 people with severe obesity and 1,117 control individuals without obesity, we identified 13 rare variants in the gene encoding 5-HT2CR (HTR2C) in 19 unrelated people (3 males and 16 females). Eleven variants caused a loss of function in HEK293 cells. All people who carried variants had hyperphagia and some degree of maladaptive behavior. Knock-in male mice harboring a human loss-of-function HTR2C variant developed obesity and reduced social exploratory behavior; female mice heterozygous for the same variant showed similar deficits with reduced severity. Using the 5-HT2CR agonist lorcaserin, we found that depolarization of appetite-suppressing proopiomelanocortin neurons was impaired in knock-in mice. In conclusion, we demonstrate that 5-HT2CR is involved in the regulation of human appetite, weight and behavior. Our findings suggest that melanocortin receptor agonists might be effective in treating severe obesity in individuals carrying HTR2C variants. We suggest that HTR2C should be included in diagnostic gene panels for severe childhood-onset obesity.


Asunto(s)
Obesidad Mórbida , Receptor de Serotonina 5-HT2C , Animales , Niño , Femenino , Humanos , Masculino , Ratones , Células HEK293 , Obesidad/genética , Receptor de Serotonina 5-HT2C/genética , Serotonina , Agonistas del Receptor de Serotonina 5-HT2/farmacología , Adaptación Psicológica
12.
Cell Metab ; 34(12): 1932-1946.e7, 2022 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-36243005

RESUMEN

Low-grade, sustained inflammation in white adipose tissue (WAT) characterizes obesity and coincides with type 2 diabetes mellitus (T2DM). However, pharmacological targeting of inflammation lacks durable therapeutic effects in insulin-resistant conditions. Through a computational screen, we discovered that the FDA-approved rheumatoid arthritis drug auranofin improved insulin sensitivity and normalized obesity-associated abnormalities, including hepatic steatosis and hyperinsulinemia in mouse models of T2DM. We also discovered that auranofin accumulation in WAT depleted inflammatory responses to a high-fat diet without altering body composition in obese wild-type mice. Surprisingly, elevated leptin levels and blunted beta-adrenergic receptor activity achieved by leptin receptor deletion abolished the antidiabetic effects of auranofin. These experiments also revealed that the metabolic benefits of leptin reduction were superior to immune impacts of auranofin in WAT. Our studies uncover important metabolic properties of anti-inflammatory treatments and contribute to the notion that leptin reduction in the periphery can be accomplished to treat obesity and T2DM.


Asunto(s)
Artritis Reumatoide , Diabetes Mellitus Tipo 2 , Animales , Ratones , Ratones Obesos , Hipoglucemiantes , Auranofina/farmacología , Auranofina/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Obesidad/tratamiento farmacológico
13.
Elife ; 112022 05 30.
Artículo en Inglés | MEDLINE | ID: mdl-35635747

RESUMEN

DNA Methyltransferase 3 A (DNMT3A) is an important facilitator of differentiation of both embryonic and hematopoietic stem cells. Heterozygous germline mutations in DNMT3A lead to Tatton-Brown-Rahman Syndrome (TBRS), characterized by obesity and excessive height. While DNMT3A is known to impact feeding behavior via the hypothalamus, here we investigated a role in adipocyte progenitors utilizing heterozygous knockout mice that recapitulate cardinal TBRS phenotypes. These mice become morbidly obese due to adipocyte enlargement and tissue expansion. Adipose tissue in these mice exhibited defects in preadipocyte maturation and precocious activation of inflammatory gene networks, including interleukin-6 signaling. Adipocyte progenitor cell lines lacking DNMT3A exhibited aberrant differentiation. Furthermore, mice in which Dnmt3a was specifically ablated in adipocyte progenitors showed enlarged fat depots and increased progenitor numbers, partly recapitulating the TBRS obesity phenotypes. Loss of DNMT3A led to constitutive DNA hypomethylation, such that the DNA methylation landscape of young adipocyte progenitors resemble that of older wild-type mice. Together, our results demonstrate that DNMT3A coordinates both the central and local control of energy storage required to maintain normal weight and prevent inflammatory obesity.


