Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 42
Filtrar
Mais filtros










Intervalo de ano de publicação
1.
Diabetes ; 2021 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-34675004

RESUMO

We previously showed that global deletion of the cytochrome P450 epoxygenase Cyp2c44, a major epoxyeicosatrienoic acid (EET) producing enzyme in mice, leads to impaired hepatic insulin signaling resulting in insulin resistance. This finding led us to investigate whether administration of a water soluble EET analog restores insulin signaling in vivo in Cyp2c44(-/-) mice and investigated the underlying mechanisms by which this effect is exerted. Cyp2c44(-/-) mice treated with the analog EET-A for 4 weeks improved fasting glucose and glucose tolerance compared to Cyp2c44(-/-) mice treated with vehicle alone. This beneficial effect was accompanied by enhanced hepatic insulin signaling, decreased expression of gluconeogenic genes and increased expression of glycogenic genes. Mechanistically, we show that insulin-stimulated phosphorylation of insulin receptor ß (IRß) is impaired in primary Cyp2c44(-/-) hepatocytes and this can be restored by cotreatment with EET-A and insulin. Plasma membrane fractionations of livers indicated that EET-A enhances the retention of IRß in membrane rich fractions, thus potentiating its activation. Altogether, EET analogs ameliorate insulin signaling in a genetic model of hepatic insulin resistance by stabilizing membrane-associated IRß and potentiating insulin signaling.

2.
Cell Rep ; 37(2): 109813, 2021 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-34644565

RESUMO

A heterozygous missense mutation of the islet ß cell-enriched MAFA transcription factor (p.Ser64Phe [S64F]) is found in patients with adult-onset ß cell dysfunction (diabetes or insulinomatosis), with men more prone to diabetes than women. This mutation engenders increased stability to the unstable MAFA protein. Here, we develop a S64F MafA mouse model to determine how ß cell function is affected and find sex-dependent phenotypes. Heterozygous mutant males (MafAS64F/+) display impaired glucose tolerance, while females are slightly hypoglycemic with improved blood glucose clearance. Only MafAS64F/+ males show transiently higher MafA protein levels preceding glucose intolerance and sex-dependent changes to genes involved in Ca2+ signaling, DNA damage, aging, and senescence. MAFAS64F production in male human ß cells also accelerate cellular senescence and increase senescence-associated secretory proteins compared to cells expressing MAFAWT. These results implicate a conserved mechanism of accelerated islet aging and senescence in promoting diabetes in MAFAS64F carriers in a sex-biased manner.

3.
Int J Pediatr Otorhinolaryngol ; 149: 110862, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34340006

RESUMO

OBJECTIVE: To examine the effect of postoperative steroid dosage on postoperative telephone calls, emergency department (ED) visits, and hemorrhage rates for two groups receiving different steroid dosing following radiofrequency ablation tonsillectomy. STUDY DESIGN: Retrospective chart review between January 1, 2014 and January 1, 2019. SETTING: Tertiary care pediatric hospital. METHODS: Two postoperative steroid dosing protocols studied: 1) three postoperative doses of 0.5 mg/kg dexamethasone, or 2) three postoperative doses of 4 mg dexamethasone. Otherwise, postoperative care and pain control were similar for all patients. We hypothesized that standardized steroid dosing would achieve similar postoperative outcomes when compared to weight-based dosing with regards to patient phone calls, ED visits, readmission rates, and bleeding rates. RESULTS: Overall, 279 patients were included (n = 100 at 4 mg, n = 179 at 0.5 mg/kg). There were no differences between groups in age, gender, race, BMI, or comorbidities (P > 0.05). Readmission and ED visit rates were 2.8% and 12.2% respectively, with no significant difference between groups (P > 0.05)). The overall hemorrhage rate was 6.3%, including those patients presenting to the ED but not requiring intervention for bleeding concerns. There was no difference in hemorrhage rates between groups (P = 0.22); the hemorrhage rate requiring operative intervention was 1.4% with no difference between groups (P = 0.27). Postoperative phone calls to physicians' office occurred in 13.3% of cases with no difference between groups (P = 0.41). CONCLUSION: Comparable rates of readmission, ED visits, hemorrhage, and patient phone calls were seen with a standard dose of 4 mg versus 0.5 mg/kg weight-based dosing of a short course of postoperative dexamethasone following radiofrequency ablation tonsillectomy.


