RESUMO
Discovered 20 years ago, fibroblast growth factor (FGF)19, and its mouse ortholog FGF15, were the first members of a new subfamily of FGFs able to act as hormones. During fetal life, FGF15/19 is involved in organogenesis, affecting the development of the ear, eye, heart, and brain. At adulthood, FGF15/19 is mainly produced by the ileum, acting on the liver to repress hepatic bile acid synthesis and promote postprandial nutrient partitioning. In rodents, pharmacologic doses of FGF19 induce the same antiobesity and antidiabetic actions as FGF21, with these metabolic effects being partly mediated by the brain. However, activation of hepatocyte proliferation by FGF19 has long been a challenge to its therapeutic use. Recently, genetic reengineering of the molecule has resolved this issue. Despite a global overlap in expression pattern and function, murine FGF15 and human FGF19 exhibit several differences in terms of regulation, molecular structure, signaling, and biological properties. As most of the knowledge originates from the use of FGF19 in murine models, differences between mice and humans in the biology of FGF15/19 have to be considered for a successful translation from bench to bedside. This review summarizes the basic knowledge concerning FGF15/19 in mice and humans, with a special focus on regulation of production, morphogenic properties, hepatocyte growth, bile acid homeostasis, as well as actions on glucose, lipid, and energy homeostasis. Moreover, implications and therapeutic perspectives concerning FGF19 in human diseases (including obesity, type 2 diabetes, hepatic steatosis, biliary disorders, and cancer) are also discussed.
Assuntos
Doenças Biliares/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fígado Gorduroso/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/uso terapêutico , Neoplasias/tratamento farmacológico , Obesidade/tratamento farmacológico , Animais , HumanosRESUMO
Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic form of isolated gonadotropin-releasing hormone (GnRH) deficiency caused by mutations in > 30 genes. Fibroblast growth factor receptor 1 (FGFR1) is the most frequently mutated gene in CHH and is implicated in GnRH neuron development and maintenance. We note that a CHH FGFR1 mutation (p.L342S) decreases signaling of the metabolic regulator FGF21 by impairing the association of FGFR1 with ß-Klotho (KLB), the obligate co-receptor for FGF21. We thus hypothesized that the metabolic FGF21/KLB/FGFR1 pathway is involved in CHH Genetic screening of 334 CHH patients identified seven heterozygous loss-of-function KLB mutations in 13 patients (4%). Most patients with KLB mutations (9/13) exhibited metabolic defects. In mice, lack of Klb led to delayed puberty, altered estrous cyclicity, and subfertility due to a hypothalamic defect associated with inability of GnRH neurons to release GnRH in response to FGF21. Peripheral FGF21 administration could indeed reach GnRH neurons through circumventricular organs in the hypothalamus. We conclude that FGF21/KLB/FGFR1 signaling plays an essential role in GnRH biology, potentially linking metabolism with reproduction.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Síndrome de Kallmann/genética , Proteínas de Membrana/genética , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Animais , Células COS , Caenorhabditis elegans/genética , Chlorocebus aethiops , Estudos de Coortes , Feminino , Fatores de Crescimento de Fibroblastos/genética , Hormônio Liberador de Gonadotropina/genética , Células HEK293 , Humanos , Hipotálamo/metabolismo , Proteínas Klotho , Masculino , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Neurônios/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genéticaRESUMO
Type 1 diabetes (T1DM) results from destruction of most insulin-secreting pancreatic ß-cells. The persistence of ß-cells decades after the onset of the disease indicates that the resistance of individual cells to the autoimmune insult is heterogeneous and might depend on the metabolic status of a cell at a given moment. The aim of this study is to investigate whether activation of nicotinic acetylcholine receptors (nACh-Rs) could increase ß-cell resistance against the adverse environment prevailing at the onset of T1DM. Here, we show that nACh-R activation by nicotine and choline, 2 agonists of the receptor, decreases murine and human ß-cell apoptosis induced by proinflammatory cytokines known to be present in the islet environment at the onset of T1DM. The protective mechanism activated by nicotine and choline involves attenuation of mitochondrial outer membrane permeabilization via modulation of endoplasmic reticulum stress, of the activity of B-cell lymphoma 2 family proteins and cytoplasmic calcium levels. Local inflammation and endoplasmic reticulum stress being key determinants of ß-cell death in T1DM, we conclude that pharmacological activation of nACh-R could represent a valuable therapeutic option in the modulation of ß-cell death in T1DM.
