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1.
Nat Commun ; 11(1): 578, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31996685

RESUMO

Lipid droplets (LDs) are key subcellular organelles for regulating lipid metabolism. Although several subcellular organelles participate in lipid metabolism, it remains elusive whether physical contacts between subcellular organelles and LDs might be involved in lipolysis upon nutritional deprivation. Here, we demonstrate that peroxisomes and peroxisomal protein PEX5 mediate fasting-induced lipolysis by stimulating adipose triglyceride lipase (ATGL) translocation onto LDs. During fasting, physical contacts between peroxisomes and LDs are increased by KIFC3-dependent movement of peroxisomes toward LDs, which facilitates spatial translocations of ATGL onto LDs. In addition, PEX5 could escort ATGL to contact points between peroxisomes and LDs in the presence of fasting cues. Moreover, in adipocyte-specific PEX5-knockout mice, the recruitment of ATGL onto LDs was defective and fasting-induced lipolysis is attenuated. Collectively, these data suggest that physical contacts between peroxisomes and LDs are required for spatiotemporal translocation of ATGL, which is escorted by PEX5 upon fasting, to maintain energy homeostasis.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Jejum/efeitos adversos , Gotículas Lipídicas/metabolismo , Lipólise/fisiologia , Receptor 1 de Sinal de Orientação para Peroxissomos/metabolismo , Peroxissomos/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Análise Espaço-Temporal , Células 3T3-L1/metabolismo , Adipócitos/metabolismo , Animais , Caenorhabditis elegans , Sinais (Psicologia) , Citoesqueleto , Cinesina/metabolismo , Metabolismo dos Lipídeos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nutrientes , Receptor 1 de Sinal de Orientação para Peroxissomos/genética , Peroxissomos/genética , Transdução de Sinais
2.
J Physiol Pharmacol ; 70(3)2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31539888

RESUMO

Adipose triglyceride lipase (ATGL) hydrolyses the first bond of triacylglycerols. The activity of the enzyme is elevated by comparative gene identification 58 (CGI-58), and reduced by G0/G1 switch gene 2 (G0S2) protein. There are no data on the effect of acute exercise on the behavior of particular components of the lipolytic complex in different skeletal muscle types, therefore, the aim of the present study was to examine that topic. The experiments were carried out on four groups of male Wistar rats: 1) control 2) rats running on a treadmill at the speed of 18 m/min for 30 min, 3) at the speed of 18 m/min for 120 min, 4) for 30 min at the speed of 28 m/min. We found that each exercise bout induced numerous changes in the expression of mRNA and protein ATGL, hormone-sensitive lipase, CGI-58 and G0S2 in the investigated muscles. These changes, depended to a large extent on a muscle type. In general, the strongest pro-lipolytic response was observed in the soleus, followed by the red section of the gastrocnemius (RG). On the other hand, in the white section of the gastrocnemius protein expression of the components of the lipolytic complex was reduced in response to exercise. These changes were not accompanied by alterations in muscle triacylglycerol content, with the exception of a reduction observed in the RG following 2-hour run. We conclude that a single bout of exercise induces significant effect on the expression of components of the lipolytic complex in skeletal muscle, and that the magnitude of this effect depends on muscle oxidative capacity, as well as the duration and intensity of exercise.


Assuntos
Lipólise/fisiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Condicionamento Físico Animal/fisiologia , RNA Mensageiro/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Lipase/metabolismo , Masculino , Ratos , Ratos Wistar , Esterol Esterase/metabolismo , Triglicerídeos/metabolismo
3.
Crit Care ; 23(1): 236, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31262340

RESUMO

BACKGROUND: ICU-acquired weakness is a debilitating consequence of prolonged critical illness that is associated with poor outcome. Recently, premorbid obesity has been shown to protect against such illness-induced muscle wasting and weakness. Here, we hypothesized that this protection was due to increased lipid and ketone availability. METHODS: In a centrally catheterized, fluid-resuscitated, antibiotic-treated mouse model of prolonged sepsis, we compared markers of lipolysis and fatty acid oxidation in lean and obese septic mice (n = 117). Next, we compared markers of muscle wasting and weakness in septic obese wild-type and adipose tissue-specific ATGL knockout (AAKO) mice (n = 73), in lean septic mice receiving either intravenous infusion of lipids or standard parenteral nutrition (PN) (n = 70), and in lean septic mice receiving standard PN supplemented with either the ketone body 3-hydroxybutyrate or isocaloric glucose (n = 49). RESULTS: Obese septic mice had more pronounced lipolysis (p ≤ 0.05), peripheral fatty acid oxidation (p ≤ 0.05), and ketogenesis (p ≤ 0.05) than lean mice. Blocking lipolysis in obese septic mice caused severely reduced muscle mass (32% loss vs. 15% in wild-type, p < 0.001) and specific maximal muscle force (59% loss vs. 0% in wild-type; p < 0.001). In contrast, intravenous infusion of lipids in lean septic mice maintained specific maximal muscle force up to healthy control levels (p = 0.6), whereas this was reduced with 28% in septic mice receiving standard PN (p = 0.006). Muscle mass was evenly reduced with 29% in both lean septic groups (p < 0.001). Lipid administration enhanced fatty acid oxidation (p ≤ 0.05) and ketogenesis (p < 0.001), but caused unfavorable liver steatosis (p = 0.01) and a deranged lipid profile (p ≤ 0.01). Supplementation of standard PN with 3-hydroxybutyrate also attenuated specific maximal muscle force up to healthy control levels (p = 0.1), but loss of muscle mass could not be prevented (25% loss in both septic groups; p < 0.001). Importantly, this intervention improved muscle regeneration markers (p ≤ 0.05) without the unfavorable side effects seen with lipid infusion. CONCLUSIONS: Obesity-induced muscle protection during sepsis is partly mediated by elevated mobilization and metabolism of endogenous fatty acids. Furthermore, increased availability of ketone bodies, either through ketogenesis or through parenteral infusion, appears to protect against sepsis-induced muscle weakness also in the lean.