Assuntos
Ablação por Radiofrequência , Tonsilectomia , Criança , Humanos , Dor Pós-Operatória/tratamento farmacológico , Dor Pós-Operatória/epidemiologia , Readmissão do Paciente , Hemorragia Pós-Operatória/epidemiologia , Estudos Retrospectivos , Esteroides , Tonsilectomia/efeitos adversos
4.
Metabolites ; 11(5)2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065318

RESUMO

Mechanisms of sex differences in hypertriglyceridemia remain poorly understood. Small heterodimer partner (SHP) is a nuclear receptor that regulates bile acid, glucose, and lipid metabolism. SHP also regulates transcriptional activity of sex hormone receptors and may mediate sex differences in triglyceride (TG) metabolism. Here, we test the hypothesis that hepatic SHP mediates sex differences in TG metabolism using hepatocyte-specific SHP knockout mice. Plasma TGs in wild-type males were higher than in wild-type females and hepatic deletion of SHP lowered plasma TGs in males but not in females, suggesting hepatic SHP mediates plasma TG metabolism in a sex-specific manner. Additionally, hepatic deletion of SHP failed to lower plasma TGs in gonadectomized male mice or in males with knockdown of the liver androgen receptor, suggesting hepatic SHP modifies plasma TG via an androgen receptor pathway. Furthermore, the TG lowering effect of hepatic deletion of SHP was caused by increased clearance of postprandial TG and accompanied with decreased plasma levels of ApoC1, an inhibitor of lipoprotein lipase activity. These data support a role for hepatic SHP in mediating sex-specific effects on plasma TG metabolism through androgen receptor signaling. Understanding how hepatic SHP regulates TG clearance may lead to novel approaches to lower plasma TGs and mitigate cardiovascular disease risk.

5.
Physiol Rep ; 9(4): e14732, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33625789

RESUMO

Elevated triglycerides (TGs) and impaired TG clearance increase the risk of cardiovascular disease in both men and women, but molecular mechanisms remain poorly understood. Cholesteryl ester transfer protein (CETP) is a lipid shuttling protein known for its effects on high-density lipoprotein cholesterol. Although mice lack CETP, transgenic expression of CETP in mice alters TG metabolism in males and females by sex-specific mechanisms. A unifying mechanism explaining how CETP alters TG metabolism in both males and females remains unknown. Since low-density lipoprotein receptor (LDLR) regulates both TG clearance and very low density lipoprotein (VLDL) production, LDLR may be involved in CETP-mediated alterations in TG metabolism in both males and females. We hypothesize that LDLR is required for CETP to alter TG metabolism in both males and females. We used LDLR null mice with and without CETP to demonstrate that LDLR is required for CETP to raise plasma TGs and to impair TG clearance in males. We also demonstrate that LDLR is required for CETP to increase TG production and to increase the expression and activity of VLDL synthesis targets in response to estrogen. Additionally, we show that LDLR is required for CETP to enhance ß-oxidation. These studies support that LDLR is required for CETP to regulate TG metabolism in both males and females.

6.
Sensors (Basel) ; 21(1)2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33406602

RESUMO

Hearing loss is a disabling condition that increases with age and has been linked to difficulties in walking and increased risk of falls. The purpose of this study is to investigate changes in gait parameters associated with hearing loss in a group of older adults aged 60 or greater. Custom-engineered footwear was used to collect spatiotemporal gait data in an outpatient clinical setting. Multivariable linear regression was used to determine the relationship between spatiotemporal gait parameters and high and low frequency hearing thresholds of the poorer hearing ear, the left ear, and the right ear, respectively, adjusting for age, sex, race/ethnicity, and the Dizziness Handicap Inventory-Screening version score. Worsening high and low frequency hearing thresholds were associated with increased variability in double support period. Effects persisted after adjusting for the effects of age and perceived vestibular disability and were greater for increases in hearing thresholds for the right ear compared to the left ear. These findings illustrate the importance of auditory feedback for balance and coordination and may suggest a right ear advantage for the influence of auditory feedback on gait.