Assuntos
Apoptose/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Ilhotas Pancreáticas/efeitos dos fármacos , Agonistas Nicotínicos/uso terapêutico , Animais , Cálcio/metabolismo , Caspase 3/metabolismo , Colina , Técnicas de Cultura , Avaliação Pré-Clínica de Medicamentos , Estresse do Retículo Endoplasmático , Feminino , Regulação da Expressão Gênica , Genes bcl-2 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Membranas Mitocondriais/metabolismo , Nicotina , Agonistas Nicotínicos/farmacologia , Óxido Nítrico/metabolismoRESUMO
Diets rich in omega-3s have been thought to prevent both obesity and osteoporosis. However, conflicting findings are reported, probably as a result of gene by nutritional interactions. Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear receptor that improves insulin sensitivity but causes weight gain and bone loss. Fish oil is a natural agonist for PPARγ and thus may exert its actions through the PPARγ pathway. We examined the role of PPARγ in body composition changes induced by a fish or safflower oil diet using two strains of C57BL/6J (B6); i.e. B6.C3H-6T (6T) congenic mice created by backcrossing a small locus on Chr 6 from C3H carrying 'gain of function' polymorphisms in the Pparγ gene onto a B6 background, and C57BL/6J mice. After 9months of feeding both diets to female mice, body weight, percent fat and leptin levels were less in mice fed the fish oil vs those fed safflower oil, independent of genotype. At the skeletal level, fish oil preserved vertebral bone mineral density (BMD) and microstructure in B6 but not in 6T mice. Moreover, fish oil consumption was associated with an increase in bone marrow adiposity and a decrease in BMD, cortical thickness, ultimate force and plastic energy in femur of the 6T but not the B6 mice. These effects paralleled an increase in adipogenic inflammatory and resorption markers in 6T but not B6. Thus, compared to safflower oil, fish oil (high ratio omega-3/-6) prevents weight gain, bone loss, and changes in trabecular microarchitecture in the spine with age. These beneficial effects are absent in mice with polymorphisms in the Pparγ gene (6T), supporting the tenet that the actions of n-3 fatty acids on bone microstructure are likely to be genotype dependent. Thus caution must be used in interpreting dietary intervention trials with skeletal endpoints in mice and in humans.
Assuntos
Osso e Ossos/metabolismo , Dieta , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-6/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Tecido Adiposo Marrom/anatomia & histologia , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/anatomia & histologia , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Adiposidade/efeitos dos fármacos , Adiposidade/fisiologia , Animais , Biomarcadores/metabolismo , Fenômenos Biomecânicos/efeitos dos fármacos , Composição Corporal/efeitos dos fármacos , Densidade Óssea/efeitos dos fármacos , Medula Óssea/efeitos dos fármacos , Medula Óssea/fisiologia , Osso e Ossos/efeitos dos fármacos , Contagem de Células , Suplementos Nutricionais , Feminino , Fêmur/anatomia & histologia , Fêmur/efeitos dos fármacos , Fêmur/fisiologia , Óleos de Peixe/farmacologia , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Coluna Vertebral/anatomia & histologia , Coluna Vertebral/efeitos dos fármacos , Coluna Vertebral/fisiologia , Tíbia/anatomia & histologia , Tíbia/efeitos dos fármacos , Tíbia/fisiologiaRESUMO
BACKGROUND: Lipopolysaccharide (LPS) injection in the corpus callosum (CC) of rat pups results in diffuse white matter injury similar to the main neuropathology of preterm infants. The aim of this study was to characterize the structural and metabolic markers of acute inflammatory injury by high-field magnetic resonance imaging (MRI) magnetic resonance spectroscopy (MRS) in vivo. METHODS: Twenty-four hours after a 1-mg/kg injection of LPS in postnatal day 3 rat pups, diffusion tensor imaging and proton nuclear magnetic spectroscopy ((1)H NMR) were analyzed in conjunction to determine markers of cell death and inflammation using immunohistochemistry and gene expression. RESULTS: MRI and MRS in the CC revealed an increase in lactate and free lipids and a decrease of the apparent diffusion coefficient. Detailed evaluation of the CC showed a marked apoptotic response assessed by fractin expression. Interestingly, the degree of reduction in the apparent diffusion coefficient correlated strongly with the natural logarithm of fractin expression, in the same region of interest. LPS injection further resulted in increased activated microglia clustered in the cingulum, widespread astrogliosis, and increased expression of genes for interleukin (IL)-1, IL-6, and tumor necrosis factor. CONCLUSION: This model was able to reproduce the typical MRI hallmarks of acute diffuse white matter injury seen in preterm infants and allowed the evaluation of in vivo biomarkers of acute neuropathology after inflammatory challenge.
