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1.
EMBO Rep ; 18(7): 1123-1138, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28539390

RESUMO

BAT-controlled thermogenic activity is thought to be required for its capacity to prevent the development of insulin resistance. This hypothesis predicts that mediators of thermogenesis may help prevent diet-induced insulin resistance. We report that the mitochondrial fusion protein Mitofusin 2 (Mfn2) in BAT is essential for cold-stimulated thermogenesis, but promotes insulin resistance in obese mice. Mfn2 deletion in mice through Ucp1-cre (BAT-Mfn2-KO) causes BAT lipohypertrophy and cold intolerance. Surprisingly however, deletion of Mfn2 in mice fed a high fat diet (HFD) results in improved insulin sensitivity and resistance to obesity, while impaired cold-stimulated thermogenesis is maintained. Improvement in insulin sensitivity is associated with a gender-specific remodeling of BAT mitochondrial function. In females, BAT mitochondria increase their efficiency for ATP-synthesizing fat oxidation, whereas in BAT from males, complex I-driven respiration is decreased and glycolytic capacity is increased. Thus, BAT adaptation to obesity is regulated by Mfn2 and with BAT-Mfn2 absent, BAT contribution to prevention of insulin resistance is independent and inversely correlated to whole-body cold-stimulated thermogenesis.


Assuntos
Tecido Adiposo Marrom/metabolismo , GTP Fosfo-Hidrolases/deficiência , GTP Fosfo-Hidrolases/genética , Resistência à Insulina , Termogênese/genética , Animais , Dieta Hiperlipídica , Metabolismo Energético , Feminino , Glicólise , Masculino , Camundongos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Obesidade
2.
Immunology ; 142(3): 363-73, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24456224

RESUMO

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are known to have many immunomodulatory effects. We have previously shown that the PPARγ agonist rosiglitazone is beneficial when used early in prevention of disease in murine models of systemic lupus erythematosus (SLE) and SLE-related atherosclerosis. In this report, we demonstrate that another PPARγ agonist, pioglitazone is also beneficial as a treatment for early murine lupus, indicating that this is a class effect and not agent-specific. We further attempt to define the ability of PPARγ agonists to ameliorate established or severe autoimmune disease using two mouse models: the MRL.lpr SLE model and the gld.apoE(-/-) model of accelerated atherosclerosis and SLE. We demonstrate that, in contrast to the marked amelioration of disease seen when PPARγ agonist treatment was started before disease onset, treatment with rosiglitazone after disease onset in MRL.lpr or gld.apoE(-/-) mice had minimal beneficial effect on the development of the autoimmune phenotype; however, rosiglitazone treatment remained highly effective at reducing lupus-associated atherosclerosis in gld.apoE(-/-) mice after disease onset or when mice were maintained on a high cholesterol Western diet. These results suggest that beneficial effects of PPARγ agonists on the development of autoimmunity might be limited to the early stages of disease, but that atherosclerosis, a major cause of death in SLE patients, may be ameliorated even in established or severe disease.


Assuntos
Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/prevenção & controle , PPAR gama/agonistas , Tiazolidinedionas/farmacologia , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR gama/imunologia , Pioglitazona , Rosiglitazona , Tiazolidinedionas/química , Tiazolidinedionas/uso terapêutico
3.
Heliyon ; 9(1): e12900, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36685442

RESUMO

Coccidioidomycosis rates in endemic areas such as California and Arizona have been increasing in recent years. Most common manifestations in symptomatic individuals involve the lungs. Disseminated disease occurs when the infection spreads beyond the lungs. Disseminated disease occurs in about 1% of all coccidiomycosis cases. Diagnosis in classically non-endemic regions can be difficult as coccidiomycosis can mimic a variety of other illnesses which can lead to delays in initiating appropriate therapy. We report a case of severe disseminated coccidiomycosis involving the soft tissue, bone, and intra-abdominal organs in a previously healthy individual that was initially thought to be a malignancy. With climate change possibly altering the traditional endemic regions and expanding Coccidioides to new territories, this case reinforces the importance of maintaining a broad differential as well as awareness of disease manifestations for healthcare providers who do not regularly treat Coccidioides.