Assuntos
Tecido Adiposo/fisiopatologia , Lipólise/fisiologia , Debilidade Muscular/etiologia , Sepse/complicações , Animais , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacocinética , Cetonas/metabolismo , Metabolismo dos Lipídeos/fisiologia , Masculino , Camundongos , Debilidade Muscular/metabolismo , Debilidade Muscular/fisiopatologia , Obesidade/fisiopatologia , Fatores de Proteção , Sepse/metabolismo , Sepse/fisiopatologia
4.
Int J Mol Sci ; 20(14)2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31330820

RESUMO

Maintaining a robust epithelial barrier requires the accumulation of tight junction proteins, LSR/angulin-1 and tricellulin, at the tricellular contacts. Alterations in the localization of these proteins temporarily cause epithelial barrier dysfunction, which is closely associated with not only physiological differentiation but also cancer progression and metastasis. In normal human endometrial tissues, the endometrial cells undergo repeated proliferation and differentiation under physiological conditions. Recent observations have revealed that the localization and expression of LSR/angulin-1 and tricellulin are altered in a menstrual cycle-dependent manner. Moreover, it has been shown that endometrial cancer progression affects these alterations. This review highlights the differences in the localization and expression of tight junction proteins in normal endometrial cells and endometrial cancers and how they cause functional changes in cells.


Assuntos
Neoplasias do Endométrio/metabolismo , Neoplasias/metabolismo , Receptores de Lipoproteínas/metabolismo , Proteínas de Junções Íntimas/metabolismo , Animais , Células Epiteliais/metabolismo , Feminino , Humanos , Lipólise/fisiologia , Receptores de Lipoproteínas/fisiologia , Proteínas de Junções Íntimas/fisiologia
5.
Nat Commun ; 10(1): 2756, 2019 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-31227702

RESUMO

Flight loss in birds is as characteristic of the class Aves as flight itself. Although morphological and physiological differences are recognized in flight-degenerate bird species, their contributions to recurrent flight degeneration events across modern birds and underlying genetic mechanisms remain unclear. Here, in an analysis of 295 million nucleotides from 48 bird genomes, we identify two convergent sites causing amino acid changes in ATGLSer321Gly and ACOT7Ala197Val in flight-degenerate birds, which to our knowledge have not previously been implicated in loss of flight. Functional assays suggest that Ser321Gly reduces lipid hydrolytic ability of ATGL, and Ala197Val enhances acyl-CoA hydrolytic activity of ACOT7. Modeling simulations suggest a switch of main energy sources from lipids to carbohydrates in flight-degenerate birds. Our results thus suggest that physiological convergence plays an important role in flight degeneration, and anatomical convergence often invoked may not.


Assuntos
Evolução Biológica , Aves/fisiologia , Metabolismo Energético/genética , Voo Animal/fisiologia , Genoma/genética , Animais , Metabolismo dos Carboidratos/fisiologia , Genômica/métodos , Lipase/genética , Lipase/metabolismo , Lipólise/fisiologia , Palmitoil-CoA Hidrolase/genética , Palmitoil-CoA Hidrolase/metabolismo , Filogenia
6.
Cells ; 8(5)2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-31035700

RESUMO

White adipose tissue (WAT) lipolysis contributes to energy balance during fasting. Lipolysis can proceed by the sequential hydrolysis of triglycerides (TGs) by adipose triglyceride lipase (ATGL), then of diacylglycerols (DGs) by hormone-sensitive lipase (HSL). We showed that the combined genetic deficiency of ATGL and HSL in mouse adipose tissue produces a striking different phenotype from that of isolated ATGL deficiency, inconsistent with the linear model of lipolysis. We hypothesized that the mechanism might be functional redundancy between ATGL and HSL. To test this, the TG hydrolase activity of HSL was measured in WAT. HSL showed TG hydrolase activity. Then, to test ATGL for activity towards DGs, radiolabeled DGs were incubated with HSL-deficient lipid droplet fractions. The content of TG increased, suggesting DG-to-TG synthesis rather than DG hydrolysis. TG synthesis was abolished by a specific ATGL inhibitor, suggesting that ATGL functions as a transacylase when HSL is deficient, transferring an acyl group from one DG to another, forming a TG plus a monoglyceride (MG) that could be hydrolyzed by monoglyceride lipase. These results reveal a previously unknown physiological redundancy between ATGL and HSL, a mechanism for the epistatic interaction between Pnpla2 and Lipe. It provides an alternative lipolytic pathway, potentially important in patients with deficient lipolysis.