Assuntos
Biomarcadores/metabolismo , Encefalite/diagnóstico , Leucoencefalopatias/diagnóstico , Animais , Imagem de Tensor de Difusão , Humanos , Imuno-Histoquímica , Recém-Nascido Prematuro , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Ácido Láctico/metabolismo , Lipopolissacarídeos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Ratos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Nicotinic acetylcholine receptors (nAChRs) are membrane ligand-gated cation channels whose activation is triggered by the binding of the endogenous neurotransmitter acetylcholine or other biologic compounds including nicotine. Their roles in synaptic transmission in the central and peripheral nervous system as well as in the neuromuscular junction have been extensively studied. Recent implications of nAChRs in intracellular signaling and their detection in peripheral nonneural cells (including epithelial cells and immune cells) have renewed the interest for this class of ionotropic receptors. In the present review, we focus our attention on the potential use of nicotinic cholinergic signaling in the treatment of metabolic diseases (such as obesity and diabetes) in browsing functions of nAChRs in adipose tissue and pancreatic islet biology. In fact, different nAChR subunits can be detected in these metabolic tissues, as well as in immune cells interacting with them. Various rodent models of obesity and diabetes benefit from stimulation of the nicotinic cholinergic pathway, whereas mice deficient for some nAChRs, in particular the α7 nAChR subunit, harbor a worsened metabolic phenotype. In contrast to potential therapeutic applications in metabolic diseases, an overstimulation of this signaling pathway during the early stage of development (typically through nicotine exposure during fetal life) presents deleterious consequences on ontogeny and functionality of adipose tissue and the endocrine pancreas which persist throughout life.
Assuntos
Tecido Adiposo/fisiologia , Diabetes Mellitus/metabolismo , Ilhotas Pancreáticas/fisiologia , Obesidade/metabolismo , Receptores Colinérgicos/metabolismo , Acetilcolina/metabolismo , Animais , Diabetes Mellitus/terapia , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Knockout , Terapia de Alvo Molecular , Nicotina/metabolismo , Obesidade/terapia , Transdução de SinaisRESUMO
Abnormally high GH/IGF-I levels, most often caused by adenomas arising from pituitary somatotrophs, generate deleterious effects. We recently described a targeted secretion inhibitor (SXN101742) comprising a GHRH domain and the endopeptidase domain of botulinum toxin serotype D (GHRH-light chain endopeptidase type D domain [LC/D] associated to a heavy chain translocation domain [HN]) able to down-regulate the GH/IGF-I axis. In the present study, we compared the effect of a single iv bolus of a related molecule developed for clinical studies (SXN101959, 1 mg/kg) with a sc infusion of the somatostatin analog octreotide (SMS201-995, 10 µg/kg · h) to lower GH/IGF-I activity in growing male rats. Ten days after administration of SXN101959 or initiation of the octreotide infusion, body and pituitary weights, body length, GH peaks, and IGF-I production were reduced by both treatments but to a greater extent with SXN101959. In contrast to unaltered GH gene expression and increased GH storage in pituitaries from octreotide-treated rats, the inhibition of GH secretion was associated with a collapse of both GH mRNA and protein level in pituitaries from SXN101959-treated rats, in line with a specific decrease in hypothalamic GHRH production, not observed with octreotide. SXN101959 did not induce major apoptotic events in anterior pituitary and exhibited a reversible mode of action with full recovery of somatotroph cell functionality 30 days after treatment. Octreotide infusion permanently decreased ghrelin levels, whereas SXN101959 only transiently attenuated ghrelinemia. Both treatments limited bone mass acquisition and altered specifically tissues development. In conclusion, SXN101959 exerts a powerful and reversible inhibitory action on the somatotropic axis. Specific features of SXN101959, including long duration of action coupled to a strong inhibition of pituitary GH synthesis, represent advantages when treating overproduction of GH.
