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1.
J Pathol ; 261(3): 335-348, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37650293

RESUMO

FGF15 and its human orthologue, FGF19, are members of the endocrine FGF family and are secreted by ileal enterocytes in response to bile acids. FGF15/19 mainly targets the liver, but recent studies indicate that it also regulates skeletal muscle mass and adipose tissue plasticity. The aim of this study was to determine the role(s) of the enterokine FGF15/19 during the development of cardiac hypertrophy. Studies in a cohort of humans suffering from heart failure showed increased circulating levels of FGF19 compared with control individuals. We found that mice lacking FGF15 did not develop cardiac hypertrophy in response to three different pathophysiological stimuli (high-fat diet, isoproterenol, or cold exposure). The heart weight/tibia length ratio and the cardiomyocyte area (as measures of cardiac hypertrophy development) under hypertrophy-inducing conditions were lower in Fgf15-null mice than in wild-type mice, whereas the levels of the cardiac damage marker atrial natriuretic factor (Nppa) were up-regulated. Echocardiographic measurements showed similar results. Moreover, the genes involved in fatty acid metabolism were down-regulated in Fgf15-null mice. Conversely, experimental increases in FGF15 induced cardiac hypertrophy in vivo, without changes in Nppa and up-regulation of metabolic genes. Finally, in vitro studies using cardiomyocytes showed that FGF19 had a direct effect on these cells promoting hypertrophy. We have identified herein an inter-organ signaling pathway that runs from the gut to the heart, acts through the enterokine FGF15/19, and is involved in cardiac hypertrophy development and regulation of fatty acid metabolism in the myocardium. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

2.
Mol Ther Nucleic Acids ; 29: 599-613, 2022 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-36090751

RESUMO

Circulating lipopolysaccharide-binding protein (LBP) is increased in individuals with liver steatosis. We aimed to evaluate the possible impact of liver LBP downregulation using lipid nanoparticle-containing chemically modified LBP small interfering RNA (siRNA) (LNP-Lbp UNA-siRNA) on the development of fatty liver. Weekly LNP-Lbp UNA-siRNA was administered to mice fed a standard chow diet, a high-fat and high-sucrose diet, and a methionine- and choline-deficient diet (MCD). In mice fed a high-fat and high-sucrose diet, which displayed induced liver lipogenesis, LBP downregulation led to reduced liver lipid accumulation, lipogenesis (mainly stearoyl-coenzyme A desaturase 1 [Scd1]) and lipid peroxidation-associated oxidative stress markers. LNP-Lbp UNA-siRNA also resulted in significantly decreased blood glucose levels during an insulin tolerance test. In mice fed a standard chow diet or an MCD, in which liver lipogenesis was not induced or was inhibited (especially Scd1 mRNA), liver LBP downregulation did not impact on liver steatosis. The link between hepatocyte LBP and lipogenesis was further confirmed in palmitate-treated Hepa1-6 cells, in primary human hepatocytes, and in subjects with morbid obesity. Altogether, these data indicate that siRNA against liver Lbp mRNA constitutes a potential target therapy for obesity-associated fatty liver through the modulation of hepatic Scd1.

3.
Biomed Pharmacother ; 151: 113156, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35643066

RESUMO

BACKGROUND AND AIMS: The sexual dimorphism in fat-mass distribution and circulating leptin and insulin levels is well known, influencing the progression of obesity-associated metabolic disease. Here, we aimed to investigate the possible role of lipopolysaccharide-binding protein (LBP) in this sexual dimorphism. METHODS: The relationship between plasma LBP and fat mass was evaluated in 145 subjects. The effects of Lbp downregulation, using lipid encapsulated unlocked nucleomonomer agent containing chemically modified-siRNA delivery system, were evaluated in mice. RESULTS: Plasma LBP levels were associated with fat mass and leptin levels in women with obesity, but not in men with obesity. In mice, plasma LBP downregulation led to reduced weight, fat mass and leptin gain after a high-fat and high-sucrose diet (HFHS) in females, in parallel to increased expression of adipogenic and thermogenic genes in visceral adipose tissue. This was not observed in males. Plasma LBP downregulation avoided the increase in serum LPS levels in HFHS-fed male and female mice. Serum LPS levels were positively correlated with body weight and fat mass gain, and negatively with markers of adipose tissue function only in female mice. The sexually dimorphic effects were replicated in mice with established obesity. Of note, LBP downregulation led to recovery of estrogen receptor alpha (Esr1) mRNA levels in females but not in males. CONCLUSION: LBP seems to exert a negative feedback on ERα-mediated estrogen action, impacting on genes involved in thermogenesis. The known decreased estrogen action and negative effects of metabolic endotoxemia may be targeted through LBP downregulation.