Assuntos
Tecido Adiposo Branco/metabolismo , Diglicerídeos/metabolismo , Lipase/metabolismo , Esterol Esterase/metabolismo , Triglicerídeos/metabolismo , Animais , Metabolismo Energético/fisiologia , Lipólise/fisiologia , Camundongos , Camundongos Endogâmicos C57BL
7.
Am J Physiol Endocrinol Metab ; 317(2): E185-E193, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30964706

RESUMO

Weight regain after weight loss is a well-described phenomenon in both humans and animal models of obesity. Reduced energy expenditure and increased caloric intake are considered the main drivers of weight regain. We hypothesized that adipose tissue with obesity memory (OM) has a tissue-autonomous lipolytic defect, allowing for increased efficiency of lipid storage. We utilized a mouse model of diet-induced obesity, which was subjected to 60% caloric restriction to achieve lean body weight, followed by a short period of high-fat diet (HFD) rechallenge. Age-matched lean mice fed HFD for the first time were used as the control group. Upon rechallenge with HFD, mice with OM had higher respiratory exchange ratios than lean mice with no OM despite comparable body weight, suggesting higher utilization of glucose over fatty acid oxidation. White adipose tissue explants with OM had comparable lipolytic response after caloric restriction; however, reduced functional lipolytic response to norepinephrine was noted as early as 5 days after rechallenge with HFD and was accompanied by reduction in hormone-sensitive lipase serine phosphorylation. The relative lipolytic defect was associated with increased expression of inflammatory genes and a decrease in adrenergic receptor genes, most notably Adrb3. Taken together, white adipose tissue of lean mice with OM shows increased sensitization to HFD compared with white adipose tissue with no OM, rendering it resistant to catecholamine-induced lipolysis. This relative lipolytic defect is tissue-autonomous and could play a role in the rapid weight regain observed after weight loss.


Assuntos
Tecido Adiposo Branco/metabolismo , Lipólise/fisiologia , Ganho de Peso/fisiologia , Animais , Dieta Hiperlipídica , Gorduras na Dieta/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Lipólise/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Receptores Adrenérgicos beta 3/genética , Receptores Adrenérgicos beta 3/metabolismo , Esterol Esterase/genética , Esterol Esterase/metabolismo , Ganho de Peso/genética
8.
Life Sci ; 227: 201-211, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-31002917

RESUMO

AIMS: Colorectal cancer syndrome has been one of the greatest concerns in the world. Although several epidemiological studies have shown that hepatic low lipoprotein lipase (LPL) mRNA expression may be associated with dyslipidemia and tumor progression, it is still not known whether the liver plays an essential role in hyperlipidemia of ApcMin/+ mice. MAIN METHODS: We measured the expression of metabolic enzymes that involved fatty acid uptake, de novo lipogenesis (DNL), ß-oxidation and investigated hepatic triglyceride production in the liver of wild-type and ApcMin/+ mice. KEY FINDINGS: We found that hepatic fatty acid uptake and DNL decreased, but there was no significant difference in fatty acid ß-oxidation. Interestingly, the production of hepatic very low-density lipoprotein-triglyceride (VLDL-TG) decreased at 20 weeks of age, but marked steatosis was observed in the livers of the ApcMin/+ mouse. To further explore hypertriglyceridemia, we assessed the function of hepatic glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) for the first time. GPIHBP1 is governed by the transcription factor octamer-binding transcription factor-1 (Oct-1) which are involved in the nuclear factor-κB (NF-κB) signaling pathway in the liver of ApcMin/+ mice. Importantly, it was also confirmed that sn50 (100 µg/mL, an inhibitor of the NF-κB) reversed the tumor necrosis factor α (TNFα)-induced Oct-1 and GPIHBP1 reduction in HepG2 cells. SIGNIFICANCE: Altogether, these findings highlighted a novel role of GPIHBP1 that might be responsible for hypertriglyceridemia in ApcMin/+ mice. Hypertriglyceridemia in these mice may be associated with their hepatic lipid metabolism development.


Assuntos
Fígado/metabolismo , Receptores de Lipoproteínas/fisiologia , Triglicerídeos/metabolismo , Animais , Caquexia/metabolismo , Caquexia/fisiopatologia , Neoplasias do Colo/fisiopatologia , Ácidos Graxos/metabolismo , Fígado Gorduroso/patologia , Regulação da Expressão Gênica/genética , Células Hep G2 , Humanos , Hiperlipidemias/genética , Metabolismo dos Lipídeos/genética , Lipídeos/fisiologia , Lipogênese/fisiologia , Lipólise/fisiologia , Lipoproteínas VLDL/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 1 de Transcrição de Octâmero/fisiologia , Receptores de Lipoproteínas/genética , Receptores de Lipoproteínas/metabolismo , Triglicerídeos/genética , Fator de Necrose Tumoral alfa/fisiologia
9.
Am J Physiol Endocrinol Metab ; 317(2): E194-E199, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31013145