Asunto(s)
Discapacidad Intelectual , Errores Innatos del Metabolismo , Obesidad Mórbida , Adipogénesis , Animales , ADN , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , ADN Metiltransferasa 3A , Discapacidad Intelectual/genética , Ratones
14.
Physiol Rep ; 10(9): e15293, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35510313

RESUMEN

Plasma biomarkers that reflect energy balance disorders in people living with HIV (PLWH) remain limited. Growth differentiation factor 15 (GDF15) abundance in plasma of mice and humans induces negative energy balance but also becomes highly elevated in obesity and other metabolic diseases. We sought to compare plasma GDF15 levels in PLWH and HIV-negative persons and mouse models expressing the HIV accessory protein Vpr (that recapitulate HIV-associated metabolic disorders) and determine their relationship to metabolic parameters. We measured liver Gdf15 mRNA levels and plasma GDF15 levels in male Vpr mice and littermate controls. In parallel, we analyzed plasma GDF15 levels in 18 male PLWH on stable, long-term antiretroviral therapy and 13 HIV-negative men (6 healthy controls and 7 with metabolic syndrome). Plasma GDF15 levels were correlated with anthropometric and immune cell parameters in humans. Gene expression analysis of Vpr mouse liver demonstrated elevated Gdf15 mRNA. Plasma GDF15 levels were also higher in Vpr mouse models. Levels of plasma GDF15 in PLWH were greater than in both HIV-negative groups and correlated positively with the CD4/CD8 T cell ratio in PLWH. Plasma GDF15 levels correlated positively with age in the HIV-negative subjects but not in PLWH. Since GDF15 levels predict fatty liver disease and energy balance disorders, further studies are warranted to determine the effect of GDF15 in mediating the metabolic disturbances that occur in Vpr mice and PLWH.


Asunto(s)
Factor 15 de Diferenciación de Crecimiento/genética , Infecciones por VIH , Síndrome Metabólico , Femenino , Infecciones por VIH/complicaciones , Humanos , Masculino , Obesidad/metabolismo , ARN Mensajero/genética
15.
Endocrinology ; 163(2)2022 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-34882766

RESUMEN

An extensive literature base combined with advances in sequencing technologies demonstrate microRNA levels correlate with various metabolic diseases. Mechanistic studies also establish microRNAs regulate central metabolic pathways and thus play vital roles in maintaining organismal energy balance and metabolic homeostasis. This review highlights research progress on the roles and regulation of microRNAs in the peripheral tissues that confer insulin sensitivity. We discuss sequencing technologies used to comprehensively define the target spectrum of microRNAs in metabolic disease that complement studies reporting physiologic roles for microRNAs in the regulation of glucose and lipid metabolism in animal models. We also discuss the emerging roles of exosomal microRNAs as endocrine signals to regulate lipid and carbohydrate metabolism.


Asunto(s)
Resistencia a la Insulina/genética , MicroARNs/fisiología , Tejido Adiposo , Animales , Metabolismo Energético/genética , Regulación de la Expresión Génica , Glucosa/metabolismo , Homeostasis , Humanos , Metabolismo de los Lípidos/genética , Enfermedades Metabólicas/genética
16.
Cell Mol Gastroenterol Hepatol ; 13(3): 925-947, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34890841

