RESUMO
Adipose tissue is the site of long-term energy storage. During the fasting state, exercise, and cold exposure, the white adipose tissue mobilizes energy for peripheral tissues through lipolysis. The mobilization of lipids from white adipose tissue to the liver can lead to excess triglyceride accumulation and fatty liver disease. Although the white adipose tissue is known to release free fatty acids, a comprehensive analysis of lipids mobilized from white adipocytes in vivo has not been completed. In these studies, we provide a comprehensive quantitative analysis of the adipocyte-secreted lipidome and show that there is interorgan crosstalk with liver. Our analysis identifies multiple lipid classes released by adipocytes in response to activation of lipolysis. Time-dependent analysis of the serum lipidome showed that free fatty acids increase within 30 min of ß3-adrenergic receptor activation and subsequently decrease, followed by a rise in serum triglycerides, liver triglycerides, and several ceramide species. The triglyceride composition of liver is enriched for linoleic acid despite higher concentrations of palmitate in the blood. To further validate that these findings were a specific consequence of lipolysis, we generated mice with conditional deletion of adipose tissue triglyceride lipase exclusively in adipocytes. This loss of in vivo adipocyte lipolysis prevented the rise in serum free fatty acids and hepatic triglycerides. Furthermore, conditioned media from adipocytes promotes lipid remodeling in hepatocytes with concomitant changes in genes/pathways mediating lipid utilization. Together, these data highlight critical role of adipocyte lipolysis in interorgan crosstalk between adipocytes and liver.
Assuntos
Ácidos Graxos não Esterificados , Lipólise , Camundongos , Animais , Lipólise/fisiologia , Ácidos Graxos não Esterificados/metabolismo , Lipidômica , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Fígado/metabolismo , Triglicerídeos/metabolismoRESUMO
The minor allele of rs373863828, a missense variant in CREB3 Regulatory Factor, is associated with several cardiometabolic phenotypes in Polynesian peoples. To better understand the variant, we tested the association of rs373863828 with a panel of correlated phenotypes (body mass index [BMI], weight, height, HDL cholesterol, triglycerides, and total cholesterol) using multivariate Bayesian association and network analyses in a Samoa cohort (n = 1632), Aotearoa New Zealand cohort (n = 1419), and combined cohort (n = 2976). An expanded set of phenotypes (adding estimated fat and fat-free mass, abdominal circumference, hip circumference, and abdominal-hip ratio) was tested in the Samoa cohort (n = 1496). In the Samoa cohort, we observed significant associations (log10 Bayes Factor [BF] ≥ 5.0) between rs373863828 and the overall phenotype panel (8.81), weight (8.30), and BMI (6.42). In the Aotearoa New Zealand cohort, we observed suggestive associations (1.5 < log10 BF < 5) between rs373863828 and the overall phenotype panel (4.60), weight (3.27), and BMI (1.80). In the combined cohort, we observed concordant signals with larger log10 BFs. In the Samoa-specific expanded phenotype analyses, we also observed significant associations between rs373863828 and fat mass (5.65), abdominal circumference (5.34), and hip circumference (5.09). Bayesian networks provided evidence for a direct association of rs373863828 with weight and indirect associations with height and BMI.
Assuntos
Adiposidade , População das Ilhas do Pacífico , Proteínas Supressoras de Tumor , Humanos , Teorema de Bayes , Índice de Massa Corporal , Análise Multivariada , Obesidade/genética , Proteínas Supressoras de Tumor/genética , Mutação de Sentido IncorretoRESUMO
OBJECTIVES: Recent studies suggest that early menarche may increase cardiometabolic morbidity and mortality. Yet few studies have examined this association in the Pacific Islands, where obesity prevalence is among the highest globally. We sought to examine associations between age at menarche and cardiometabolic risk in Samoa. METHODS: Participants were from the Soifua Manuia study (n = 285, age 32-72 years) conducted in Samoa from 2017 to 2019. Logistic regressions were conducted to estimate odds of obesity, hypertension, diabetes, dyslipidemia, and metabolic syndrome per one-year increase in age at menarche. Linear regressions were conducted to examine associations between age at menarche and continuous measures of adiposity, blood pressure, insulin resistance, and serum lipids. RESULTS: Median age at menarche was 14 years (IQR = 2). After controlling for relevant covariates, each one-year increase in age at menarche was associated with a 15% decrease (OR = 0.85, 95% CI: 0.72-1.01, p = .067) in odds of hypertension, but a 21% increase (OR = 1.21, 95% CI: 1.01-1.45, p = .044) in odds of diabetes and 18% increase (OR = 1.18, 95% CI: 0.98-1.42, p = .081) in odds of high total cholesterol. Each additional year in age at menarche was associated with a 1.60 ± 0.52 kg (p = .002) decrease in lean mass and 1.56 ± 0.51 kg (p = .003) decrease in fat-free mass. CONCLUSIONS: Associations between age at menarche and cardiometabolic risk may be population-specific and are likely influenced by both current and historical nutritional and epidemiological contexts. Prospective studies are needed to clarify the role of childhood adiposity and other early life exposures on age at menarche and subsequent cardiometabolic risk.
