RESUMO
We recently showed that interleukin (IL)-6-type cytokine signaling in adipocytes induces free fatty acid release from visceral adipocytes, thereby promoting obesity-induced hepatic insulin resistance and steatosis. In addition, IL-6-type cytokines may increase the release of leptin from adipocytes and by those means induce glucagon-like peptide 1 (GLP-1) secretion. We thus hypothesized that IL-6-type cytokine signaling in adipocytes may regulate insulin secretion. To this end, mice with adipocyte-specific knockout of gp130, the signal transducer protein of IL-6, were fed a high-fat diet for 12 weeks. Compared with control littermates, knockout mice showed impaired glucose tolerance and circulating leptin, GLP-1, and insulin levels were reduced. In line, leptin release from isolated adipocytes was reduced, and intestinal proprotein convertase subtilisin/kexin type 1 (Pcsk1) expression, the gene encoding PC1/3, which controls GLP-1 production, was decreased in knockout mice. Importantly, treatment with the GLP-1 receptor antagonist exendin 9-39 abolished the observed difference in glucose tolerance between control and knockout mice. Ex vivo, supernatant collected from isolated adipocytes of gp130 knockout mice blunted Pcsk1 expression and GLP-1 release from GLUTag cells. In contrast, glucose- and GLP-1-stimulated insulin secretion was not affected in islets of knockout mice. In conclusion, adipocyte-specific IL-6 signaling induces intestinal GLP-1 release to enhance insulin secretion, thereby counteracting insulin resistance in obesity.
Assuntos
Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Citocinas/farmacologia , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Interleucina-6/farmacologia , Animais , Receptor gp130 de Citocina/genética , Receptor gp130 de Citocina/metabolismo , Ingestão de Alimentos , Teste de Tolerância a Glucose , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pró-Proteína Convertase 1/genética , Pró-Proteína Convertase 1/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/efeitos dos fármacosRESUMO
Nonalcoholic fatty liver disease is one of the most prevalent metabolic disorders and it tightly associates with obesity, type 2 diabetes, and cardiovascular disease. Reduced mitochondrial lipid oxidation contributes to hepatic fatty acid accumulation. Here, we show that the Fas cell surface death receptor (Fas/CD95/Apo-1) regulates hepatic mitochondrial metabolism. Hepatic Fas overexpression in chow-fed mice compromises fatty acid oxidation, mitochondrial respiration, and the abundance of mitochondrial respiratory complexes promoting hepatic lipid accumulation and insulin resistance. In line, hepatocyte-specific ablation of Fas improves mitochondrial function and ameliorates high-fat-diet-induced hepatic steatosis, glucose tolerance, and insulin resistance. Mechanistically, Fas impairs fatty acid oxidation via the BH3 interacting-domain death agonist (BID). Mice with genetic or pharmacological inhibition of BID are protected from Fas-mediated impairment of mitochondrial oxidation and hepatic steatosis. We suggest Fas as a potential novel therapeutic target to treat obesity-associated fatty liver and insulin resistance.Hepatic steatosis is a common disease closely associated with metabolic syndrome and insulin resistance. Here Item et al. show that Fas, a member of the TNF receptor superfamily, contributes to mitochondrial dysfunction, steatosis development, and insulin resistance under high fat diet.
Assuntos
Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Mitocôndrias Hepáticas/metabolismo , Receptor fas/metabolismo , Animais , Dieta Hiperlipídica , Proteína Ligante Fas/genética , Proteína Ligante Fas/metabolismo , Ácidos Graxos/metabolismo , Resistência à Insulina , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Camundongos Transgênicos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Triglicerídeos/metabolismo , Receptor fas/genéticaRESUMO
The deleterious effect of chronic activation of the IL-1ß system on type 2 diabetes and other metabolic diseases is well documented. However, a possible physiological role for IL-1ß in glucose metabolism has remained unexplored. Here we found that feeding induced a physiological increase in the number of peritoneal macrophages that secreted IL-1ß, in a glucose-dependent manner. Subsequently, IL-1ß contributed to the postprandial stimulation of insulin secretion. Accordingly, lack of endogenous IL-1ß signaling in mice during refeeding and obesity diminished the concentration of insulin in plasma. IL-1ß and insulin increased the uptake of glucose into macrophages, and insulin reinforced a pro-inflammatory pattern via the insulin receptor, glucose metabolism, production of reactive oxygen species, and secretion of IL-1ß mediated by the NLRP3 inflammasome. Postprandial inflammation might be limited by normalization of glycemia, since it was prevented by inhibition of the sodium-glucose cotransporter SGLT2. Our findings identify a physiological role for IL-1ß and insulin in the regulation of both metabolism and immunity.