Assuntos
Leptina , Lipopolissacarídeos , Proteínas de Fase Aguda , Tecido Adiposo , Animais , Proteínas de Transporte , Dieta Hiperlipídica , Regulação para Baixo , Estrogênios/metabolismo , Feminino , Humanos , Leptina/metabolismo , Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Glicoproteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/metabolismo
4.
Mol Ther Nucleic Acids ; 27: 870-879, 2022 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-35141047

RESUMO

Lipopolysaccharide binding protein (Lbp) has been recently identified as a relevant component of innate immunity response associated to adiposity. Here, we aimed to investigate the impact of adipose tissue Lbp on weight gain and white adipose tissue (WAT) in male and female mice fed an obesogenic diet. Specific adipose tissue Lbp gene knockdown was achieved through lentiviral particles containing shRNA-Lbp injected through surgery intervention. In males, WAT Lbp mRNA levels increased in parallel to fat accretion, and specific WAT Lbp gene knockdown led to reduced body weight gain, decreased fat accretion-related gene and protein expression, and increased inguinal WAT basal lipase activity, in parallel to lowered plasma free fatty acids, leptin, triglycerides but higher glycerol levels, resulting in slightly improved insulin action in the insulin tolerance test. In both males and females, inguinal WAT Lbp gene knockdown resulted in increased Ucp1 and Ppargc1a mRNA and Ucp1 protein levels, confirming adipose Lbp as a WAT browning repressor. In perigonadal WAT, Lbp gene knockdown also resulted in increased Ucp1 mRNA levels, but only in female mice, in which it was 500-fold increased. These data suggest specific adipose tissue Lbp gene knockdown as a possible therapeutic approach in the prevention of obesity-associated fat accretion.

5.
Pharmacol Res ; 166: 105486, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33556481

RESUMO

Chronic systemic low-level inflammation in metabolic disease is known to affect adipose tissue biology. Lysozyme (LYZ) is a major innate immune protein but its role in adipose tissue has not been investigated. Here, we aimed to investigate LYZ in human and rodents fat depots, and its possible role in obesity-associated adipose tissue dysfunction. LYZ mRNA and protein were identified to be highly expressed in adipose tissue from subjects with obesity and linked to systemic chronic-low grade inflammation, adipose tissue inflammation and metabolic disturbances, including hyperglycemia, dyslipidemia and decreased markers of adipose tissue adipogenesis. These findings were confirmed in experimental models after a high-fat diet in mice and rats and also in ob/ob mice. Importantly, specific inguinal and perigonadal white adipose tissue lysozyme (Lyz2) gene knockdown in high-fat diet-fed mice resulted in improved adipose tissue inflammation in parallel to reduced lysozyme activity. Of note, Lyz2 gene knockdown restored adipogenesis and reduced weight gain in this model. In conclusion, altogether these observations point to lysozyme as a new actor in obesity-associated adipose tissue dysfunction. The therapeutic targeting of lysozyme production might contribute to improve adipose tissue metabolic homeostasis.


Assuntos
Adipogenia , Dieta Hiperlipídica/efeitos adversos , Inflamação/genética , Muramidase/genética , Tecido Adiposo/metabolismo , Animais , Técnicas de Silenciamento de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Obesidade/genética , Ratos Wistar
6.
Am J Physiol Endocrinol Metab ; 320(4): E822-E834, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33615874

RESUMO

Fibroblast growth factor-21 (FGF21) is a hormonal regulator of metabolism; it promotes glucose oxidation and the thermogenic capacity of adipose tissues. The levels of ß-klotho (KLB), the co-receptor required for FGF21 action, are decreased in brown (BAT) and white (WAT) adipose tissues during obesity, diabetes, and lipodystrophy. Reduced ß-klotho levels have been proposed to account for FGF21 resistance in these conditions. In this study, we explored whether downregulation of ß-klotho affects metabolic regulation and the thermogenic responsiveness of adipose tissues using mice with total (KLB-KO) or partial (KLB-heterozygotes) ablation of ß-klotho. We herein show that KLB gene dosage was inversely associated with adiposity in mice. Upon cold exposure, impaired browning of subcutaneous WAT and milder alterations in BAT were associated with reduced KLB gene dosage in mice. Cultured brown and beige adipocytes from mice with total or partial ablation of the KLB gene showed reduced thermogenic responsiveness to ß3-adrenergic activation by treatment with CL316,243, indicating that these effects were cell-autonomous. Deficiency in FGF21 mimicked the KLB-reduction-induced impairment of thermogenic responsiveness in brown and beige adipocytes. These results indicate that the levels of KLB in adipose tissues determine their thermogenic capacity to respond to cold and/or adrenergic stimuli. Moreover, an autocrine action of FGF21 in brown and beige adipocytes may account for the ability of the KLB level to influence thermogenic responsiveness.NEW & NOTEWORTHY Reduced levels of KLB (the obligatory FGF21 co-receptor), as occurring in obesity and type 2 diabetes, reduce the thermogenic responsiveness of adipose tissues in cold-exposed mice. Impaired response to ß3-adrenergic activation in brown and beige adipocytes with reduced KLB occurs in a cell-autonomous manner involving an autocrine action of FGF21.