RESUMEN

BACKGROUND & AIMS: Sphingosine 1-phosphate receptors (S1PRs) are a group of G-protein-coupled receptors that confer a broad range of functional effects in chronic inflammatory and metabolic diseases. S1PRs also may mediate the development of nonalcoholic steatohepatitis (NASH), but the specific subtypes involved and the mechanism of action are unclear. METHODS: We investigated which type of S1PR isoforms is activated in various murine models of NASH. The mechanism of action of S1PR4 was examined in hepatic macrophages isolated from high-fat, high-cholesterol diet (HFHCD)-fed mice. We developed a selective S1PR4 functional antagonist by screening the fingolimod (2-amino-2-[2-(4- n -octylphenyl)ethyl]-1,3- propanediol hydrochloride)-like sphingolipid-focused library. RESULTS: The livers of various mouse models of NASH as well as hepatic macrophages showed high expression of S1pr4. Moreover, in a cohort of NASH patients, expression of S1PR4 was 6-fold higher than those of healthy controls. S1pr4+/- mice were protected from HFHCD-induced NASH and hepatic fibrosis without changes in steatosis. S1pr4 depletion in hepatic macrophages inhibited lipopolysaccharide-mediated Ca++ release and deactivated the Nod-like receptor pyrin domain-containning protein 3 (NLRP3) inflammasome. S1P increased the expression of S1pr4 in hepatic macrophages and activated NLRP3 inflammasome through inositol trisphosphate/inositol trisphosphate-receptor-dependent [Ca++] signaling. To further clarify the biological function of S1PR4, we developed SLB736, a novel selective functional antagonist of SIPR4. Similar to S1pr4+/- mice, administration of SLB736 to HFHCD-fed mice prevented the development of NASH and hepatic fibrosis, but not steatosis, by deactivating the NLRP3 inflammasome. CONCLUSIONS: S1PR4 may be a new therapeutic target for NASH that mediates the activation of NLRP3 inflammasome in hepatic macrophages.


Asunto(s)
Inflamasomas , Enfermedad del Hígado Graso no Alcohólico , Animales , Humanos , Inflamasomas/metabolismo , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Receptores de Esfingosina-1-Fosfato
17.
Diabetes ; 70(9): 2014-2025, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34233931

RESUMEN

Persons living with HIV (PLWH) manifest chronic disorders of brown and white adipose tissues that lead to diabetes and metabolic syndrome. The mechanisms that link viral factors to defective adipose tissue function and abnormal energy balance in PLWH remain incompletely understood. Here, we explored how the HIV accessory protein viral protein R (Vpr) contributes to adaptive thermogenesis in two mouse models and human adipose tissues. Uncoupling protein 1 (UCP1) gene expression was strongly increased in subcutaneous white adipose tissue (WAT) biopsy specimens from PLWH and in subcutaneous WAT of the Vpr mice, with nearly equivalent mRNA copy number. Histology and functional studies confirmed beige transformation in subcutaneous but not visceral WAT in the Vpr mice. Measurements of energy balance indicated Vpr mice displayed metabolic inflexibility and could not shift efficiently from carbohydrate to fat metabolism during day-night cycles. Furthermore, Vpr mice showed a marked inability to defend body temperature when exposed to 4°C. Importantly, Vpr couples higher tissue catecholamine levels with UCP1 expression independent of ß-adrenergic receptors. Our data reveal surprising deficits of adaptive thermogenesis that drive metabolic inefficiency in HIV-1 Vpr mouse models, providing an expanded role for viral factors in the pathogenesis of metabolic disorders in PLWH.


Asunto(s)
Tejido Adiposo Blanco/metabolismo , Obesidad/metabolismo , Termogénesis/fisiología , Productos del Gen vpr del Virus de la Inmunodeficiencia Humana/metabolismo , Tejido Adiposo Pardo/metabolismo , Adulto , Temperatura Corporal/fisiología , Metabolismo Energético/fisiología , Femenino , Humanos , Persona de Mediana Edad , Proteína Desacopladora 1/metabolismo
18.
Mol Metab ; 48: 101221, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33771728

RESUMEN

OBJECTIVE: White adipose tissue (WAT) expansion regulates energy balance and overall metabolic homeostasis. The absence or loss of WAT occurring through lipodystrophy and lipoatrophy contributes to the development of hepatic steatosis and insulin resistance. We previously demonstrated that sole small ubiquitin-like modifier (SUMO) E2-conjugating enzyme Ube2i represses human adipocyte differentiation. The role of Ube2i during WAT development remains unknown. METHODS: To determine how Ube2i impacts body composition and energy balance, we generated adipocyte-specific Ube2i knockout mice (Ube2ia-KO). CRISPR/Cas9 gene editing inserted loxP sites flanking exons 3 and 4 at the Ube2i locus. Subsequent genetic crosses to Adipoq-Cre transgenic mice allowed deletion of Ube2i in white and brown adipocytes. We measured multiple metabolic endpoints that describe energy balance and carbohydrate metabolism in Ube2ia-KO and littermate controls during postnatal growth. RESULTS: Surprisingly, Ube2ia-KO mice developed hyperinsulinemia and hepatic steatosis. Global energy balance defects emerged from dysfunctional WAT marked by pronounced local inflammation, loss of serum adipokines, hepatomegaly, and near absence of major adipose tissue depots. We observed progressive lipoatrophy that commences in the early adolescent period. CONCLUSIONS: Our results demonstrate that Ube2i expression in mature adipocytes allows WAT expansion during postnatal growth. Deletion of Ube2i in fat cells compromises and diminishes adipocyte function that induces WAT inflammation and ectopic lipid accumulation in the liver. Our findings reveal an indispensable role for Ube2i during white adipocyte expansion and endocrine control of energy balance.