Assuntos
Diabetes Mellitus Tipo 2/imunologia , Inflamação/imunologia , Células Secretoras de Insulina/fisiologia , Interleucina-1beta/metabolismo , Macrófagos/fisiologia , Animais , Células Cultivadas , Glucose/metabolismo , Humanos , Inflamassomos/metabolismo , Insulina/metabolismo , Interleucina-1beta/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Período Pós-Prandial , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Transportador 2 de Glucose-Sódio/metabolismoRESUMO
Hepatic steatosis and insulin resistance are among the most prevalent metabolic disorders and are tightly associated with obesity and type 2 diabetes. However, the underlying mechanisms linking obesity to hepatic lipid accumulation and insulin resistance are incompletely understood. Glycoprotein 130 (gp130) is the common signal transducer of all interleukin 6 (IL-6) cytokines. We provide evidence that gp130-mediated adipose tissue lipolysis promotes hepatic steatosis and insulin resistance. In obese mice, adipocyte-specific gp130 deletion reduced basal lipolysis and enhanced insulin's ability to suppress lipolysis from mesenteric but not epididymal adipocytes. Consistently, free fatty acid levels were reduced in portal but not in systemic circulation of obese knockout mice. Of note, adipocyte-specific gp130 knockout mice were protected from high-fat diet-induced hepatic steatosis as well as from insulin resistance. In humans, omental but not subcutaneous IL-6 mRNA expression correlated positively with liver lipid accumulation (r = 0.31, P < 0.05) and negatively with hyperinsulinemic-euglycemic clamp glucose infusion rate (r = -0.28, P < 0.05). The results show that IL-6 cytokine-induced lipolysis may be restricted to mesenteric white adipose tissue and that it contributes to hepatic insulin resistance and steatosis. Therefore, blocking IL-6 cytokine signaling in (mesenteric) adipocytes may be a novel approach to blunting detrimental fat-liver crosstalk in obesity.
Assuntos
Gordura Abdominal/metabolismo , Receptor gp130 de Citocina/genética , Fígado Gorduroso/genética , Resistência à Insulina , Interleucina-6/genética , Fígado/metabolismo , Obesidade/genética , Gordura Subcutânea/metabolismo , Adipócitos/metabolismo , Tecido Adiposo Branco/metabolismo , Animais , Western Blotting , Receptor gp130 de Citocina/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Feminino , Técnica Clamp de Glucose , Humanos , Interleucina-6/metabolismo , Lipólise , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Omento/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Reduced kidney mass and/or function may result in multiple metabolic derangements, including insulin resistance. However, underlying mechanisms are poorly understood. Herein, we aimed to determine the impact of reduced kidney mass on glucose metabolism in lean and obese mice. To that end, 7-week-old C57BL/6J mice underwent uninephrectomy (UniNx) or sham operation. After surgery, animals were fed either a chow (standard) diet or a high-fat diet (HFD), and glucose homeostasis was assessed 20 weeks after surgery. Intraperitoneal glucose tolerance was similar in sham-operated and UniNx mice. However, insulin-stimulated glucose disposal in vivo was significantly diminished in UniNx mice, whereas insulin-stimulated glucose uptake into isolated skeletal muscle was similar in sham-operated and UniNx mice. Of note, capillary density was significantly reduced in skeletal muscle of HFD-fed UniNx mice. In contrast, hepatic insulin sensitivity was improved in UniNx mice. Furthermore, adipose tissue hypoxia-inducible factor 1α expression and inflammation were reduced in HFD-fed UniNx mice. Treatment with the angiotensin II receptor blocker telmisartan improved glucose tolerance and hepatic insulin sensitivity in HFD-fed sham-operated but not UniNx mice. In conclusion, UniNx protects from obesity-induced adipose tissue inflammation and hepatic insulin resistance, but it reduces muscle capillary density and, thus, deteriorates HFD-induced skeletal muscle glucose disposal.