Assuntos
Surdez , Perda Auditiva , Acidentes por Quedas , Idoso , Feminino , Marcha , Perda Auditiva/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Caminhada
7.
Lipids ; 56(1): 17-29, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32783209

RESUMO

Elevated postprandial triacylglycerols (TAG) are an important risk factor for cardiovascular disease. Men have higher plasma TAG and impaired TAG clearance compared to women, which may contribute to sex differences in risk of cardiovascular disease. Understanding mechanisms of sex differences in TAG metabolism may yield novel therapeutic targets to prevent cardiovascular disease. Cholesteryl ester transfer protein (CETP) is a lipid shuttling protein known for its effects on high-density lipoprotein (HDL) cholesterol levels. Although mice lack CETP, we previously demonstrated that transgenic CETP expression in female mice alters TAG metabolism. The impact of CETP on TAG metabolism in males, however, is not well understood. Here, we demonstrate that CETP expression increases plasma TAG in males, especially in very-low density lipoprotein (VLDL), by impairing postprandial plasma TAG clearance compared to wild-type (WT) males. Gonadal hormones were required for CETP to impair TAG clearance, suggesting a role for sex hormones for this effect. Testosterone replacement in the setting of gonadectomy was sufficient to restore the effect of CETP on TAG. Lastly, liver androgen receptor (AR) was required for CETP to increase plasma TAG. Thus, expression of CETP in males raises plasma TAG by impairing TAG clearance via testosterone signaling to AR. Further understanding of how CETP and androgen signaling impair TAG clearance may lead to novel approaches to reduce TAG and mitigate risk of cardiovascular disease.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Receptores Androgênicos/metabolismo , Triglicerídeos/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
9.
Diabetes ; 67(12): 2494-2506, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30213825

RESUMO

In clinical trials, inhibition of cholesteryl ester transfer protein (CETP) raises HDL cholesterol levels but does not robustly improve cardiovascular outcomes. Approximately two-thirds of trial participants are obese. Lower plasma CETP activity is associated with increased cardiovascular risk in human studies, and protective aspects of CETP have been observed in mice fed a high-fat diet (HFD) with regard to metabolic outcomes. To define whether CETP inhibition has different effects depending on the presence of obesity, we performed short-term anacetrapib treatment in chow- and HFD-fed CETP transgenic mice. Anacetrapib raised HDL cholesterol and improved aspects of HDL functionality, including reverse cholesterol transport, and HDL's antioxidative capacity in HFD-fed mice was better than in chow-fed mice. Anacetrapib worsened the anti-inflammatory capacity of HDL in HFD-fed mice. The HDL proteome was markedly different with anacetrapib treatment in HFD- versus chow-fed mice. Despite benefits on HDL, anacetrapib led to liver triglyceride accumulation and insulin resistance in HFD-fed mice. Overall, our results support a physiologic importance of CETP in protecting from fatty liver and demonstrate context selectivity of CETP inhibition that might be important in obese subjects.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/genética , HDL-Colesterol/sangue , Dieta Hiperlipídica , Fígado Gorduroso/genética , Resistência à Insulina/fisiologia , Animais , Anticolesterolemiantes/farmacologia , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Fígado Gorduroso/metabolismo , Camundongos , Camundongos Transgênicos , Oxazolidinonas/farmacologia
10.
Mol Metab ; 15: 45-55, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29858147

RESUMO

BACKGROUND: Endogenous sex hormones are important for metabolic health in men and women. Before menopause, women are protected from atherosclerotic cardiovascular disease (ASCVD) relative to men. Women have fewer cardiovascular complications of obesity compared to men with obesity. Endogenous estrogens have been proposed as a mechanism that lessens ASCVD risk, as risk of glucose and lipid abnormalities increases when endogenous estrogens decline with menopause. While baseline risk is higher in males than females, endogenously produced androgens are also protective against fatty liver, diabetes and ASCVD, as risk goes up with androgen deprivation and with the decline in androgens with age. SCOPE OF REVIEW: In this review, we discuss evidence of how endogenous sex hormones and hormone treatment approaches impact fatty acid, triglyceride, and cholesterol metabolism to influence metabolic and cardiovascular risk. We also discuss potential reasons for why treatment strategies with estrogens and androgens in older individuals fail to fully recapitulate the effects of endogenous sex hormones. MAJOR CONCLUSIONS: The pathways that confer ASCVD protection for women are of potential therapeutic relevance. Despite protection relative to men, ASCVD is still the major cause of mortality in women. Additionally, diabetic women have similar ASCVD risk as diabetic men, suggesting that the presence of diabetes may offset the protective cardiovascular effects of being female through unknown mechanisms.