Assuntos
Doenças Cardiovasculares , Diabetes Mellitus , Hipertensão , Obesidade Infantil , Adulto , Feminino , Humanos , Pré-Escolar , Pessoa de Meia-Idade , Idoso , Menarca/fisiologia , Fatores de Risco , Índice de Massa Corporal , Fatores Etários , Hipertensão/epidemiologia , Hipertensão/etiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologiaRESUMO
PURPOSE OF REVIEW: Hypertriglyceridemia-induced acute pancreatitis (HTG-AP) should be considered in all cases of acute pancreatitis and triglyceride levels measured early, so that appropriate early and long-term treatment can be initiated. RECENT FINDINGS: In most cases of HTG-AP, conservative management (nothing by mouth, intravenous fluid resuscitation and analgesia) is sufficient to achieve triglyceride levels less than 500âmg/dl. Intravenous insulin and plasmapheresis are sometimes used, although prospective studies showing clinical benefits are lacking. Pharmacological management of hypertriglyceridemia (HTG) should start early and target triglyceride levels of less than 500âmg/dl to reduce the risk or recurrent acute pancreatitis. In addition to currently used fenofibrate and omega-3 fatty acids, several novel agents are being studied for long-term treatment of HTG. These emerging therapies focus mainly on modifying the action of lipoprotein lipase (LPL) through inhibition of apolipoprotein CIII and angiopoietin-like protein 3. Dietary modifications and avoidance of secondary factors that worsen triglyceride levels should also be pursued. In some cases of HTG-AP, genetic testing may help personalize management and improve outcomes. SUMMARY: Patients with HTG-AP require acute and long-term management of HTG with the goal of reducing and maintaining triglyceride levels to less than 500âmg/dl.
Assuntos
Hipertrigliceridemia , Pancreatite , Humanos , Pancreatite/tratamento farmacológico , Pancreatite/etiologia , Doença Aguda , Estudos Prospectivos , Hipertrigliceridemia/complicações , Hipertrigliceridemia/tratamento farmacológico , Triglicerídeos/uso terapêuticoRESUMO
BACKGROUND AND AIMS: The primary goals of this study were to clarify 1) the effect of weight loss by lifestyle intervention on circulating total angiopoietin-like protein 8 (ANGPTL8), and 2) the role of physical activity on serum total ANGPTL8 in northern Americans with obesity but without diabetes. METHODS AND RESULTS: A total of 130 subjects with body mass index (BMI) ⧠35 kg/m2 but without diabetes were recruited, and 121 subjects completed a weight loss program for data analysis. Abdominal adipose tissue was determined by non-contrast computed tomography (CT). Serum total ANGPTL8 was higher in the group with obesity than in the lean control group. Serum total ANGPTL8 was positively correlated with waist circumference (WC), BMI, fasting insulin, HOMA-IR, HOMA-B, QUICKI, hs-CRP, IL-6, and leptin. Serum total ANGPTL8 did not significantly differ between the two intervention groups at baseline, and it was significantly lower after weight loss, with comparable changes with diet only and diet plus physical activity. CONCLUSION: Among northern Americans with obesity but without diabetes, a lifestyle modification resulted in significant reduction of circulating total ANGPTL8 concentrations in a 6-month weight-loss period. Although addition of physical activity resulted in greater total and liver fat loss, it did not promote further significant decline of serum total ANGPTL8 beyond diet alone.