Assuntos
Tecido Adiposo/metabolismo , Resistência à Insulina/fisiologia , Rim/metabolismo , Fígado/metabolismo , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Animais , Dieta Hiperlipídica , Fígado Gorduroso/metabolismo , Glucose/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Inflamação/metabolismo , Insulina/metabolismo , Rim/cirurgia , Masculino , Camundongos , Camundongos Obesos , Triglicerídeos/metabolismoRESUMO
Contracting muscle releases interleukin-6 (IL-6) enabling the metabolic switch from carbohydrate to fat utilization. Similarly, metabolism is switched during transition from fed to fasting state. Herein, we examined a putative role for IL-6 in the metabolic adaptation to normal fasting. In lean C57BL/6J mice, 6 h of food withdrawal increased gene transcription levels of IL-6 in skeletal muscle but not in white adipose tissue. Concomitantly, circulating IL-6 and free fatty acid (FFA) levels were significantly increased, whereas respiratory quotient (RQ) was reduced in 6-h fasted mice. In white adipose tissue, phosphorylation of hormone-sensitive lipase (HSL) was increased on fasting, indicating increased lipolysis. Intriguingly, fasting-induced increase in circulating IL-6 levels and parallel rise in FFA concentration were absent in obese and glucose-intolerant mice. A causative role for IL-6 in the physiological adaptation to fasting was further supported by the fact that fasting-induced increase in circulating FFA levels was significantly blunted in lean IL-6 knockout (KO) and lean C57BL/6J mice treated with neutralizing IL-6 antibody. Consistently, phosphorylation of HSL was significantly reduced in adipose tissue of IL-6-depleted mice. Hence, our findings suggest a novel role for IL-6 in energy supply during early fasting.
Assuntos
Jejum/psicologia , Ácidos Graxos não Esterificados/metabolismo , Interleucina-6/fisiologia , Adaptação Fisiológica/fisiologia , Animais , Metabolismo Energético/fisiologia , Interleucina-6/deficiência , Interleucina-6/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos AnimaisRESUMO
Low-grade inflammation in adipose tissue and liver has been implicated in obesity-associated insulin resistance and type 2 diabetes. Yet, the contribution of inflammatory cells to the pathogenesis of skeletal muscle insulin resistance remains elusive. In a large cohort of obese human individuals, blood monocyte Fas (CD95) expression correlated with systemic and skeletal muscle insulin resistance. To test a causal role for myeloid cell Fas expression in the development of skeletal muscle insulin resistance, we generated myeloid/haematopoietic cell-specific Fas-depleted mice. Myeloid/haematopoietic Fas deficiency prevented the development of glucose intolerance in high fat-fed mice, in ob/ob mice, and in mice acutely challenged by LPS. In vivo, ex vivo and in vitro studies demonstrated preservation of muscle insulin responsiveness with no effect on adipose tissue or liver. Studies using neutralizing antibodies demonstrated a role for TNFα as mediator between myeloid Fas and skeletal muscle insulin resistance, supported by significant correlations between monocyte Fas expression and circulating TNFα in humans. In conclusion, our results demonstrate an unanticipated crosstalk between myeloid cells and skeletal muscle in the development of obesity-associated insulin resistance.