Assuntos
Doenças Cardiovasculares/metabolismo , Hormônios Gonadais/metabolismo , Metabolismo dos Lipídeos , Lipoproteínas/metabolismo , Animais , Doenças Cardiovasculares/epidemiologia , Humanos , Fatores Sexuais
11.
Circulation ; 138(17): 1850-1863, 2018 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-29794082

RESUMO

BACKGROUND: We previously showed that mice lacking MΦLRP1-/- (low-density lipoprotein receptor-related protein 1 in macrophages) undergo accelerated atherosclerotic plaque formation due to changes in macrophages including increased apoptosis, decreased efferocytosis, and exaggerated transition to the inflammatory M1 phenotype. Here we sought to explore the role of macrophage low-density lipoprotein receptor-related protein 1 during regression of atherosclerosis since regressing plaques are characterized by transitioning of macrophages to M2 status as inflammation resolves. METHODS: Apolipoprotein E-/- mice on a high-fat diet for 12 weeks were reconstituted with bone marrow from apolipoprotein E-producing wild-type or MΦLRP1-/- mice, and then placed on a chow diet for 10 weeks (n=9 to 11 mice/group). A cohort of apolipoprotein E-/- mice reconstituted with apolipoprotein E-/- bone marrow served as baseline controls (n=9). RESULTS: Plaques of both wild-type and MΦLRP1-/- bone marrow recipients regressed compared with controls (11% and 22%, respectively; P<0.05), and plaques of MΦLRP1-/- recipients were 13% smaller than those of wild-type recipients ( P<0.05). Recipients of MΦLRP1-/- marrow had 36% fewer M1 macrophages ( P<0.01) and 2.5-fold more CCR7 (C-C chemokine receptor type 7)-positive macrophages in the plaque relative to wild-type mice ( P<0.01). Additionally, in vivo studies of cellular egress showed a 4.6-fold increase in 5-ethynyl-2´-deoxyuridine-labeled CCR7+ macrophages in mediastinal lymph nodes. Finally, in vivo studies of reverse cholesterol transport showed a 1.4-fold higher reverse cholesterol transport in MΦLRP1-/- recipient mice ( P<0.01). CONCLUSIONS: Absence of macrophage low-density lipoprotein receptor-related protein 1 unexpectedly accelerates atherosclerosis regression, enhances reverse cholesterol transport, and increases expression of the motility receptor CCR7, which drives macrophage egress from lesions.


Assuntos
Aorta/metabolismo , Doenças da Aorta/metabolismo , Aterosclerose/metabolismo , Macrófagos/metabolismo , Placa Aterosclerótica , Receptores CCR7/metabolismo , Receptores de LDL/deficiência , Proteínas Supressoras de Tumor/deficiência , Animais , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Apoptose , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Colesterol/metabolismo , Modelos Animais de Doenças , Feminino , Deleção de Genes , Predisposição Genética para Doença , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Macrófagos/patologia , Camundongos Knockout para ApoE , Necrose , Fenótipo , Receptores de LDL/genética , Transdução de Sinais , Proteínas Supressoras de Tumor/genética , Regulação para Cima
12.
Laryngoscope ; 128(11): 2500-2502, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29658106

RESUMO

The influenza A virus has accounted for the majority of influenza infections in the 2017 to 2018 flu season, with the typical clinical presentation including fever, myalgias, malaise, and nonproductive cough. Notably this season, we have recognized a cluster of influenza A cases presenting as severe neck and facial swelling, with the subsequent diagnosis of sialadenitis. Whereas previous authors have demonstrated isolated case reports of sialadenitis associated with influenza A infection, herein we describe the clinical history, laboratory values, and radiographic findings of four patients presenting to our institution in January 2018 with acute sialadenitis and influenza A infection. Laryngoscope, 2500-2502, 2018.