RESUMO

Positron emission tomography (PET) radiopharmaceuticals can noninvasively measure free fatty acid (FFA) uptake into adipose tissue. We studied 29 volunteers to test whether abdominal and femoral subcutaneous adipose tissue FFA uptake measured using [1-11C]palmitate PET agrees with FFA storage rates measured using an intravenous bolus of [1-14C]palmitate and adipose biopsies. The dynamic left ventricular cavity PET images combined with blood sample radioactivity corrected for the 11CO2 content were used to create the blood time activity curve (TAC), and the constant (Ki) was determined using Patlak analysis of the TACs generated for regions of interest in abdominal subcutaneous fat. These data were used to calculate palmitate uptake rates in abdominal subcutaneous adipose tissue (µmol·kg-1·min-1). Immediately after the dynamic imaging, a static image of the thigh was taken to measure the standardized uptake value (SUV) in thigh adipose tissue, which was scaled to each participant's abdominal adipose tissue SUV to calculate thigh adipose palmitate uptake rates. Abdominal adipose palmitate uptake using PET [1-11C]palmitate was correlated with, but significantly (P < 0.001) greater than, FFA storage measured using [1-14C]palmitate and adipose biopsy. Thigh adipose palmitate measured using PET calculation was positively correlated (R2 = 0.44, P < 0.0001) with and not different from the biopsy approach. The relative differences between PET measured abdominal subcutaneous adipose tissue palmitate uptake and biopsy-measured palmitate storage were positively correlated (P = 0.03) with abdominal subcutaneous fat. We conclude that abdominal adipose tissue FFA uptake measured using PET does not equate to adipose FFA storage measured using biopsy techniques.


Assuntos
Tecido Adiposo/patologia , Ácidos Graxos não Esterificados/farmacocinética , Tomografia por Emissão de Pósitrons , Gordura Subcutânea/diagnóstico por imagem , Gordura Subcutânea/metabolismo , Tecido Adiposo/diagnóstico por imagem , Adiposidade/fisiologia , Adulto , Biópsia , Distribuição da Gordura Corporal/métodos , Índice de Massa Corporal , Isótopos de Carbono/análise , Isótopos de Carbono/farmacocinética , Radioisótopos de Carbono/análise , Radioisótopos de Carbono/farmacocinética , Feminino , Humanos , Peso Corporal Ideal/fisiologia , Lipólise/fisiologia , Masculino , Obesidade/metabolismo , Obesidade/patologia , Sobrepeso/metabolismo , Sobrepeso/patologia , Ácido Palmítico/química , Ácido Palmítico/farmacocinética , Tomografia por Emissão de Pósitrons/métodos
10.
Biochem Pharmacol ; 164: 45-52, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30905656

RESUMO

Elevated circulating free fatty acid (FFA) level is closely linked to the pathogenesis of insulin resistance and type 2 diabetes mellitus. Activation of the adenosine A1 receptor (A1R) inhibits lipolysis in adipocytes and hence reduces the concentration of FFA, which represents a potential target for the development of antilipolytic agents. We aimed to assess the binding affinity as well as target binding kinetics of A1R agonists and further delineate a possible relationship with their antilipolytic effect in adipocytes. Radioligand binding assays were performed to determine the affinity and kinetics of three representative A1R agonists, namely CPA, LUF6944 and LUF6941, on the rat A1R. Functional responses to these agonists were examined in both a recombinant cell system and physiologically relevant rat adipocytes. The three A1R agonists displayed similar affinity while divergent target binding kinetics on the rat A1R. Irrespective of equilibrium binding affinity, temporal analysis of receptor signaling demonstrated persistent functional responses for the long residence time agonist, despite removal of excess agonist, in both a recombinant cell system and in rat adipocytes. By contrast, such effect was less pronounced or even lost for agonists with medium or short receptor residence time, respectively. Our results indicate that ligand receptor binding kinetics rather than their affinity or potency play an essential role in regulating cellular responses. The long residence time A1R agonist produces a sustained wash-resistant antilipolytic effect in rat adipocytes and thus may represent a potential antilipolytic alternative for further investigation.


Assuntos
Agonistas do Receptor A1 de Adenosina/administração & dosagem , Agonistas do Receptor A1 de Adenosina/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Lipólise/efeitos dos fármacos , Animais , Células CHO , Cricetinae , Cricetulus , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/metabolismo , Relação Dose-Resposta a Droga , Lipólise/fisiologia , Ratos
11.
Nutrients ; 11(3)2019 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-30845686