4.
Mol Metab ; 55: 101403, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34823065

RESUMO

OBJECTIVE: The contribution of beta-cell dysfunction to type 2 diabetes (T2D) is not restricted to insulinopenia in the late stages of the disease. Elevated fasting insulinemia in normoglycemic humans is a major factor predicting the onset of insulin resistance and T2D, demonstrating an early alteration of beta-cell function in T2D. Moreover, an early and chronic increase in fasting insulinemia contributes to insulin resistance in high-fat diet (HFD)-fed mice. However, whether there are genetic factors that promote beta-cell-initiated insulin resistance remains undefined. Human variants of the mitochondrial transporter ABCB10, which regulates redox by increasing bilirubin synthesis, have been associated with an elevated risk of T2D. The effects of T2D ABCB10 variants on ABCB10 expression and the actions of ABCB10 in beta-cells are unknown. METHODS: The expression of beta-cell ABCB10 was analyzed in published transcriptome datasets from human beta-cells carrying the T2D-risk ABCB10 variant. Insulin sensitivity, beta-cell proliferation, and secretory function were measured in beta-cell-specific ABCB10 KO mice (Ins1Cre-Abcb10flox/flox). The short-term role of beta-cell ABCB10 activity on glucose-stimulated insulin secretion (GSIS) was determined in isolated islets. RESULTS: Carrying the T2Drisk allele G of ABCB10 rs348330 variant was associated with increased ABCB10 expression in human beta-cells. Constitutive deletion of Abcb10 in beta-cells protected mice from hyperinsulinemia and insulin resistance by limiting HFD-induced beta-cell expansion. An early limitation in GSIS and H2O2-mediated signaling caused by elevated ABCB10 activity can initiate an over-compensatory expansion of beta-cell mass in response to HFD. Accordingly, increasing ABCB10 expression was sufficient to limit GSIS capacity. In health, ABCB10 protein was decreased during islet maturation, with maturation restricting beta-cell proliferation and elevating GSIS. Finally, ex-vivo and short-term deletion of ABCB10 in islets isolated from HFD-fed mice increased H2O2 and GSIS, which was reversed by bilirubin treatments. CONCLUSIONS: Beta-cell ABCB10 is required for HFD to induce insulin resistance in mice by amplifying beta-cell mass expansion to maladaptive levels that cause fasting hyperinsulinemia.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Resistência à Insulina/genética , Células Secretoras de Insulina/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Feminino , Glucose/metabolismo , Teste de Tolerância a Glucose , Insulina/metabolismo , Resistência à Insulina/fisiologia , Secreção de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/fisiologia , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo
5.
Sci Transl Med ; 13(594)2021 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-34011630

RESUMO

Although the role of hydrophilic antioxidants in the development of hepatic insulin resistance and nonalcoholic fatty liver disease has been well studied, the role of lipophilic antioxidants remains poorly characterized. A known lipophilic hydrogen peroxide scavenger is bilirubin, which can be oxidized to biliverdin and then reduced back to bilirubin by cytosolic biliverdin reductase. Oxidation of bilirubin to biliverdin inside mitochondria must be followed by the export of biliverdin to the cytosol, where biliverdin is reduced back to bilirubin. Thus, the putative mitochondrial exporter of biliverdin is expected to be a major determinant of bilirubin regeneration and intracellular hydrogen peroxide scavenging. Here, we identified ABCB10 as a mitochondrial biliverdin exporter. ABCB10 reconstituted into liposomes transported biliverdin, and ABCB10 deletion caused accumulation of biliverdin inside mitochondria. Obesity with insulin resistance up-regulated hepatic ABCB10 expression in mice and elevated cytosolic and mitochondrial bilirubin content in an ABCB10-dependent manner. Revealing a maladaptive role of ABCB10-driven bilirubin synthesis, hepatic ABCB10 deletion protected diet-induced obese mice from steatosis and hyperglycemia, improving insulin-mediated suppression of glucose production and decreasing lipogenic SREBP-1c expression. Protection was concurrent with enhanced mitochondrial function and increased inactivation of PTP1B, a phosphatase disrupting insulin signaling and elevating SREBP-1c expression. Restoration of cellular bilirubin content in ABCB10 KO hepatocytes reversed the improvements in mitochondrial function and PTP1B inactivation, demonstrating that bilirubin was the maladaptive effector linked to ABCB10 function. Thus, we identified a fundamental transport process that amplifies intracellular bilirubin redox actions, which can exacerbate insulin resistance and steatosis in obesity.