Assuntos
Vírus da Influenza A , Influenza Humana/virologia , Sialadenite/virologia , Doença Aguda , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Sialadenite/diagnóstico , Sialadenite/terapia , Estados Unidos
13.
Mol Metab ; 8: 106-116, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29331506

RESUMO

OBJECTIVE: Hepatocyte deletion of estrogen receptor alpha (LKO-ERα) worsens fatty liver, dyslipidemia, and insulin resistance in high-fat diet fed female mice. However, whether or not hepatocyte ERα regulates reverse cholesterol transport (RCT) in mice has not yet been reported. METHODS AND RESULTS: Using LKO-ERα mice and wild-type (WT) littermates fed a Western-type diet, we found that deletion of hepatocyte ERα impaired in vivo RCT measured by the removal of 3H-cholesterol from macrophages to the liver, and subsequently to feces, in female mice but not in male mice. Deletion of hepatocyte ERα decreased the capacity of isolated HDL to efflux cholesterol from macrophages and reduced the ability of isolated hepatocytes to accept cholesterol from HDL ex vivo in both sexes. However, only in female mice, LKO-ERα increased serum cholesterol levels and increased HDL particle sizes. Deletion of hepatocyte ERα increased adiposity and worsened insulin resistance to a greater degree in female than male mice. All of the changes lead to a 5.6-fold increase in the size of early atherosclerotic lesions in female LKO-ERα mice compared to WT controls. CONCLUSIONS: Estrogen signaling through hepatocyte ERα plays an important role in RCT and is protective against lipid retention in the artery wall during early stages of atherosclerosis in female mice fed a Western-type diet.


Assuntos
Aterosclerose/metabolismo , Colesterol/metabolismo , Receptor alfa de Estrogênio/metabolismo , Hepatócitos/metabolismo , Obesidade/metabolismo , Animais , Aterosclerose/etiologia , Transporte Biológico , Células Cultivadas , Dieta Ocidental/efeitos adversos , Receptor alfa de Estrogênio/genética , Feminino , Resistência à Insulina , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Fatores Sexuais
14.
Adv Exp Med Biol ; 1043: 227-256, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29224098

RESUMO

Before menopause, women are protected from atherosclerotic heart disease associated with obesity relative to men. Sex hormones have been proposed as a mechanism that differentiates this risk. In this review, we discuss the literature around how the endogenous sex hormones and hormone treatment approaches after menopause regulate fatty acid, triglyceride, and cholesterol metabolism to influence cardiovascular risk.The important regulatory functions of estrogen signaling pathways with regard to lipid metabolism have been in part obscured by clinical trials with hormone treatment of women after menopause, due to different formulations, routes of delivery, and pairings with progestins. Oral hormone treatment with several estrogen preparations increases VLDL triglyceride production. Progestins oppose this effect by stimulating VLDL clearance in both humans and animals. Transdermal estradiol preparations do not increase VLDL production or serum triglycerides.Many aspects of sex differences in atherosclerotic heart disease risk are influenced by the distributed actions of estrogens in the muscle, adipose, and liver. In humans, 17ß-estradiol (E2) is the predominant circulating estrogen and signals through estrogen receptor alpha (ERα), estrogen receptor beta (ERß), and G-protein-coupled estrogen receptor (GPER). Over 1000 human liver genes display a sex bias in their expression, and the top biological pathways are in lipid metabolism and genes related to cardiovascular disease. Many of these genes display variation depending on estrus cycling in the mouse. Future directions will likely rely on targeting estrogens to specific tissues or specific aspects of the signaling pathways in order to recapitulate the protective physiology of premenopause therapeutically after menopause.


Assuntos
Doenças Cardiovasculares/metabolismo , Estrogênios/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/prevenção & controle , Receptor alfa de Estrogênio/metabolismo , Terapia de Reposição de Estrogênios , Feminino , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Menopausa/metabolismo , Camundongos , Modelos Animais , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Fatores de Proteção , Fatores de Risco , Caracteres Sexuais , Fatores Sexuais , Transdução de Sinais , Especificidade da Espécie
15.
Otol Neurotol ; 38(10): 1490-1499, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28984811