RESUMO

We investigated whether the difference in miso consumption between the Japanese diets of 1975 and 2010 has influenced the observed increase in diet-induced obesity. To recreate the 2010 and 1975 Japanese high-fat diets with the corresponding proportions of miso, freeze-dried miso was added to high-fat mouse feed at 1.6% and 2.6%, respectively. When 5-week-old male Institute of Cancer Research (ICR) mice were provided each of these diets ad libitum for 8 weeks, it was found that the white adipose tissue weight and adipocyte area were lower in mice receiving the 1975 diet than in those receiving the 2010 diet. Therefore, high miso consumption is one reason why the 1975 Japanese diet tended to not lead to obesity. Next, the combined effects of treadmill exercise and miso consumption were investigated. The mice were divided into three groups, which were provided either a high-fat diet (group C), a high-fat diet with exercise (group C + E), or a miso-supplemented high-fat diet with exercise (group M + E) for 8 weeks. In this experiment, the white adipose tissue weight and adipocyte area in group M + E were lower than in group C. When the mRNA expression of lipid metabolism-associated genes in adipose tissue was measured, we found that expression of Hsl (lipase, hormone sensitive), which is involved in lipolysis, and Pparγ (peroxisome proliferator activated receptor gamma), which regulates adipocyte differentiation upstream of Hsl, was increased in group M + E. These results clearly demonstrated that lipid accumulation in the adipose tissues is suppressed by miso consumption in combination with exercise.


Assuntos
Suplementos Nutricionais , Gordura Intra-Abdominal/metabolismo , Obesidade/metabolismo , Condicionamento Físico Animal/fisiologia , Alimentos de Soja , Adipócitos/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Lipólise/fisiologia , Masculino , Camundongos , Obesidade/etiologia
12.
J Dairy Sci ; 102(5): 4628-4638, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30827564

RESUMO

Fetuin-A (FetA) is an adipokine and free fatty acid (FFA) carrier linked to adipose tissue (AT) function in monogastrics and ruminants. In dairy cows, plasma and AT FetA decrease after parturition, coinciding with reduced lipogenesis and increased lipolysis. In monogastrics, FetA enhances lipogenesis, but its role on lipid mobilization of ruminants is unclear. We hypothesized that FetA modulates lipid mobilization in bovine AT by enhancing the lipogenic activity of adipocytes. Our objective was to determine the effects of FetA on lipogenesis and lipolysis in cultured primary adipocytes from dairy cows. Preadipocytes from the tailhead subcutaneous AT depot were induced to differentiate in a 7-d coculture in vitro model. The effects of FetA on lipolytic responses of adipocytes were evaluated after a 2-h ß-adrenergic stimulation with 1 µM isoproterenol (ISO) alone or combined with 0.1 mg/mL of FetA (FetA+ISO), and in cells treated with medium alone (CON) or with 0.1 mg/mL of FetA (FetA). Lipogenic responses of adipocytes treated with CON or FetA from d 5 to 7 of differentiation were assessed by fatty acid (FA) uptake quantification and triacylglycerol (TAG) accumulation, and the gene and protein expression of lipogenic markers. Bovine adipocytes abundantly expressed FetA gene and protein and secreted 48 ± 3.5 ng/DNA relative fluorescence units (RFU). Adrenergic stimulation with ISO increased lipolysis compared with CON, as reflected in the release of glycerol (0.12 ± 0.04 vs. 0.04 ± 0.02 nM/DNA RFU) and FFA (15 ± 13 vs. 6.2 ± 2.4 nM/DNA RFU). Lipolysis induced by ISO was attenuated by the addition of FetA (FetA+ISO) as reflected by lower glycerol (0.06 ± 0.04 nM/DNA RFU) and FFA (5.7 ± 2.7 nM/DNA RFU) release compared with ISO alone. Compared with CON, FetA enhanced lipogenic responses as demonstrated by higher FA uptake and increased accumulation of TAG. Exposure to FetA upregulated 1-acylglycerol-3-phosphate acyltransferase-2 (AGPAT2) gene expression and protein content, as well as its activity. Adipocytes exposed to FetA increased the secretion of the metabolite of AGPAT2, phosphatidic acid. In conclusion, FetA attenuates lipolytic responses and enhances lipogenesis in bovine adipocytes. The upregulation of the rate-limiting lipogenic enzyme AGPAT2 by FetA suggests a potential pathway by which this adipokine promotes TAG synthesis in adipocytes. These findings suggest that FetA is a potential target for lipid mobilization modulation in AT of dairy cows.


Assuntos
Bovinos/fisiologia , Regulação da Expressão Gênica , Lipogênese/fisiologia , Lipólise/fisiologia , alfa-2-Glicoproteína-HS/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Ácidos Graxos não Esterificados/metabolismo , Feminino , Isoproterenol/farmacologia , Mobilização Lipídica/fisiologia , Parto , Gravidez , Gordura Subcutânea/efeitos dos fármacos , Gordura Subcutânea/metabolismo , Triglicerídeos/metabolismo
13.
Br J Surg ; 106(5): 616-625, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30725479