Assuntos
Biliverdina , Mitocôndrias , Animais , Antioxidantes , Bilirrubina , Fígado , Camundongos , Obesidade
6.
Front Physiol ; 10: 687, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31258484

RESUMO

Objective: Thoracic perivascular adipose tissue (PVAT) has been shown to release factors that influence the functioning of neighboring vascular tissue. Cardiovascular complications of obesity are on the rise; therefore, this study set out to determine if adipose-specific ablation of vascular endothelial growth factor-A (VEGF-A) plays a role in the maintenance of aortic structure and function. Methods: Adipose-specific VEGF-A-deficient mice were previously generated. Fabp4cre(+). VEGF flox/flox and Fabp4cre(-). VEGF flox/flox mice were maintained on chow diet. PVAT gene expression was measured with real-time quantitative PCR. Aortic vasomotor response was assessed with isometric tension measurements. Collagen deposition was analyzed histologically in the vascular media and compared using ratiometric pigment density. Results: PVAT-specific adiponectin expression was decreased in Fabp4cre(+). VEGF flox/flox mice. Isometric tension measurements revealed a dose-dependent dysfunction in response to acetylcholine within the distal aortic segment of Fabp4cre(+). VEGF flox/flox . Fabp4cre(+). VEGF flox/flox mice exhibited increased aortic deposition of collagen within the thoracic adventitial and medial spaces. Conclusion: These data demonstrate that decreased expression of VEGF-A within the surrounding adipose tissue microenvironment of the thoracic aorta has a detrimental effect on aortic integrity and vascular function. Modulation of angiogenic pathways within PVAT may offer an important avenue toward the treatment of adipose tissue dysfunction in obesity and its vascular complications.

7.
Cell Metab ; 27(5): 1138-1155.e6, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29719227

RESUMO

Inter-tissue communication via secreted proteins has been established as a vital mechanism for proper physiologic homeostasis. Here, we report a bioinformatics framework using a mouse reference population, the Hybrid Mouse Diversity Panel (HMDP), which integrates global multi-tissue expression data and publicly available resources to identify and functionally annotate novel circuits of tissue-tissue communication. We validate this method by showing that we can identify known as well as novel endocrine factors responsible for communication between tissues. We further show the utility of this approach by identification and mechanistic characterization of two new endocrine factors. Adipose-derived Lipocalin-5 is shown to enhance skeletal muscle mitochondrial function, and liver-secreted Notum promotes browning of white adipose tissue, also known as "beiging." We demonstrate the general applicability of the method by providing in vivo evidence for three additional novel molecules mediating tissue-tissue interactions.


Assuntos
Sistema Endócrino/metabolismo , Homeostase , Lipocalinas/metabolismo , Proteômica/métodos , Tecido Adiposo/metabolismo , Animais , Células Cultivadas , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/metabolismo
8.
Int J Parasitol ; 45(4): 203-7, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25666929

RESUMO

ES-62 is an anti-inflammatory phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae. Accelerated atherosclerosis frequently occurs in systemic lupus erythematosus, resulting in substantial cardiovascular morbidity and mortality. We examined the effects of ES-62 in the gld.apoE(-/-) mouse model of this condition. Treatment with ES-62 did not substantially modulate renal pathology but caused decreased anti-nuclear autoantibody levels. Moreover, a striking 60% reduction in aortic atherosclerotic lesions was observed, with an associated decrease in macrophages and fibrosis. We believe that these latter findings constitute the first example of a defined parasitic worm product with therapeutic potential in atherosclerosis: ES-62-based drugs may represent a novel approach to control accelerated atherosclerosis in systemic lupus erythematosus.


Assuntos
Aterosclerose/prevenção & controle , Proteínas de Helminto/administração & dosagem , Fatores Imunológicos/administração & dosagem , Lúpus Eritematoso Sistêmico/complicações , Animais , Anticorpos Antinucleares/sangue , Aterosclerose/patologia , Modelos Animais de Doenças , Fibrose/patologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Knockout
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