Assuntos
Hormônios Peptídicos , Programas de Redução de Peso , Proteína 8 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina , Índice de Massa Corporal , Exercício Físico , Humanos , Obesidade/diagnóstico , Obesidade/terapia , Estudos Prospectivos , Redução de PesoRESUMO
OBJECTIVES: C-reactive protein (CRP) has been associated with adiposity and cardiometabolic disease risk in many populations but remains remarkably understudied in Pacific Islander populations. Here, we provide the first examination of correlates of CRP in adult Samoans (n = 108, ages 35-55 years) to test the hypotheses that CRP exhibits sex-dependent associations with measures of BMI, adiposity, and cardiometabolic disease risks. METHODS: We analyzed associations between measures of adiposity (total fat mass, visceral fat mass, percent total body fat), body mass index (BMI), cardiometabolic risks, behaviors, demographics, and CRP. Unadjusted analyses of CRP were undertaken using Pearson's pairwise, and Spearman's rank correlations; one-way analysis of variance and Kruskal-Wallis tests assessed variables by CRP quartiles. Adjusted analyses of CRP correlates were examined using generalized linear regression. RESULTS: Serum CRP ranged from 0.08 to 13.3 mg/L (median 1.4 mg/L) and varied significantly by sex t (108) = -2.47, p = .015. CRP was weakly to moderately associated with measures of adiposity and BMI (r and ρ ranged between 0.25 and 0.50, p < .05) and some cardiometabolic markers (including HbA1c, fasting insulin, and insulin resistance). CRP was significantly associated with percent body fat in women and men, adjusting for other variables. CONCLUSIONS: These data are among the first to demonstrate CRP correlates in a sample of adult Samoans. CRP differed by sex and was associated with BMI, adiposity, and some cardiometabolic risk markers. These data align with findings in other populations.
Assuntos
Proteína C-Reativa , Resistência à Insulina , Adiposidade/fisiologia , Adulto , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , ObesidadeRESUMO
Following cardiac injury, increased adrenergic drive plays an important role in compensating for reduced cardiac function. However, chronic excess adrenergic stimulation can be detrimental to cardiac pathophysiology and can also affect other organs including adipose tissue, leading to increased lipolysis. Interestingly, inhibition of adipose triglyceride lipase (ATGL), a rate-limiting enzyme in lipolysis, in adipocytes ameliorates cardiac dysfunction in a heart failure model. Thus, we investigated whether inhibition of adipocyte ATGL can mitigate the adverse cardiac effects of chronic adrenergic stimulation and explored the underlying mechanisms. To do this, isoproterenol (ISO) was continuously administered to C57Bl/6N mice for 2 wk with or without an ATGL inhibitor (Atglistatin). We found that Atglistatin alleviated ISO-induced cardiac remodeling and reduced ISO-induced upregulation of galectin-3, a marker of activated macrophages and a potent inducer of fibrosis, in white adipose tissue (WAT), heart, and the circulation. To test whether the beneficial effects of Atglistatin occur via inhibition of adipocyte ATGL, adipocyte-specific ATGL knockout (atATGL-KO) mice were utilized for similar experiments. Subsequently, the same cardioprotective effects of atATGL-KO following ISO administration were observed. Furthermore, Atglistatin and atATGL-KO abolished ISO-induced galectin-3 secretion from excised WAT. We further demonstrated that activation of cardiac fibroblasts by the conditioned media of ISO-stimulated WAT is galectin-3-dependent. In conclusion, the inhibition of adipocyte ATGL ameliorated ISO-induced cardiac remodeling possibly by reducing galectin-3 secretion from adipose tissue. Thus, inhibition of adipocyte ATGL might be a potential target to prevent some of the adverse effects of chronic excess adrenergic drive.NEW & NOTEWORTHY The reduction of lipolysis by adipocyte ATGL inhibition ameliorates cardiac remodeling induced by chronic ß-adrenergic stimulation likely via reducing galectin-3 secretion from adipose tissue. Our findings highlight that suppressing lipolysis in adipocytes may be a potential therapeutic target for patients with heart failure whose sympathetic nervous system is activated. Furthermore, galectin-3 might be involved in the mechanisms by which excessive lipolysis in adipose tissues influences remote cardiac pathologies and thus warrants further investigation.
Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Anti-Inflamatórios/farmacologia , Inibidores Enzimáticos/farmacologia , Cardiopatias/prevenção & controle , Mediadores da Inflamação/metabolismo , Isoproterenol , Lipase/antagonistas & inibidores , Compostos de Fenilureia/farmacologia , Remodelação Ventricular/efeitos dos fármacos , Tecido Adiposo Branco/enzimologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Galectina 3/metabolismo , Cardiopatias/induzido quimicamente , Cardiopatias/enzimologia , Cardiopatias/fisiopatologia , Lipase/metabolismo , Lipólise/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Comunicação Parácrina , Transdução de SinaisRESUMO
Adipose tissue lipolysis occurs during the development of heart failure as a consequence of chronic adrenergic stimulation. However, the impact of enhanced adipose triacylglycerol hydrolysis mediated by adipose triglyceride lipase (ATGL) on cardiac function is unclear. To investigate the role of adipose tissue lipolysis during heart failure, we generated mice with tissue-specific deletion of ATGL (atATGL-KO). atATGL-KO mice were subjected to transverse aortic constriction (TAC) to induce pressure-mediated cardiac failure. The cardiac mouse lipidome and the human plasma lipidome from healthy controls (n = 10) and patients with systolic heart failure (HFrEF, n = 13) were analyzed by MS-based shotgun lipidomics. TAC-induced increases in left ventricular mass (LVM) and diastolic LV inner diameter were significantly attenuated in atATGL-KO mice compared to wild type (wt) -mice. More importantly, atATGL-KO mice were protected against TAC-induced systolic LV failure. Perturbation of lipolysis in the adipose tissue of atATGL-KO mice resulted in the prevention of the major cardiac lipidome changes observed after TAC in wt-mice. Profound changes occurred in the lipid class of phosphatidylethanolamines (PE) in which multiple PE-species were markedly induced in failing wt-hearts, which was attenuated in atATGL-KO hearts. Moreover, selected heart failure-induced PE species in mouse hearts were also induced in plasma samples from patients with chronic heart failure. TAC-induced cardiac PE induction resulted in decreased PC/ PE-species ratios associated with increased apoptotic marker expression in failing wt-hearts, a process absent in atATGL-KO hearts. Perturbation of adipose tissue lipolysis by ATGL-deficiency ameliorated pressure-induced heart failure and the potentially deleterious cardiac lipidome changes that accompany this pathological process, namely the induction of specific PE species. Non-cardiac ATGL-mediated modulation of the cardiac lipidome may play an important role in the pathogenesis of chronic heart failure.
Assuntos
Tecido Adiposo/metabolismo , Insuficiência Cardíaca/etiologia , Hipertensão/complicações , Lipase/fisiologia , Metabolismo dos Lipídeos/genética , Miocárdio/metabolismo , Disfunção Ventricular Esquerda/etiologia , Animais , Estudos de Casos e Controles , Células Cultivadas , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Lipase/genética , Lipase/metabolismo , Masculino , Metaboloma/genética , Camundongos , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Remodelação VentricularRESUMO
BACKGROUND: The "Foafoaga O le Ola (Beginning of Life)" study is a prospective birth cohort of n = 160 Samoan mother-infant dyads established in 2017-2018. A primary study aim is to explore how a missense variant at CREBRF rs373863828 impacts growth in early life, given its association with increased body size but lower risk of diabetes in adult Samoans. Here, we examine body size and composition by genotype among toddlers aged 18.7-24.5 months. METHODS: Height, weight, head circumference, mid-upper-arm circumference, and abdominal circumference, as well as subscapular, triceps, iliac crest and thigh skinfold thickness were measured among 107 toddlers with known rs373863828 genotype; 42 of these toddlers completed dual-energy X-ray absorptiometry (DXA) scans from which body composition (total body less head fat mass, lean mass, bone mass, % fat mass and % fat-free mass) was estimated. RESULTS: After controlling for sex and age, toddlers with at least one copy of the CREBRF minor allele (AA/AG) were 1.31 cm taller (SE = 0.64, p = 0.045) than toddlers with the GG genotype. CONCLUSION: Whether greater linear growth in early childhood could contribute to the metabolically protective effects associated with the CREBRF variant in adulthood should be explored in future studies.
Assuntos
Coorte de Nascimento , Composição Corporal , Absorciometria de Fóton , Adolescente , Adulto , Estatura , Pré-Escolar , Humanos , Lactente , Estudos Prospectivos , Dobras Cutâneas , Adulto JovemRESUMO
In mammals, white adipose tissue (WAT) stores and releases lipids, whereas brown adipose tissue (BAT) oxidizes lipids to fuel thermogenesis. In obese individuals, WAT undergoes profound changes; it expands, becomes dysfunctional, and develops a low-grade inflammatory state. Importantly, BAT content and activity decline in obese subjects, mainly as a result of the conversion of brown adipocytes to white-like unilocular cells. Here, we show that BAT "whitening" is induced by multiple factors, including high ambient temperature, leptin receptor deficiency, ß-adrenergic signaling impairment, and lipase deficiency, each of which is capable of inducing macrophage infiltration, brown adipocyte death, and crown-like structure (CLS) formation. Brown-to-white conversion and increased CLS formation were most marked in BAT from adipose triglyceride lipase (Atgl)-deficient mice, where, according to transmission electron microscopy, whitened brown adipocytes contained enlarged endoplasmic reticulum, cholesterol crystals, and some degenerating mitochondria, and were surrounded by an increased number of collagen fibrils. Gene expression analysis showed that BAT whitening in Atgl-deficient mice was associated to a strong inflammatory response and NLRP3 inflammasome activation. Altogether, the present findings suggest that converted enlarged brown adipocytes are highly prone to death, which, by promoting inflammation in whitened BAT, may contribute to the typical inflammatory state seen in obesity.
Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Morte Celular , Inflamação/metabolismo , Inflamação/patologia , Animais , Lipase/deficiência , Lipase/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Accumulation of myeloid cells in the liver, notably dendritic cells (DCs) and monocytes/macrophages (MCs), is a major component of the metainflammation of obesity. However, the mechanism(s) stimulating hepatic DC/MC infiltration remain ill defined. Herein, we addressed the hypothesis that adipose tissue (AT) free fatty acids (FFAs) play a central role in the initiation of hepatic DC/MC accumulation, using a number of mouse models of altered FFA supply to the liver. In two models of acute FFA elevation (lipid infusion and fasting) hepatic DC/MC and triglycerides (TGs) but not AT DC/MC were increased without altering plasma cytokines (PCs; TNFα and monocyte chemoattractant protein 1) and with variable effects on oxidative stress (OxS) markers. However, fasting in mice with profoundly reduced AT lipolysis (AT-specific deletion of adipose TG lipase; AAKO) failed to elevate liver DC/MC, TG, or PC, but liver OxS increased. Livers of obese AAKO mice that are known to be resistant to steatosis were similarly protected from inflammation. In high-fat feeding studies of 1, 3, 6, or 20-wk duration, liver DC/MC accumulation dissociated from PC and OxS but tracked with liver TGs. Furthermore, decreasing OxS by ~80% in obese mice failed to decrease liver DC/MC. Therefore, FFA and more specifically AT-derived FFA stimulate hepatic DC/MC accumulation, thus recapitulating the pathology of the obese liver. In a number of cases the effects of FFA can be dissociated from OxS and PC but match well with liver TG, a marker of FFA oversupply.
Assuntos
Tecido Adiposo/metabolismo , Jejum/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Fígado/metabolismo , Células Mieloides/metabolismo , Animais , Citocinas/sangue , Dieta Hiperlipídica , Ácidos Graxos não Esterificados/farmacologia , Lipase/genética , Lipase/metabolismo , Lipólise/fisiologia , Fígado/efeitos dos fármacos , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Triglicerídeos/metabolismoRESUMO
Despite advancements in therapies for cardiovascular disease and heart failure (HF), the incidence and prevalence of HF are increasing. Previous work has suggested that inhibiting adipose triglyceride lipase (ATGL) in adipose tissue during HF development may assist in the treatment of HF. The ability to specifically target the adipocyte as a potential treatment for HF is a novel approach that could significantly influence the management of HF in the future. Our objectives were to assess the cardiac structural and functional effects of pharmacological inhibition of ATGL in mice with HF, to assess whether ATGL inhibition works in an adipocyte-autonomous manner, and to determine the role that adiposity and glucose homeostasis play in this HF treatment approach. Using a known ATGL inhibitor, atglistatin, as well as mice with germline deletion of adipocyte-specific ATGL, we tested the effectiveness of ATGL inhibition in mice with pressure overload-induced HF. Here, we show that atglistatin can prevent the functional decline in HF and provide evidence that specifically targeting ATGL in the adipocyte is sufficient to prevent worsening of HF. We further demonstrate that the benefit resulting from atglistatin in HF is not dependent on previously suggested improvements in glucose homeostasis, nor are the benefits derived from increased adiposity. Overall, the results of this study suggest that adipocyte-specific pharmacological inhibition of ATGL may represent a novel therapeutic option for HF. NEW & NOTEWORTHY This work shows for the first time that the adipose triglyceride lipase (ATGL)-specific inhibitor atglistatin can prevent worsening heart failure. Furthermore, using mice with adipocyte-specific ATGL ablation, this study demonstrates that ATGL inhibition works in an adipocyte-autonomous manner to ameliorate a functional decline in heart failure. Overall, this work demonstrates that specifically targeting the adipocyte to inhibit ATGL is a potential treatment for heart failure.
Assuntos
Adipócitos/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Lipase/antagonistas & inibidores , Lipólise/efeitos dos fármacos , Compostos de Fenilureia/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Adipócitos/enzimologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Lipase/genética , Lipase/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
Lipid accumulation is a pathological feature of every type of kidney injury. Despite this striking histological feature, physiological accumulation of lipids in the kidney is poorly understood. We studied whether the accumulation of lipids in the fasted kidney are derived from lipoproteins or NEFAs. With overnight fasting, kidneys accumulated triglyceride, but had reduced levels of ceramide and glycosphingolipid species. Fasting led to a nearly 5-fold increase in kidney uptake of plasma [14C]oleic acid. Increasing circulating NEFAs using a ß adrenergic receptor agonist caused a 15-fold greater accumulation of lipid in the kidney, while mice with reduced NEFAs due to adipose tissue deficiency of adipose triglyceride lipase had reduced triglycerides. Cluster of differentiation (Cd)36 mRNA increased 2-fold, and angiopoietin-like 4 (Angptl4), an LPL inhibitor, increased 10-fold. Fasting-induced kidney lipid accumulation was not affected by inhibition of LPL with poloxamer 407 or by use of mice with induced genetic LPL deletion. Despite the increase in CD36 expression with fasting, genetic loss of CD36 did not alter fatty acid uptake or triglyceride accumulation. Our data demonstrate that fasting-induced triglyceride accumulation in the kidney correlates with the plasma concentrations of NEFAs, but is not due to uptake of lipoprotein lipids and does not involve the fatty acid transporter, CD36.