Assuntos
Toxinas Botulínicas/farmacologia , Hormônio do Crescimento/antagonistas & inibidores , Fator de Crescimento Insulin-Like I/metabolismo , Octreotida/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Animais , Desenvolvimento Ósseo/efeitos dos fármacos , Hormônio do Crescimento/metabolismo , Fator de Crescimento Insulin-Like I/genética , Masculino , RatosRESUMO
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an endocrine disruptor affecting the reproductive system in humans. The aim of this study was to evaluate the effects of TCDD administered to pregnant mice at two different doses (2-10 ng/kg/day), on imprinted genes in the male offspring. The degree of methylation and the mRNA expression of Snrpn, Peg3 and Igf2r were analyzed in the sperm, skeletal muscle and liver. TCDD administration (10 ng/kg/day) decreased the sperm count in the male offspring. It did not affect methylation but increased mRNA expression of Snrpn, Peg3, Igf2r and Air ncRNA. In muscle and liver, TCDD (10 ng/kg/day) induced increases in methylation and decreases in mRNA expression of Igf2r. These results show that the robust effects of TCDD on the mRNA expression of Snrpn, Peg3 and Igf2r genes in the sperm and of Igf2r in the muscle and liver are unrelated to changes in methylation in their respective genes.
Assuntos
Disruptores Endócrinos/toxicidade , Dibenzodioxinas Policloradas/toxicidade , Animais , Metilação de DNA , Feminino , Impressão Genômica , Fatores de Transcrição Kruppel-Like/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Troca Materno-Fetal , Camundongos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Gravidez , RNA Mensageiro/metabolismo , Receptor IGF Tipo 2/genética , Contagem de Espermatozoides , Proteínas Centrais de snRNP/genéticaRESUMO
Botulinum neurotoxins (BoNTs) are zinc endopeptidases that block release of the neurotransmitter acetylcholine in neuromuscular synapses through cleavage of soluble N-ethylmaleimide-sensitive fusion (NSF) attachment protein receptor (SNARE) proteins, which promote fusion of synaptic vesicles to the plasma membrane. We designed and tested a BoNT-derived targeted secretion inhibitor (TSI) targeting pituitary somatotroph cells to suppress growth hormone (GH) secretion and treat acromegaly. This recombinant protein, called SXN101742, contains a modified GH-releasing hormone (GHRH) domain and the endopeptidase domain of botulinum toxin serotype D (GHRH-LHN/D, where HN/D indicates endopeptidase and translocation domain type D). In vitro, SXN101742 targeted the GHRH receptor and depleted a SNARE protein involved in GH exocytosis, vesicle-associated membrane protein 2 (VAMP2). In vivo, administering SXN101742 to growing rats produced a dose-dependent inhibition of GH synthesis, storage, and secretion. Consequently, hepatic IGF1 production and resultant circulating IGF1 levels were reduced. Accordingly, body weight, body length, organ weight, and bone mass acquisition were all decreased, reflecting the biological impact of SXN101742 on the GH/IGF1 axis. An inactivating 2-amino acid substitution within the zinc coordination site of the endopeptidase domain completely abolished SXN101742 inhibitory actions on GH and IGF1. Thus, genetically reengineered BoNTs can be targeted to nonneural cells to selectively inhibit hormone secretion, representing a new approach to treating hormonal excess.