RESUMO

BACKGROUND: Visceral obesity is one of the risk factors for clinically relevant pancreatic fistula after pancreatic resection. The objective of this study was to evaluate the impact of intraperitoneal lipolysis on postoperative pancreatic fistula. METHODS: The degree of intraperitoneal lipolysis was investigated by measuring the free fatty acid concentration in drain discharge in patients after pancreatic resection. An experimental pancreatic fistula model was prepared by pancreatic transection, and the impact of intraperitoneal lipolysis was evaluated by intraperitoneal administration of triolein (triglyceride) with, or without orlistat (lipase inhibitor). RESULTS: Thirty-three patients were included in the analysis. The free fatty acid concentration in drain discharge on postoperative day 1 was significantly associated with the development of a clinically relevant pancreatic fistula (P = 0·004). A higher free fatty acid concentration in drain discharge was associated with more visceral adipose tissue (P = 0·009). In the experimental model that included 98 rats, intraperitoneal lipolysis caused an increased amount of pancreatic juice leakage and multiple organ dysfunction. Intraperitoneal administration of a lipase inhibitor reduced lipolysis and prevented deterioration of the fistula. CONCLUSION: Intraperitoneal lipolysis significantly exacerbates pancreatic fistula after pancreatic resection. Inhibition of lipolysis by intraperitoneal administration of a lipase inhibitor could be a promising therapy to reduce clinically relevant postoperative pancreatic fistula. Surgical relevance Clinically, there are two types of pancreatic fistula after pancreatic resections: harmless biochemical leak and harmful clinically relevant pancreatic fistula. Visceral obesity is one of the known risk factors for clinically relevant pancreatic fistula; however, the underlying mechanisms remained to be elucidated. Patients with clinically relevant pancreatic fistula had a higher free fatty acid concentration in the drain discharge, suggesting a relationship between intraperitoneal lipolysis and pancreatic fistula. The experimental model of pancreatic fistula demonstrated that intraperitoneal lipolysis caused deterioration in pancreatic fistula, suggesting that intraperitoneal lipolysis is one of the mechanisms that drives biochemical leakage to clinically relevant pancreatic fistula. Intraperitoneal administration of a lipase inhibitor prevented lipolysis as well as pancreatic fistula deterioration in the experimental model, suggesting a future clinical application for lipase inhibitors in prevention of clinically relevant pancreatic fistula.


Assuntos
Gordura Intra-Abdominal/fisiopatologia , Lipólise/fisiologia , Pancreatectomia/efeitos adversos , Fístula Pancreática/etiologia , Pancreaticoduodenectomia/efeitos adversos , Idoso , Animais , Modelos Animais de Doenças , Ácidos Graxos não Esterificados/análise , Feminino , Humanos , Lipase/antagonistas & inibidores , Lipólise/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/complicações , Obesidade Abdominal/fisiopatologia , Fístula Pancreática/prevenção & controle , Suco Pancreático/fisiologia , Complicações Pós-Operatórias/fisiopatologia , Ratos Sprague-Dawley , Fatores de Risco
14.
Am J Physiol Cell Physiol ; 316(3): C365-C376, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30624981

RESUMO

The objective of this study was to investigate whether cold-induced browning of the subcutaneous (Sc) inguinal (Ing) white adipose tissue (WAT) increases the capacity of this tissue to oxidize fatty acids through uncoupling protein 1 (UCP1)-mediated thermogenesis. To accomplish that, rats were acclimated to cold (4°C for 7 days). Subsequently, interscapular and aortic brown adipose tissues (iBAT and aBAT, respectively), epididymal (Epid), and Sc Ing WAT were used for adipocyte isolation. In BAT adipocytes, cold acclimation increased UCP1 content and palmitate oxidation either in the absence or presence of oligomycin, whereas in Sc Ing adipocytes glucose and palmitate oxidation were not affected, although multilocular adipocytes were formed and UCP1 content increased upon cold acclimation in the WAT. Furthermore, isoproterenol-stimulated cold Sc Ing adipocytes exhibited significantly lower rates of palmitate oxidation than control cells when exposed to oligomycin. These findings provide evidence that, despite increasing UCP1 levels, cold acclimation essentially reduced mitochondrial uncoupling-mediated fat oxidation in Sc Ing adipocytes. Conversely, glycerol kinase and phosphoenolpyruvate carboxykinase levels, isoproterenol-induced lipolysis, as well as glycerol and palmitate incorporation into lipids significantly increased in these cells. Therefore, instead of UCP1-mediated mitochondrial uncoupling, cold acclimation increased the capacity of Sc Ing adipocytes to export fatty acids and enhanced key components of the triacylglycerol resynthesis pathway in the Sc Ing WAT.


Assuntos
Lipólise/fisiologia , Mitocôndrias/metabolismo , Proteínas Mitocondriais/metabolismo , Triglicerídeos/metabolismo , Proteína Desacopladora 1/metabolismo , Aclimatação/fisiologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Temperatura Baixa , Metabolismo Energético/fisiologia , Masculino , Oxirredução , Ratos , Ratos Wistar , Termogênese/fisiologia
15.
FASEB J ; 33(4): 4741-4754, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30608881