Assuntos
Jejum/sangue , Jejum/metabolismo , Ácidos Graxos não Esterificados/sangue , Rim/metabolismo , Triglicerídeos/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , OxirreduçãoRESUMO
Endurance exercise training induces substantial adaptive cardiac modifications such as left ventricular hypertrophy (LVH). Simultaneously to the development of LVH, adipose tissue (AT) lipolysis becomes elevated upon endurance training to cope with enhanced energy demands. In this study, we investigated the impact of adipose tissue lipolysis on the development of exercise-induced cardiac hypertrophy. Mice deficient for adipose triglyceride lipase (Atgl) in AT (atATGL-KO) were challenged with chronic treadmill running. Exercise-induced AT lipolytic activity was significantly reduced in atATGL-KO mice accompanied by the absence of a plasma fatty acid (FA) increase. These processes were directly associated with a prominent attenuation of myocardial FA uptake in atATGL-KO and a significant reduction of the cardiac hypertrophic response to exercise. FA serum profiling revealed palmitoleic acid (C16:1n7) as a new molecular co-mediator of exercise-induced cardiac hypertrophy by inducing nonproliferative cardiomyocyte growth. In parallel, serum FA analysis and echocardiography were performed in 25 endurance athletes. In consonance, the serum C16:1n7 palmitoleate level exhibited a significantly positive correlation with diastolic interventricular septum thickness in those athletes. No correlation existed between linoleic acid (18:2n6) and diastolic interventricular septum thickness. Collectively, our data provide the first evidence that adipose tissue lipolysis directly promotes the development of exercise-induced cardiac hypertrophy involving the lipokine C16:1n7 palmitoleate as a molecular co-mediator. The identification of a lipokine involved in physiological cardiac growth may help to develop future lipid-based therapies for pathological LVH or heart failure.
Assuntos
Tecido Adiposo/metabolismo , Cardiomegalia/etiologia , Ácidos Graxos Monoinsaturados/metabolismo , Lipólise , Condicionamento Físico Animal , Animais , Cardiomegalia/metabolismo , Linhagem Celular , Camundongos , Camundongos KnockoutRESUMO
Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme mediating triacylglycerol hydrolysis in virtually all cells, including adipocytes and skeletal myocytes, and hence, plays a critical role in mobilizing fatty acids. Global ATGL deficiency promotes skeletal myopathy and exercise intolerance in mice and humans, and yet the tissue-specific contributions to these phenotypes remain unknown. The goal of this study was to determine the relative contribution of ATGL-mediated triacylglycerol hydrolysis in adipocytes vs. skeletal myocytes to acute exercise performance. To achieve this goal, we generated murine models with adipocyte- and skeletal myocyte-specific targeted deletion of ATGL. We then subjected untrained mice to acute peak and submaximal exercise interventions and assessed exercise performance and energy substrate metabolism. Impaired ATGL-mediated lipolysis within adipocytes reduced peak and submaximal exercise performance, reduced peripheral energy substrate availability, shifted energy substrate preference toward carbohydrate oxidation, and decreased HSL Ser(660) phosphorylation and mitochondrial respiration within skeletal muscle. In contrast, impaired ATGL-mediated lipolysis within skeletal myocytes was not sufficient to reduce peak and submaximal exercise performance or peripheral energy substrate availability and instead tended to enhance metabolic flexibility during peak exercise. Furthermore, the expanded intramyocellular triacylglycerol pool in these mice was reduced following exercise in association with preserved HSL phosphorylation, suggesting that HSL may compensate for impaired ATGL action in skeletal muscle during exercise. These data suggest that adipocyte rather than skeletal myocyte ATGL-mediated lipolysis plays a greater role during acute exercise in part because of compensatory mechanisms that maintain lipolysis in muscle, but not adipose tissue, when ATGL is absent.