Assuntos
Regulação para Baixo/efeitos dos fármacos , Hormônio do Crescimento/metabolismo , Inibidores do Crescimento/farmacologia , Fator de Crescimento Insulin-Like I/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Acromegalia/tratamento farmacológico , Animais , Área Sob a Curva , Peso Corporal/efeitos dos fármacos , Toxinas Botulínicas/química , Toxinas Botulínicas/genética , Linhagem Celular , AMP Cíclico/metabolismo , Relação Dose-Resposta a Droga , Hormônio do Crescimento/sangue , Hormônio Liberador de Hormônio do Crescimento/química , Hormônio Liberador de Hormônio do Crescimento/genética , Inibidores do Crescimento/química , Lâmina de Crescimento/efeitos dos fármacos , Lâmina de Crescimento/crescimento & desenvolvimento , Lâmina de Crescimento/patologia , Fator de Crescimento Insulin-Like I/genética , Fígado/metabolismo , Masculino , Tamanho do Órgão/efeitos dos fármacos , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , Hipófise/patologia , Prolactina/metabolismo , Estrutura Terciária de Proteína , Proteólise , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão/química , Proteína 2 Associada à Membrana da Vesícula/químicaRESUMO
Presently, a growing interest is focused on the origins of the "Metabolic Syndrome", a cluster of several metabolic disorders linking obesity, dyslipidemia, hypertension and type 2 diabetes mellitus. Clearly, genetic predisposition and deleterious lifestyle, including low physical activity and hypercaloric alimentation, have an influence on the occurrence of the Metabolic Syndrome. However, recent data suggest that the Metabolic Syndrome could also be "programmed" during intrauterine life by diverse insults to the growing foetus. Nicotine is the main stimulant and dependence-forming alkaloid found in tobacco, and despite medical advice, statistics show that 20-30% of female smokers continue the habit during gestation, representing around 10% of all pregnancies. In consequence, nicotine is one of the most universally dangerous chemicals to which developing foetuses are exposed. The present review focuses on recent epidemiological surveys and experimental animal studies that provide evidences indicating that pre- and postnatal nicotine exposure might be a contributing factor for the occurrence of metabolic disorders later in life.
Assuntos
Doenças Cardiovasculares/metabolismo , Feto/efeitos dos fármacos , Doenças Metabólicas/metabolismo , Nicotina/farmacologia , Efeitos Tardios da Exposição Pré-Natal , Animais , Glicemia/metabolismo , Doenças Cardiovasculares/etiologia , Feminino , Homeostase , Humanos , Nicotina/efeitos adversos , Nicotina/metabolismo , Obesidade/etiologia , Obesidade/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/fisiologia , Gravidez , Fumar/efeitos adversosRESUMO
Despite medical advice, 20-30% of female smokers continue to smoke during pregnancy. Epidemiological studies have associated maternal smoking with increased risk of obesity and type-2 diabetes in the offspring. In the present study, we investigated the impact of prenatal nicotine exposure (3 mg/kg in Sprague Dawley rats via osmotic Alzet minipumps) on the early endocrine pancreas and adipose tissue development in rat pups before weaning. Body weight, fat deposition, food intake and food efficiency, cold tolerance, spontaneous physical activity, glucose utilization, and insulin sensitivity were also examined at adulthood. Prenatal nicotine exposure led to a decrease in endocrine pancreatic islet size and number at 7 d of life (postnatal d 7), which corroborates with a decrease in gene expression of specific transcription factors such as pancreatic and duodenal homeobox 1, Pax-6, Nkx6.1, and of hormones such as insulin and glucagon. The prenatal nicotine exposure also led to an increase in epididymal white adipose tissue weight at weaning (postnatal d 21), and marked hypertrophy of adipocytes, with increased gene expression of proadipogenic transcription factors such as CAAT-enhancer-binding protein-alpha, peroxisome proliferator activated receptor-gamma, and sterol regulatory element binding protein-1C. These early tissue alterations led to significant metabolic consequences, as shown by increased body weight and fat deposition, increased food efficiency on high-fat diet, cold intolerance, reduced physical activity, and glucose intolerance combined with insulin resistance observed at adulthood. These results prove a direct association between fetal nicotine exposure and offspring metabolic syndrome with early signs of dysregulations of adipose tissue and pancreatic development.