RESUMO

Lipidomic techniques can improve our understanding of complex lipid interactions that regulate metabolic diseases. Here, a serum phospholipidomics analysis identified associations between phosphatidylglycerols (PGs) and gut microbiota dysbiosis. Compared with the other phospholipids, serum PGs were the most elevated in patients with low microbiota gene richness, which were normalized after a dietary intervention that restored gut microbial diversity. Serum PG levels were positively correlated with metagenomic functional capacities for bacterial LPS synthesis and host markers of low-grade inflammation; transcriptome databases identified PG synthase, the first committed enzyme in PG synthesis, as a potential mediator. Experiments in mice and cultured human-derived macrophages demonstrated that LPS induces PG release. Acute PG treatment in mice altered adipose tissue gene expression toward remodeling and inhibited ex vivo lipolysis in adipose tissue, suggesting that PGs favor lipid storage. Indeed, several PG species were associated with the severity of obesity in mice and humans. Finally, despite enrichment in PGs in bacterial membranes, experiments employing gnotobiotic mice colonized with recombinant PG overproducing Lactococcus lactis showed limited direct contribution of microbial PGs to the host. In summary, PGs are inflammation-responsive lipids indirectly regulated by the gut microbiota via endotoxins and regulate adipose tissue homeostasis in obesity.-Kayser, B. D., Lhomme, M., Prifti, E., Da Cunha, C., Marquet, F., Chain, F., Naas, I., Pelloux, V., Dao, M.-C., Kontush, A., Rizkalla, S. W., Aron-Wisnewsky, J., Bermúdez-Humarán, L. G., Oakley, F., Langella, P., Clément, K., Dugail, I. Phosphatidylglycerols are induced by gut dysbiosis and inflammation, and favorably modulate adipose tissue remodeling in obesity.


Assuntos
Tecido Adiposo/metabolismo , Disbiose/metabolismo , Inflamação/metabolismo , Obesidade/metabolismo , Fosfatidilgliceróis/metabolismo , Animais , Feminino , Humanos , Lipólise/fisiologia , Masculino , Metagenômica/métodos , Camundongos
16.
Diabetologia ; 62(3): 494-503, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30506451

RESUMO

AIMS/HYPOTHESIS: Lack of insulin and infection/inflammation are the two most common causes of diabetic ketoacidosis (DKA). We used insulin withdrawal followed by insulin administration as a clinical model to define effects on substrate metabolism and to test whether increased levels of counter-regulatory hormones and cytokines and altered adipose tissue signalling participate in the early phases of DKA. METHODS: Nine individuals with type 1 diabetes, without complications, were randomly studied twice, in a crossover design, for 5 h followed by 2.5 h high-dose insulin clamp: (1) insulin-controlled euglycaemia (control) and (2) after 14 h of insulin withdrawal in a university hospital setting. RESULTS: Insulin withdrawal increased levels of glucose (6.1 ± 0.5 vs 18.6 ± 0.5 mmol/l), NEFA, 3-OHB (127 ± 18 vs 1837 ± 298 µmol/l), glucagon, cortisol and growth hormone and decreased HCO3- and pH, without affecting catecholamine or cytokine levels. Whole-body energy expenditure, endogenous glucose production (1.55 ± 0.13 vs 2.70 ± 0.31 mg kg-1 min-1), glucose turnover, non-oxidative glucose disposal, lipid oxidation, palmitate flux (73 [range 39-104] vs 239 [151-474] µmol/min), protein oxidation and phenylalanine flux all increased, whereas glucose oxidation decreased. In adipose tissue, Ser473 phosphorylation of Akt and mRNA levels of G0S2 decreased, whereas CGI-58 (also known as ABHD5) mRNA increased. Protein levels of adipose triglyceride lipase (ATGL) and hormone-sensitive lipase phosphorylations were unaltered. Insulin therapy decreased plasma glucose concentrations dramatically after insulin withdrawal, without any detectable effect on net forearm glucose uptake. CONCLUSIONS/INTERPRETATION: Release of counter-regulatory hormones and overall increased catabolism, including lipolysis, are prominent features of preacidotic ketosis induced by insulin withdrawal, and dampening of Akt insulin signalling and transcriptional modulation of ATGL activity are involved. The lack of any increase in net forearm glucose uptake during insulin therapy after insulin withdrawal indicates muscle insulin resistance. TRIAL REGISTRATION: ClinicalTrials.gov NCT02077348 FUNDING: This study was supported by Aarhus University and the KETO Study Group/Danish Agency for Science Technology and Innovation.


Assuntos
Tecido Adiposo/metabolismo , Citocinas/sangue , Diabetes Mellitus Tipo 1/tratamento farmacológico , Metabolismo Energético/fisiologia , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Cetose/metabolismo , Adulto , Glicemia/metabolismo , Estudos Cross-Over , Diabetes Mellitus Tipo 1/metabolismo , Humanos , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos/fisiologia , Lipólise/fisiologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
17.
Mol Cell Biol ; 39(2)2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30397073

RESUMO

Oxygen is a key molecule for efficient energy production in living organisms. Although aerobic organisms have adaptive processes to survive in low-oxygen environments, it is poorly understood how lipolysis, the first step of energy production from stored lipid metabolites, would be modulated during hypoxia. Here, we demonstrate that fasting-induced lipolysis is downregulated by hypoxia through the hypoxia-inducible factor (HIF) signaling pathway. In Caenorhabditis elegans and mammalian adipocytes, hypoxia suppressed protein kinase A (PKA)-stimulated lipolysis, which is evolutionarily well conserved. During hypoxia, the levels of PKA activity and adipose triglyceride lipase (ATGL) protein were downregulated, resulting in attenuated fasting-induced lipolysis. In worms, HIF stabilization was sufficient to moderate the suppressive effect of hypoxia on lipolysis through ATGL and PKA inhibition. These data suggest that HIF activation under hypoxia plays key roles in the suppression of lipolysis, which might preserve energy resources in both C. elegans and mammalian adipocytes.