Assuntos
Adipócitos/metabolismo , Lipase/genética , Fibras Musculares Esqueléticas/metabolismo , Condicionamento Físico Animal/fisiologia , Esforço Físico/genética , Animais , Desempenho Atlético , Tolerância ao Exercício/genética , Feminino , Deleção de Genes , Lipase/metabolismo , Lipólise/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
BACKGROUND & AIMS: Adipose tissue (AT)-derived fatty acids (FAs) are utilized for hepatic triacylglycerol (TG) generation upon fasting. However, their potential impact as signaling molecules is not established. Herein we examined the role of exogenous AT-derived FAs in the regulation of hepatic gene expression by investigating mice with a defect in AT-derived FA supply to the liver. METHODS: Plasma FA levels, tissue TG hydrolytic activities and lipid content were determined in mice lacking the lipase co-activator comparative gene identification-58 (CGI-58) selectively in AT (CGI-58-ATko) applying standard protocols. Hepatic expression of lipases, FA oxidative genes, transcription factors, ER stress markers, hormones and cytokines were determined by qRT-PCR, Western blotting and ELISA. RESULTS: Impaired AT-derived FA supply upon fasting of CGI-58-ATko mice causes a marked defect in liver PPARα-signaling and nuclear CREBH translocation. This severely reduced the expression of respective target genes such as the ATGL inhibitor G0/G1 switch gene-2 (G0S2) and the endocrine metabolic regulator FGF21. These changes could be reversed by lipid administration and raising plasma FA levels. Impaired AT-lipolysis failed to induce hepatic G0S2 expression in fasted CGI-58-ATko mice leading to enhanced ATGL-mediated TG-breakdown strongly reducing hepatic TG deposition. On high fat diet, impaired AT-lipolysis counteracts hepatic TG accumulation and liver stress linked to improved systemic insulin sensitivity. CONCLUSIONS: AT-derived FAs are a critical regulator of hepatic fasting gene expression required for the induction of G0S2-expression in the liver to control hepatic TG-breakdown. Interfering with AT-lipolysis or hepatic G0S2 expression represents an effective strategy for the treatment of hepatic steatosis.
Assuntos
Tecido Adiposo/metabolismo , Jejum/metabolismo , Ácidos Graxos/metabolismo , Fígado Gorduroso/genética , Fatores de Crescimento de Fibroblastos/genética , Regulação da Expressão Gênica , Fígado/metabolismo , Animais , Western Blotting , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fatores de Crescimento de Fibroblastos/biossíntese , Genes de Troca , Fígado/ultraestrutura , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica , RNA/genética , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Chronic activation of ß3-adrenergic receptors (ß3-ARs) expands the catabolic activity of both brown and white adipose tissue by engaging uncoupling protein 1 (UCP1)-dependent and UCP1-independent processes. The present work examined de novo lipogenesis (DNL) and TG/glycerol dynamics in classic brown, subcutaneous "beige," and classic white adipose tissues during sustained ß3-AR activation by CL 316,243 (CL) and also addressed the contribution of TG hydrolysis to these dynamics. CL treatment for 7 days dramatically increased DNL and TG turnover similarly in all adipose depots, despite great differences in UCP1 abundance. Increased lipid turnover was accompanied by the simultaneous upregulation of genes involved in FAS, glycerol metabolism, and FA oxidation. Inducible, adipocyte-specific deletion of adipose TG lipase (ATGL), the rate-limiting enzyme for lipolysis, demonstrates that TG hydrolysis is required for CL-induced increases in DNL, TG turnover, and mitochondrial electron transport in all depots. Interestingly, the effect of ATGL deletion on induction of specific genes involved in FA oxidation and synthesis varied among fat depots. Overall, these studies indicate that FAS and FA oxidation are tightly coupled in adipose tissues during chronic adrenergic activation, and this effect critically depends on the activity of adipocyte ATGL.
Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Lipogênese/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Receptores Adrenérgicos beta 3/metabolismo , Tecido Adiposo Marrom/citologia , Tecido Adiposo Branco/citologia , Adiposidade/efeitos dos fármacos , Animais , Dioxóis/farmacologia , Feminino , Deleção de Genes , Regulação da Expressão Gênica/efeitos dos fármacos , Glicerol/metabolismo , Cinética , Lipase/deficiência , Lipase/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Triglicerídeos/metabolismoRESUMO
Activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a moderating factor between obesity and cognitive impairment in animals, but this has never been tested in humans following mild traumatic brain injury (mTBI). This is a retrospective cohort analysis of subjects enrolled at a single level 1 trauma center (n = 172). Participants completed Trail Making Test Part A and B (TMT-A and B) at six- and twelve-months, Blood samples were obtained within 24 h of mTBI and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, interleukin-18 (IL-18), and IL-1ß were assayed. Obese participants (BMI = 30-34.9) were associated with higher IL-18 (p = 0.03) and IL-1ß (p = 0.05) and severely obese participants (BMI > 35.0) were associated with higher IL-1ß (p = 0.005) than healthy weight participants. IL-1ß was associated with TMT-A at six- (p = 0.01) and twelve-months (p = 0.03) and TMT-B at twelve-months (p = 0.046). The interaction of severely obese BMI and IL-1ß was associated with TMT-B at six- (p = 0.049) and twelve-months (p = 0.02). ASC (p = 0.03) and the interaction of ASC with severely obese BMI was associated with TMTB at six- (p = 0.02) and twelve-months (p = 0.02). Obesity may augment acute inflammasome response to mTBI and influence worse long-term cognitive outcomes up to one-year post-injury.