RESUMO

OBJECTIVE: To evaluate the association between Dizziness Handicap Inventory-Screening version (DHI-S) score and spatiotemporal gait parameters using SoleSound, a newly developed, inexpensive, portable footwear-based gait analysis system. STUDY DESIGN: Cross-sectional. PATIENTS: One hundred eighteen patients recruited from otology clinic. INTERVENTION(S): Subjects completed the DHI-S survey and four uninterrupted walking laps wearing SoleSound instrumented footwear on a hard, flat surface for 100 m. MAIN OUTCOME MEASURE(S): For each subject, mean and coefficient of variation (CV) of stride length, cadence, walking speed, foot-ground clearance, double-support time, swing period, and stance-to-swing were computed by considering 40 strides of steady-state walking within each lap. Linear regression models were employed to study correlations between these variables and DHI-S scores after adjusting for age, sex, and race/ethnicity. RESULTS: Patients with higher DHI-S score took shorter steps and less steps per minute (-0.017 m and -1.1 steps/min per every four-point increase in DHI-S score, p < 0.05) than patients with a lower DHI-S score, with slower walking speed (-0.025 m/s per every four-point increase in DHI-S score, p < 0.01). Additionally, patients with higher DHI-S scores showed larger variability in all analyzed temporal parameters (+0.1% for CV of cadence, +0.5% for CV of double support period, +0.2% for CV of swing period, and +0.4% for CV of stance-to-swing, per every four-point increase in DHI-S score, p < 0.01). CONCLUSION: SoleSound was effective in measuring a wide range of gait parameters. Patients' self-perception of vestibular handicap, as assessed with DHI-S, is associated with deterioration in measurable gait parameters independent of age.


Assuntos
Tontura/fisiopatologia , Marcha/fisiologia , Equilíbrio Postural/fisiologia , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Avaliação da Deficiência , Tontura/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Testes de Função Vestibular , Vestíbulo do Labirinto/fisiologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-28352249

RESUMO

Obesity in women is increased by the loss of circulating estrogen after menopause. Shift work, which disrupts circadian rhythms, also increases the risk for obesity. It is not known whether ovarian hormones interact with the circadian system to protect females from obesity. During high-fat feeding, male C57BL/6J mice develop profound obesity and disruption of daily rhythms. Since C57BL/6J female mice did not develop diet-induced obesity (during 8 weeks of high-fat feeding), we first determined if daily rhythms in female mice were resistant to disruption from high-fat diet. We fed female PERIOD2:LUCIFERASE mice 45% high-fat diet for 1 week and measured daily rhythms. Female mice retained robust rhythms of eating behavior and locomotor activity during high-fat feeding that were similar to chow-fed females. In addition, the phase of the liver molecular timekeeping (PER2:LUC) rhythm was not altered by high-fat feeding in females. To determine if ovarian hormones protected daily rhythms in female mice from high-fat feeding, we analyzed rhythms in ovariectomized mice. During high-fat feeding, the amplitudes of the eating behavior and locomotor activity rhythms were reduced in ovariectomized females. Liver PER2:LUC rhythms were also advanced by ~4 h by high-fat feeding, but not chow, in ovariectomized females. Together these data show circulating ovarian hormones protect the integrity of daily rhythms in female mice during high-fat feeding.

17.
Arterioscler Thromb Vasc Biol ; 36(8): 1483-95, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27365402

RESUMO

OBJECTIVE: Antiatherosclerotic effects of tumor necrosis factor-α (TNF-α) blockade in patients with systemic inflammatory states are not conclusively demonstrated, which suggests that effects depend on the cause of inflammation. Macrophage LRP1 (low-density lipoprotein receptor-related protein 1) and apoE contribute to inflammation through different pathways. We studied the antiatherosclerosis effects of TNF-α blockade in hyperlipidemic mice lacking either LRP1 (MΦLRP1(-/-)) or apoE from macrophages. APPROACH AND RESULTS: Lethally irradiated low-density lipoprotein receptor (LDLR)(-/-) mice were reconstituted with bone marrow from either wild-type, MΦLRP1(-/-), apoE(-/-) or apoE(-/-)/MΦLRP1(-/-)(DKO) mice, and then treated with the TNF-α inhibitor adalimumab while fed a Western-type diet. Adalimumab reduced plasma TNF-α concentration, suppressed blood ly6C(hi) monocyte levels and their migration into the lesion, and reduced lesion cellularity and inflammation in both wild-type→LDLR(-/-) and apoE(-/-)→LDLR(-/-) mice. Overall, adalimumab reduced lesion burden by 52% to 57% in these mice. Adalimumab reduced TNF-α and blood ly6C(hi) monocyte levels in MΦLRP1(-/-)→LDLR(-/-) and DKO→LDLR(-/-) mice, but it did not suppress ly6C(hi) monocyte migration into the lesion or atherosclerosis progression. CONCLUSIONS: Our results show that TNF-α blockade exerts antiatherosclerotic effects that are dependent on the presence of macrophage LRP1.