Assuntos
Regulação da Expressão Gênica , Resistência à Insulina , Monócitos/metabolismo , Músculo Esquelético/metabolismo , Obesidade/metabolismo , Receptor fas/metabolismo , Adulto , Idoso , Animais , Anticorpos Neutralizantes/imunologia , Estudos de Coortes , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Pessoa de Meia-Idade , Obesidade/complicações , Receptor fas/deficiência , Receptor fas/genéticaRESUMO
High-fat feeding for 3-4 days impairs glucose tolerance and hepatic insulin sensitivity. However, it remains unclear whether the evolving hepatic insulin resistance is due to acute lipid overload or the result of induced adipose tissue inflammation and consequent dysfunctional adipose tissue-liver cross-talk. In the present study, feeding C57Bl6/J mice a fat-enriched diet [high-fat diet (HFD)] for 4 days induced glucose intolerance, hepatic insulin resistance (as assessed by hyperinsulinemic euglycemic clamp studies), and hepatic steatosis as well as adipose tissue inflammation (i.e., TNFα expression) compared with standard chow-fed mice. Adipocyte-specific depletion of the antiapoptotic/anti-inflammatory factor Fas (CD95) attenuated adipose tissue inflammation and improved glucose tolerance as well as hepatic insulin sensitivity without altering the level of hepatic steatosis induced by HFD. In summary, our results identify adipose tissue inflammation and resulting dysfunctional adipose tissue-liver cross-talk as an early event in the development of HFD-induced hepatic insulin resistance.
Assuntos
Tecido Adiposo/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/toxicidade , Inflamação/fisiopatologia , Resistência à Insulina/fisiologia , Fígado/efeitos dos fármacos , Adipócitos/fisiologia , Animais , Área Sob a Curva , Western Blotting , Citocinas/metabolismo , Éxons/genética , Ácidos Graxos não Esterificados/sangue , Fígado Gorduroso/metabolismo , Técnica Clamp de Glucose , Teste de Tolerância a Glucose , Insulina/sangue , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA/biossíntese , RNA/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real , Triglicerídeos/sangue , Receptor fas/metabolismoRESUMO
In established obesity, inflammation and macrophage recruitment likely contribute to the development of insulin resistance. In the current study, we set out to explore whether adipose tissue infiltration by neutrophils that occurs early (3 days) after initiating a high-fat diet (HFD) could contribute to the early occurrence of hepatic insulin resistance and to determine the role of cytosolic phospholipase A2α (cPLA2α) in this process. The 3-day HFD caused a significant upregulation of cPLA2α in periepididymal fat and in the liver. A specific antisense oligonucleotide (AS) effectively prevented cPLA2α induction, neutrophil infiltration into adipose tissue (likely involving MIP-2), and protected against 3-day HFD-induced impairment in hepatic insulin signaling and glucose over-production from pyruvate. To sort out the role of adipose neutrophil infiltration independent of cPLA2α induction in the liver, mice were injected intraperitoneally with anti-intracellular adhesion molecule-1 (ICAM-1) antibodies. This effectively prevented neutrophil infiltration without affecting cPLA2α or MIP-2, but like AS, prevented impairment in hepatic insulin signaling, the enhanced pyruvate-to-glucose flux, and the impaired insulin-mediated suppression of hepatic glucose production (assessed by clamp), which were induced by the 3-day HFD. Adipose tissue secretion of tumor necrosis factor-α (TNF-α) was increased by the 3-day HFD, but not if mice were treated with AS or ICAM-1 antibodies. Moreover, systemic TNF-α neutralization prevented 3-day HFD-induced hepatic insulin resistance, suggesting its mediatory role. We propose that an acute, cPLA2α-dependent, neutrophil-dominated inflammatory response of adipose tissue contributes to hepatic insulin resistance and glucose overproduction in the early adaptation to high-fat feeding.