Assuntos
Peso Corporal/efeitos dos fármacos , Glucose/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Nicotina/toxicidade , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Adipogenia/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/crescimento & desenvolvimento , Tecido Adiposo/metabolismo , Animais , Calorimetria , Metabolismo dos Carboidratos/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Estimulantes Ganglionares/administração & dosagem , Estimulantes Ganglionares/toxicidade , Teste de Tolerância a Glucose , Resistência à Insulina , Ilhotas Pancreáticas/crescimento & desenvolvimento , Masculino , Nicotina/administração & dosagem , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Sprague-DawleyRESUMO
Interleukin (IL)-1 is a regulator of inflammation but is also implicated in the control of energy homeostasis. Because the soluble IL-1 receptor antagonist (IL-1Ra) is markedly increased in the serum of obese patients and is overexpressed in white adipose tissue in obesity, we studied the metabolic consequences of genetic IL-1Ra ablation in mice. We have shown that IL-1Ra-/- mice have a lean phenotype due to decreased fat mass, related to a defect in adipogenesis and increased energy expenditure. The adipocytes were smaller in these animals, and the expression of genes involved in adipogenesis was reduced. Energy expenditure as measured by indirect calorimetry was elevated, and weight loss in response to a 24-h fast was increased in IL-1Ra-/- animals compared with wild-type mice. Lipid oxidation of IL-1Ra-/- mice was higher during the light period, reflecting their reduction in diurnal food intake. Interestingly, IL-1Ra-/- and IL-1Ra+/- mice presented an attenuation in high-fat diet-induced caloric hyperphagia, indicating a better adaptation to hypercaloric alimentation, which is in line with the role of IL-1Ra as a mediator of leptin resistance. Taken together, we show that IL-1Ra is an important regulator of adipogenesis, food intake, and energy expenditure.
Assuntos
Tecido Adiposo/anatomia & histologia , Ingestão de Energia , Metabolismo Energético , Sialoglicoproteínas/deficiência , Sialoglicoproteínas/metabolismo , Redução de Peso/fisiologia , Tecido Adiposo/fisiologia , Animais , Composição Corporal , Amplificação de Genes , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-1/sangue , Interleucina-6/sangue , Íntrons , Masculino , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Sialoglicoproteínas/genética , Aumento de PesoRESUMO
The secreted form of the interleukin-1 receptor antagonist (IL-1Ra) is an acute-phase protein intervening in the counterregulation of inflammatory processes. We previously showed that this cytokine antagonist is upregulated in the serum of obese patients, correlating with BMI and insulin resistance. In this study, we examined the expression pattern of IL-1Ra and showed that it is highly expressed not only in liver and spleen, but also in white adipose tissue (WAT), where it is upregulated in obesity. In WAT of obese humans, IL-1Ra was also markedly increased. Moreover, human WAT explants secreted IL-1Ra into the medium, a process that could be stimulated fivefold by interferon-beta. Finally, lipopolysaccharide administration induced a long-lasting expression of IL-1Ra in mouse WAT, suggesting that adipose tissue is an important source of IL-1Ra in both obesity and inflammation. In summary, we demonstrated that WAT is one of the most important sources of IL-1Ra quantitatively, suggesting that this tissue could represent a novel target for anti-inflammatory treatment. Moreover, it can be speculated that IL-1Ra, whose production is markedly increased in WAT in obese individuals, contributes further to weight gain because of its endocrine and paracrine effects on the hypothalamus and adipocytes, respectively.