RESUMO
The NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome has been associated with worse outcomes from severe traumatic brain injury (TBI). The NLRP3 inflammasome is also strongly associated with other pro-inflammatory conditions, such as obesity. Little is known about the potential effect of mild TBI (mTBI) on the NLRP3 inflammasome and the extent to which modifying factors, such as obesity, may augment the inflammatory response to mTBI. The purpose of this study was to evaluate the association of NLRP3 inflammasome proteins with obese body mass index (BMI ≥ 30) within 24 h of mTBI after presenting to a level 1 trauma center emergency department. This is a secondary analysis of prospectively enrolled patients with mTBI who presented to the emergency department of one U.S. Level 1 trauma center from 2013 to 2018 (n = 243). A series of regression models were built to evaluate the association of NLRP3 proteins obtained from blood plasma within 24 h of injury and BMI as well as the potential interaction effect of higher BMI with NLRP3 proteins (n = 243). A logistic regression model revealed a significant association between IL-18 (p < 0.001) in mTBI patients with obese BMI compared to mTBI patients with non-obese BMI (< 30). Moderation analyses revealed statistically significant interaction effects between apoptotic speck-like protein (ASC), caspase-1, IL-18, IL-1ß and obese BMI which worsened symptom burden, quality of life, and physical function at 2 weeks and 6 months post-injury. Higher acute concentrations of IL-1ß in the overall cohort predicted higher symptoms at 6-months and worse physical function at 2-weeks and 6-months. Higher acute concentrations of IL-18 in the overall cohort predicted worse physical function at 6-months. In this single center mTBI cohort, obese BMI interacted with higher acute concentrations of NLRP3 inflammasome proteins and worsened short- and long-term clinical outcomes.
Assuntos
Índice de Massa Corporal , Concussão Encefálica , Inflamassomos , Interleucina-18 , Proteína 3 que Contém Domínio de Pirina da Família NLR , Obesidade , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Masculino , Feminino , Obesidade/complicações , Inflamassomos/metabolismo , Adulto , Pessoa de Meia-Idade , Concussão Encefálica/complicações , Concussão Encefálica/sangue , Interleucina-18/sangue , Interleucina-18/metabolismo , Estudos Prospectivos , Interleucina-1beta/sangue , Interleucina-1beta/metabolismo , Caspase 1/metabolismoRESUMO
Biopsies of muscle and adipose tissue (AT) are useful tools to gain insights into the aging processes in these tissues. However, they are invasive procedures and their risk/benefit profile in older adults can be altered by sarcopenia, frailty, poor healing, and multimorbidity. Their success rates, safety, and tolerability in a geriatric population have not been reported in detail. Investigators in the Study of Muscle, Mobility, and Aging (SOMMA) performed biopsies of muscle and AT in older adults and prospectively collected data on biopsy success rates, safety, and tolerability. We report here the methods and outcomes of these two procedures. In total, 861 participants (aged 70-94) underwent percutaneous biopsies of the Vastus lateralis muscle with a Bergstrom needle. A subset (n = 241) also underwent percutaneous biopsies of the abdominal subcutaneous AT with the tumescent liposuction technique. Success rate was assessed by the percentage of biopsies yielding adequate specimens for analyses; tolerability by pain scores; and safety by frequency of adverse events. All data were prospectively collected. The overall muscle biopsy success rate was 97.1% and was modestly lower in women. The AT biopsy success rate was 95.9% and slightly lower in men. Minimal or no pain was reported in 68% of muscle biopsies and in 83% of AT biopsies. Adverse events occurred in 2.67% of muscle biopsies and 4.15% of AT biopsies. None was serious. In older adults, percutaneous muscle biopsies and abdominal subcutaneous AT biopsies have an excellent safety profile, often achieve adequate tissue yields for analyses, and are well tolerated.