Assuntos
Fator 1 Induzível por Hipóxia/metabolismo , Hipóxia/metabolismo , Lipase/metabolismo , Células 3T3 , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Animais , Caenorhabditis elegans , Proteínas de Transporte/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Regulação para Baixo , Lipídeos/fisiologia , Lipólise/efeitos dos fármacos , Lipólise/fisiologia , Camundongos , Nematoides , Fosforilação , Transdução de Sinais
18.
Biochim Biophys Acta Mol Basis Dis ; 1865(1): 136-146, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30391544

RESUMO

Chronic inflammation contributes to obesity mediated metabolic disturbances, including insulin resistance. Obesity is associated with altered microbial load in metabolic tissues that can contribute to metabolic inflammation. Different bacterial components such as, LPS, peptidoglycans have been shown to underpin metabolic disturbances through interaction with host innate immune receptors. Activation of Nucleotide-binding oligomerization domain-containing protein 1 (Nod1) with specific peptidoglycan moieties promotes insulin resistance, inflammation and lipolysis in adipocytes. However, it was not clear how Nod1-mediated lipolysis and inflammation is linked. Here, we tested if Nod1-mediated lipolysis caused accumulation of lipid intermediates and promoted cell autonomous inflammation in adipocytes. We showed that Nod1-mediated lipolysis caused accumulation of diacylglycerol (DAG) and activation of PKCδ in 3T3-L1 adipocytes, which was prevented with a Nod1 inhibitor. Nod1-activated PKCδ caused downstream stimulation of IRAK1/4 and was associated with increased expression of proinflammatory cytokines such as, IL-1ß, IL-18, IL-6, TNFα and MCP-1. Pharmacological inhibition or siRNA mediated knockdown of IRAK1/4 attenuated Nod1-mediated activation of NF-κB, JNK, and the expression of proinflammatory cytokines. These results reveal that Nod1-mediated lipolysis promoted accumulation of DAG, which engaged PKCδ and IRAK1/4 to augment inflammation in 3T3-L1 adipocytes.


Assuntos
Adipócitos/metabolismo , Diglicerídeos/metabolismo , Inflamação/metabolismo , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Lipólise/fisiologia , Proteína Adaptadora de Sinalização NOD1/metabolismo , Proteína Quinase C-delta/metabolismo , Células 3T3-L1 , Animais , Quimiocina CCL2/metabolismo , Citocinas/metabolismo , Técnicas de Silenciamento de Genes , Imunidade Inata , Resistência à Insulina , Quinases Associadas a Receptores de Interleucina-1/genética , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6 , Camundongos , NF-kappa B/metabolismo , Obesidade , Peptidoglicano/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
19.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(2): 181-190, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30521937

RESUMO

Diatoms are eukaryotic microalgae that play a pivotal role in biological and geochemical marine cycles. These microorganisms are at the basis of the trophic chain and their lipids are essential components (e.g. eicosapentaenoic acid, EPA) of aquatic food webs. Galactolipids are the primary lipid components of plastid membranes and form the largest lipid family of diatoms. As source of polyunsaturated fatty acids (PUFAs), these compounds are also involved in the synthesis of lipoxygenase (LOX) products such as non-volatile oxylipins and polyunsaturated aldehydes. Here, we report the first identification of two genes, namely PmLAH1 and PaLAH1, coding for lipolytic enzymes in two diatoms of the genus Pseudo-nitzschia. Functional and modeling studies evidence a patatin-like domain endowed with galactolipase and phospholipase activity at the C-terminus of both proteins. Homologues of Pseudo-nitzschia LAH1 genes were retrieved in other diatom species so far sequenced in agreement with conservation of the functional role of these proteins within the lineage.


Assuntos
Diatomáceas/metabolismo , Galactolipídeos/metabolismo , Hidrolases/metabolismo , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/metabolismo , Ácidos Graxos Insaturados/metabolismo , Galactolipídeos/fisiologia , Metabolismo dos Lipídeos/fisiologia , Lipólise/fisiologia , Lipoxigenase/metabolismo , Microalgas/metabolismo , Oxilipinas/metabolismo
20.
Dermatol Ther ; 32(2): e12626, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30175548

RESUMO

The role of adipose tissue has long been underestimated in esthetic dermatology. With the development of liposculpture and lipolysis, subcutaneous adipose tissue has gained an increasing interest. Harvested tissue has been used for lipofilling. In recent years, a better understanding of adipocyte physiology and its role in aging opened a new road for targeted treatments. Subcutaneous adipose tissue is no longer an innocent bystander in the combat of aging and the correction in esthetics. Adipose tissue is of importance for metabolic function and thermoregulation. Adipose tissue is involved in inflammation. Adipose tissue is heterogeneous in sense of function, color and size of adipocytes. The tissue is an important source of somatic stem cells.


Assuntos
Técnicas Cosméticas , Envelhecimento da Pele , Gordura Subcutânea/transplante , Adipócitos/citologia , Tecido Adiposo/transplante , Humanos , Lipólise/fisiologia
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