Assuntos
Tecido Adiposo/metabolismo , Fatores de Crescimento de Fibroblastos/fisiologia , Proteínas de Membrana/fisiologia , Termogênese/genética , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Adiposidade/genética , Animais , Comunicação Autócrina/efeitos dos fármacos , Comunicação Autócrina/genética , Células Cultivadas , Fatores de Crescimento de Fibroblastos/farmacologia , Dosagem de Genes/fisiologia , Proteínas Klotho , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Termogênese/efeitos dos fármacos
7.
Mol Metab ; 43: 101113, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33171307

RESUMO

OBJECTIVE: To determine the role of enterokine FGF15/19 in adipose tissue thermogenic adaptations. METHODS: Circulating FGF19 and gene expression (qRT-PCR) levels were assessed in subcutaneous adipose tissue from obese human patients. Effects of experimentally increased FGF15 and FGF19 levels in vivo were determined in mice using adenoviral and adeno-associated vectors. Adipose tissues were characterized in FGF15-null mice under distinct cold-related thermogenic challenges. The analyses spanned metabolic profiling, tissue characterization, histology, gene expression, and immunoblot assays. RESULTS: In humans, FGF19 levels are directly associated with UCP1 gene expression in subcutaneous adipose tissue. Experimental increases in FGF15 or FGF19 induced white fat browning in mice as demonstrated by the appearance of multilocular beige cells and markers indicative of a beige phenotype, including increased UCP1 protein levels. Mice lacking FGF15 showed markedly impaired white adipose tissue browning and a mild reduction in parameters indicative of BAT activity in response to cold-induced environmental thermogenic challenges. This was concomitant with signs of altered systemic metabolism, such as reduced glucose tolerance and impaired cold-induced insulin sensitization. CONCLUSIONS: Enterokine FGF15/19 is a key factor required for adipose tissue plasticity in response to thermogenic adaptations.


Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Termogênese/fisiologia , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiologia , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Feminino , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/fisiologia , Humanos , Insulina/metabolismo , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo , Proteína Desacopladora 1/metabolismo
8.
Am J Physiol Endocrinol Metab ; 317(5): E742-E750, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31361546

RESUMO

Adaptive induction of thermogenesis in brown adipose tissue (BAT) is essential for the survival of mammals after birth. We show here that G protein-coupled receptor protein 120 (GPR120) expression is dramatically induced after birth in mouse BAT. GPR120 expression in neonatal BAT is the highest among GPR120-expressing tissues in the mouse at any developmental stage tested. The induction of GPR120 in neonatal BAT is caused by postnatal thermal stress rather than by the initiation of suckling. GPR120-null neonates were found to be relatively intolerant to cold: close to one-third did not survive at 21°C, but all such pups survived at 25°C. Heat production in BAT was significantly impaired in GPR120-null pups. Deficiency in GPR120 did not modify brown adipocyte morphology or the anatomical architecture of BAT, as assessed by electron microscopy, but instead impaired the expression of uncoupling protein-1 and the fatty acid oxidation capacity of neonatal BAT. Moreover, GPR120 deficiency impaired fibroblast growth factor 21 (FGF21) gene expression in BAT and reduced plasma FGF21 levels. These results indicate that GPR120 is essential for neonatal adaptive thermogenesis.


Assuntos
Tecido Adiposo Marrom/fisiologia , Animais Recém-Nascidos/fisiologia , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/fisiologia , Termogênese/fisiologia , Animais , Temperatura Baixa , Ácidos Graxos/metabolismo , Feminino , Fatores de Crescimento de Fibroblastos , Glucose/metabolismo , Transtornos de Estresse por Calor/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredução , Palmitatos/metabolismo , Proteína Desacopladora 1/metabolismo
9.
Cell Metab ; 28(5): 750-763.e6, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30122557

RESUMO

The beneficial effects of brown adipose tissue (BAT) are attributed to its capacity to oxidize metabolites and produce heat, but recent data suggest that secretory properties of BAT may also be involved. Here, we identify the chemokine CXCL14 (C-X-C motif chemokine ligand-14) as a novel regulatory factor secreted by BAT in response to thermogenic activation. We found that the CXCL14 released by brown adipocytes recruited alternatively activated (M2) macrophages. Cxcl14-null mice exposed to cold showed impaired BAT activity and low recruitment of macrophages, mainly of the M2 phenotype, into BAT. CXCL14 promoted the browning of white fat and ameliorated glucose/insulin homeostasis in high-fat-diet-induced obese mice. Impairment of type 2 cytokine signaling, as seen in Stat6-null mice, blunts the action of CXCL14, promoting adipose tissue browning. We propose that active BAT is a source of CXCL14, which concertedly promotes adaptive thermogenesis via M2 macrophage recruitment, BAT activation, and the browning of white fat.