Assuntos
Tecido Adiposo/metabolismo , Dieta Hiperlipídica/efeitos adversos , Fosfolipases A2 do Grupo IV/metabolismo , Resistência à Insulina/fisiologia , Fígado/metabolismo , Infiltração de Neutrófilos/fisiologia , Animais , Immunoblotting , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
We previously reported that high load resistance exercise with superimposed whole-body vibration and sustained vascular occlusion (vibroX) markedly improves cycling endurance capacity, increases capillary-to-fibre ratio and skeletal muscle oxidative enzyme activity in untrained young women. These findings are intriguing, since increases in oxidative muscle phenotype and endurance capacity are typically induced by endurance but not heavy resistance exercise. Here, we tested the hypothesis that vibroX activates genes associated with mitochondrial biogenesis and angiogenesis. Eight healthy, recreationally resistance-trained young men performed either vibroX or resistance exercise (RES) in a randomised, cross-over design. Needle biopsies (M. vastus lateralis) were obtained at rest and 3 h post-exercise. Changes in relative gene expression levels were assessed by real-time quantitative PCR. After vibroX, vascular endothelial growth factor and peroxisome proliferator-activated receptor-γ coactivator 1α mRNA abundances increased to 2- and 4.4-fold, respectively, but did not significantly change above resting values after RES. Other genes involved in mitochondrial biogenesis were not affected by either exercise modality. While vibroX increased the expression of hexokinase II, xanthine dehydrogenase, and manganese superoxide dismutase mRNA, there were no changes in these transcripts after RES. This study demonstrates that high load resistance exercise with superimposed whole-body vibration and sustained vascular occlusion activates metabolic and angiogenic gene programs, which are usually activated after endurance but not resistance exercise. Thus, targeted modification of high load resistance exercise by vibration and vascular occlusion might represent a novel strategy to induce endurance-type muscle adaptations.
Assuntos
Proteínas de Choque Térmico/genética , Isquemia/genética , Contração Muscular , Resistência Física , Músculo Quadríceps/irrigação sanguínea , Músculo Quadríceps/metabolismo , RNA Mensageiro/metabolismo , Treinamento Resistido , Fatores de Transcrição/genética , Fator A de Crescimento do Endotélio Vascular/genética , Vibração , Adaptação Fisiológica , Adulto , Análise de Variância , Biópsia , Estudos Cross-Over , Metabolismo Energético/genética , Regulação Enzimológica da Expressão Gênica , Humanos , Isquemia/enzimologia , Isquemia/fisiopatologia , Masculino , Mitocôndrias Musculares/metabolismo , Renovação Mitocondrial/genética , Neovascularização Fisiológica/genética , Estresse Oxidativo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Músculo Quadríceps/enzimologia , Músculo Quadríceps/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Suíça , Fatores de Tempo , Regulação para Cima , Adulto JovemRESUMO
In this study, we examined whether glycemic status influences aerobic function in women with type 1 diabetes and whether aerobic function is reduced relative to healthy women. To this end, we compared several factors determining aerobic function of 29 young sedentary asymptomatic women (CON) with 9 women of similar age and activity level with type 1 diabetes [DIA, HbA1c range = 6.9-8.2%]. Calf muscle mitochondrial capacity was estimated by (31)P-magnetic resonance spectroscopy. Capillarization and muscle fiber oxidative enzyme activity were assessed from vastus lateralis and soleus muscle biopsies. Oxygen uptake and cardiac output were evaluated by ergospirometry and N(2)O/SF(6) rebreathing. Calf muscle mitochondrial capacity was not different between CON and DIA, as indicated by the identical calculated maximal rates of oxidative ATP synthesis [0.0307 (0.0070) vs. 0.0309 (0.0058) s(-1), P = 0.930]. Notably, HbA1c was negatively correlated with mitochondrial capacity in DIA (R(2) = 0.475, P = 0.040). Although HbA1c was negatively correlated with cardiac output (R(2) = 0.742, P = 0.013) in DIA, there was no difference between CON and DIA in maximal oxygen consumption [2.17 (0.34) vs. 2.21 (0.32) l/min, P = 0.764], cardiac output [12.1 (1.9) vs. 12.3 (1.8) l/min, P = 0.783], and endurance capacity [532 (212) vs. 471 (119) s, P = 0.475]. There was also no difference between the two groups either in the oxidative enzyme activity or capillary-to-fiber ratio. We conclude that mitochondrial capacity depends on HbA1c in untrained women with type 1 diabetes but is not reduced relative to untrained healthy women.