Assuntos
Adalimumab/farmacologia , Anti-Inflamatórios/farmacologia , Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Resistência a Medicamentos , Macrófagos/efeitos dos fármacos , Receptores de LDL/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Proteínas Supressoras de Tumor/metabolismo , Animais , Antígenos Ly/metabolismo , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Apoptose/efeitos dos fármacos , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Transplante de Medula Óssea , Movimento Celular/efeitos dos fármacos , Dieta Hiperlipídica , Modelos Animais de Doenças , Resistência a Medicamentos/genética , Feminino , Predisposição Genética para Doença , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos Knockout , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Necrose , Fenótipo , Placa Aterosclerótica , Receptores de LDL/deficiência , Receptores de LDL/genética , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Supressoras de Tumor/deficiência , Proteínas Supressoras de Tumor/genética , Irradiação Corporal Total
18.
J Lipid Res ; 57(8): 1541-51, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27354419

RESUMO

Elevated plasma TGs increase risk of cardiovascular disease in women. Estrogen treatment raises plasma TGs in women, but molecular mechanisms remain poorly understood. Here we explore the role of cholesteryl ester transfer protein (CETP) in the regulation of TG metabolism in female mice, which naturally lack CETP. In transgenic CETP females, acute estrogen treatment raised plasma TGs 50%, increased TG production, and increased expression of genes involved in VLDL synthesis, but not in nontransgenic littermate females. In CETP females, estrogen enhanced expression of small heterodimer partner (SHP), a nuclear receptor regulating VLDL production. Deletion of liver SHP prevented increases in TG production and expression of genes involved in VLDL synthesis in CETP mice with estrogen treatment. We also examined whether CETP expression had effects on TG metabolism independent of estrogen treatment. CETP increased liver ß-oxidation and reduced liver TG content by 60%. Liver estrogen receptor α (ERα) was required for CETP expression to enhance ß-oxidation and reduce liver TG content. Thus, CETP alters at least two networks governing TG metabolism, one involving SHP to increase VLDL-TG production in response to estrogen, and another involving ERα to enhance ß-oxidation and lower liver TG content. These findings demonstrate a novel role for CETP in estrogen-mediated increases in TG production and a broader role for CETP in TG metabolism.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/fisiologia , Fígado/metabolismo , Triglicerídeos/sangue , Animais , Receptor alfa de Estrogênio/metabolismo , Estrogênios/fisiologia , Feminino , Metabolismo dos Lipídeos , Redes e Vias Metabólicas , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Oxirredução , Triglicerídeos/biossíntese
19.
J Clin Invest ; 126(5): 1857-70, 2016 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-27064285

RESUMO

Type 2 diabetes is characterized by insulin resistance, hyperglycemia, and progressive ß cell dysfunction. Excess glucose and lipid impair ß cell function in islet cell lines, cultured rodent and human islets, and in vivo rodent models. Here, we examined the mechanistic consequences of glucotoxic and lipotoxic conditions on human islets in vivo and developed and/or used 3 complementary models that allowed comparison of the effects of hyperglycemic and/or insulin-resistant metabolic stress conditions on human and mouse islets, which responded quite differently to these challenges. Hyperglycemia and/or insulin resistance impaired insulin secretion only from human islets in vivo. In human grafts, chronic insulin resistance decreased antioxidant enzyme expression and increased superoxide and amyloid formation. In human islet grafts, expression of transcription factors NKX6.1 and MAFB was decreased by chronic insulin resistance, but only MAFB decreased under chronic hyperglycemia. Knockdown of NKX6.1 or MAFB expression in a human ß cell line recapitulated the insulin secretion defect seen in vivo. Contrary to rodent islet studies, neither insulin resistance nor hyperglycemia led to human ß cell proliferation or apoptosis. These results demonstrate profound differences in how excess glucose or lipid influence mouse and human insulin secretion and ß cell activity and show that reduced expression of key islet-enriched transcription factors is an important mediator of glucotoxicity and lipotoxicity.


Assuntos
Regulação da Expressão Gênica , Proteínas de Homeodomínio/biossíntese , Células Secretoras de Insulina/metabolismo , Transplante das Ilhotas Pancreáticas , Fator de Transcrição MafB/biossíntese , Animais , Xenoenxertos , Proteínas de Homeodomínio/genética , Humanos , Células Secretoras de Insulina/patologia , Células Secretoras de Insulina/transplante , Fator de Transcrição MafB/genética , Camundongos , Camundongos Knockout
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...