Assuntos
Tecido Adiposo Marrom/metabolismo , Quimiocinas CXC/metabolismo , Obesidade/metabolismo , Termogênese , Adipócitos Marrons/metabolismo , Adulto , Animais , Células Cultivadas , Metabolismo Energético , Feminino , Glucose/metabolismo , Humanos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Células RAW 264.7 , Ratos Wistar
10.
Artigo em Inglês | MEDLINE | ID: mdl-29661866

RESUMO

Following antiretroviral therapy, HIV-infected patients show increased circulating levels of the antidiabetic hormone fibroblast growth factor 21 (FGF21). In contrast, the expression of the FGF21-obligatory coreceptor ß-Klotho (KLB) is reduced in target tissues. This situation is comparable to the FGF21 resistance status observed in obesity and type 2 diabetes. Here, we performed the first systematic study of the effects of distinct members of different antiretroviral drug classes on the FGF21/KLB system in human hepatic, adipose, and skeletal muscle cells. Most protease inhibitors and the nonnucleoside reverse transcriptase inhibitor efavirenz induced FGF21 gene expression. Neither nucleoside reverse transcriptase inhibitors nor the viral entry inhibitor maraviroc had any effect. Among the integrase inhibitors, elvitegravir significantly induced FGF21 expression, whereas raltegravir had minor effects only in adipose cells. In human hepatocytes and adipocytes, known target cells of FGF21 action, efavirenz, elvitegravir, and the lopinavir-ritonavir combination exerted inhibitory effects on KLB gene expression. Drug treatments that elicited FGF21 induction/KLB repression were those found to induce endoplasmic reticulum (ER) stress and oxidative stress. Notably, the pharmacological agents thapsigargin and tunicamycin, which induce these stress pathways, mimicked the effects of drug treatments. Moreover, pharmacological inhibitors of either ER or oxidative stress significantly impaired lopinavir-ritonavir-induced regulation of FGF21, but not KLB. In conclusion, the present in vitro screen study identifies the antiretroviral drugs that affect FGF21/KLB expression in human cells. The present results could have important implications for the management of comorbidities resulting from side effects of specific antiretroviral drugs for the treatment of HIV-infected patients.


Assuntos
Tecido Adiposo/metabolismo , Antirretrovirais/farmacologia , Fatores de Crescimento de Fibroblastos/análise , Infecções por HIV/tratamento farmacológico , Fígado/metabolismo , Proteínas de Membrana/análise , Músculo Esquelético/metabolismo , Alcinos , Benzoxazinas/farmacologia , Ciclopropanos , Diabetes Mellitus Tipo 2/patologia , Combinação de Medicamentos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Inibidores de Integrase de HIV/farmacologia , Células Hep G2 , Humanos , Proteínas Klotho , Lopinavir/farmacologia , Maraviroc/farmacologia , Obesidade/patologia , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Quinolonas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Ritonavir/farmacologia , Tapsigargina/farmacologia , Tunicamicina/farmacologia
11.
Cell Rep ; 18(5): 1241-1255, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-28147278

RESUMO

Macrophages exert potent effector functions against invading microorganisms but constitute, paradoxically, a preferential niche for many bacterial strains to replicate. Using a model of infection by Salmonella Typhimurium, we have identified a molecular mechanism regulated by the nuclear receptor LXR that limits infection of host macrophages through transcriptional activation of the multifunctional enzyme CD38. LXR agonists reduced the intracellular levels of NAD+ in a CD38-dependent manner, counteracting pathogen-induced changes in macrophage morphology and the distribution of the F-actin cytoskeleton and reducing the capability of non-opsonized Salmonella to infect macrophages. Remarkably, pharmacological treatment with an LXR agonist ameliorated clinical signs associated with Salmonella infection in vivo, and these effects were dependent on CD38 expression in bone-marrow-derived cells. Altogether, this work reveals an unappreciated role for CD38 in bacterial-host cell interaction that can be pharmacologically exploited by activation of the LXR pathway.


Assuntos
Receptores X do Fígado/metabolismo , Macrófagos/metabolismo , NAD/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Infecções por Salmonella/metabolismo , Salmonella typhimurium/patogenicidade , ADP-Ribosil Ciclase 1/metabolismo , Citoesqueleto de Actina/metabolismo , Animais , Células COS , Linhagem Celular , Chlorocebus aethiops , Feminino , Masculino , Camundongos , Células RAW 264.7
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