Asunto(s)
Adipocitos Marrones/metabolismo , Adipocitos Blancos/metabolismo , Eliminación de Gen , Hiperinsulinismo/complicaciones , Hiperinsulinismo/metabolismo , Lipodistrofia/complicaciones , Lipodistrofia/metabolismo , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Transducción de Señal/genética , Enzimas Ubiquitina-Conjugadoras/genética , Enzimas Ubiquitina-Conjugadoras/metabolismo , Adipoquinas/sangre , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Composición Corporal/genética , Metabolismo Energético/genética , Femenino , Hiperinsulinismo/genética , Resistencia a la Insulina/genética , Lipodistrofia/genética , Masculino , Ratones , Ratones Noqueados , Enfermedad del Hígado Graso no Alcohólico/genética
19.
Nat Commun ; 12(1): 1927, 2021 03 26.
Artículo en Inglés | MEDLINE | ID: mdl-33772019

RESUMEN

Accumulating evidence suggests that chronic inflammation of metabolic tissues plays a causal role in obesity-induced insulin resistance. Yet, how specific endothelial factors impact metabolic tissues remains undefined. Bone morphogenetic protein (BMP)-binding endothelial regulator (BMPER) adapts endothelial cells to inflammatory stress in diverse organ microenvironments. Here, we demonstrate that BMPER is a driver of insulin sensitivity. Both global and endothelial cell-specific inducible knockout of BMPER cause hyperinsulinemia, glucose intolerance and insulin resistance without increasing inflammation in metabolic tissues in mice. BMPER can directly activate insulin signaling, which requires its internalization and interaction with Niemann-Pick C1 (NPC1), an integral membrane protein that transports intracellular cholesterol. These results suggest that the endocrine function of the vascular endothelium maintains glucose homeostasis. Of potential translational significance, the delivery of BMPER recombinant protein or its overexpression alleviates insulin resistance and hyperglycemia in high-fat diet-fed mice and Leprdb/db (db/db) diabetic mice. We conclude that BMPER exhibits therapeutic potential for the treatment of diabetes.


Asunto(s)
Proteínas Portadoras/genética , Endotelio Vascular/metabolismo , Resistencia a la Insulina/genética , Transducción de Señal/genética , Animales , Glucemia/metabolismo , Proteínas Portadoras/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Intolerancia a la Glucosa/genética , Células HEK293 , Humanos , Hiperinsulinismo/genética , Hiperinsulinismo/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína Niemann-Pick C1/genética , Proteína Niemann-Pick C1/metabolismo , Receptores de Leptina/genética , Receptores de Leptina/metabolismo
20.
Trends Endocrinol Metab ; 32(5): 320-332, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33712368

RESUMEN

White adipose tissue (WAT) depends on coordinated regulation of transcriptional and metabolic pathways to respond to whole-body energy demands. We highlight metabolites that contribute to biosynthetic reactions for WAT expansion. Recent studies have precisely defined how byproducts of carbohydrate and lipid metabolism affect physiological and endocrine functions in adipocytes. We emphasize the critical emerging roles of short-chain fatty acids (SCFAs) and tricarboxylic acid (TCA) cycle metabolites that connect lipogenesis to WAT energy balance and endocrine functions. These insights address how adipocytes use small molecules generated from central carbon metabolism to measure responses to nutritional stress.


Asunto(s)
Acetilcoenzima A , Tejido Adiposo Blanco , Acetilcoenzima A/metabolismo , Adipocitos/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Humanos , Metabolismo de los Lípidos
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