RESUMO
Blueberry, rich in antioxidant and anti-inflammatory phytochemicals, has been demonstrated to lower inflammatory status in adipose induced by high-fat diet (HFD) and obesity. The effect of blueberry on systemic immune functions has not been examined. C57BL/6 mice were randomised to one of three diets - low-fat diet (LFD), HFD and HFD plus 4 % (w/w) blueberry (HFD+B) - for 8 or 12 weeks. Ex vivo T-cell mitogens (concanavalin A (Con A); phytohaemagglutinin), T-cell antibody (anti-CD3; anti-CD3/CD28)-stimulated T-cell proliferation and cytokine production were assessed. After 8 weeks, both HFD groups weighed more (>4 g) than the LFD group; after 12 weeks, HFD+B-fed mice weighed more (>6 g) and had 41 % more adipose tissue than HFD-fed mice (P<0·05). After 12 weeks, T-cell proliferation was less in both HFD groups, compared with the LFD group. HFD-associated decrements in T-cell proliferation were partially (10-50 %) prevented by blueberry supplementation. At 12 weeks, splenocytes from HFD mice, but not from HFD+B mice, produced 51 % less IL-4 (CD3/CD28) and 57 % less interferon-γ (Con A) compared with splenocytes from LFD mice (P<0·05). In response to lipopolysaccharide challenge, splenocytes from both HFD groups produced 24-30 % less IL-6 and 27-33 % less TNF-α compared with splenocytes from LFD mice (P<0·05), indicating impaired acute innate immune response. By demonstrating deleterious impacts of HFD feeding on T-cell proliferation and splenocyte immune responses, our results provide insights into how HFD/obesity can disrupt systemic immune function. The protective effects of blueberry suggest that dietary blueberry can buttress T-cell and systemic immune function against HFD-obesity-associated insults.
Assuntos
Mirtilos Azuis (Planta) , Suplementos Nutricionais , Obesidade/dietoterapia , Obesidade/imunologia , Linfócitos T/imunologia , Adiposidade , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Proliferação de Células , Citocinas/biossíntese , Dieta com Restrição de Gorduras , Dieta Hiperlipídica/efeitos adversos , Imunidade Celular , Imunossupressores/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/etiologia , Linfócitos T/patologia , Aumento de PesoRESUMO
The HLA-F adjacent transcript 10 (FAT10) is a member of the ubiquitin-like gene family that alters protein function/stability through covalent ligation. Although FAT10 is induced by inflammatory mediators and implicated in immunity, the physiological functions of FAT10 are poorly defined. We report the discovery that FAT10 regulates lifespan through pleiotropic actions on metabolism and inflammation. Median and overall lifespan are increased 20% in FAT10ko mice, coincident with elevated metabolic rate, preferential use of fat as fuel, and dramatically reduced adiposity. This phenotype is associated with metabolic reprogramming of skeletal muscle (i.e., increased AMP kinase activity, ß-oxidation and -uncoupling, and decreased triglyceride content). Moreover, knockout mice have reduced circulating glucose and insulin levels and enhanced insulin sensitivity in metabolic tissues, consistent with elevated IL-10 in skeletal muscle and serum. These observations suggest novel roles of FAT10 in immune metabolic regulation that impact aging and chronic disease.
Assuntos
Adiposidade/genética , Longevidade/genética , Ubiquitinas/genética , Adipócitos/metabolismo , Animais , Biomarcadores/metabolismo , Metabolismo Energético , Feminino , Masculino , Camundongos , Camundongos Knockout , Oxirredução , Triglicerídeos/metabolismoRESUMO
Patients with type 2 diabetes (T2D) have disease-associated changes in B-cell function, but the role these changes play in disease pathogenesis is not well established. Data herein show B cells from obese mice produce a proinflammatory cytokine profile compared with B cells from lean mice. Complementary in vivo studies show that obese B cell-null mice have decreased systemic inflammation, inflammatory B- and T-cell cytokines, adipose tissue inflammation, and insulin resistance (IR) compared with obese WT mice. Reduced inflammation in obese/insulin resistant B cell-null mice associates with an increased percentage of anti-inflammatory regulatory T cells (Tregs). This increase contrasts with the sharply decreased percentage of Tregs in obese compared with lean WT mice and suggests that B cells may be critical regulators of T-cell functions previously shown to play important roles in IR. We demonstrate that B cells from T2D (but not non-T2D) subjects support proinflammatory T-cell function in obesity/T2D through contact-dependent mechanisms. In contrast, human monocytes increase proinflammatory T-cell cytokines in both T2D and non-T2D analyses. These data support the conclusion that B cells are critical regulators of inflammation in T2D due to their direct ability to promote proinflammatory T-cell function and secrete a proinflammatory cytokine profile. Thus, B cells are potential therapeutic targets for T2D.
Assuntos
Linfócitos B/imunologia , Citocinas/imunologia , Diabetes Mellitus Tipo 2/imunologia , Obesidade/imunologia , Linfócitos T Reguladores/imunologia , Animais , Linfócitos B/patologia , Diabetes Mellitus Tipo 2/patologia , Diabetes Mellitus Tipo 2/terapia , Feminino , Humanos , Inflamação/imunologia , Inflamação/patologia , Inflamação/terapia , Masculino , Camundongos , Camundongos Obesos , Obesidade/patologia , Obesidade/terapia , Linfócitos T Reguladores/patologiaRESUMO
Sqstm1/p62 functions in the non-canonical activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). However, its physiological relevance is not certain. Here, we show that p62(-/-) mice exhibited an accelerated presentation of ageing phenotypes, and tissues from these mice created a pro-oxidative environment owing to compromised mitochondrial electron transport. Accordingly, mitochondrial function rapidly declined with age in p62(-/-) mice. In addition, p62 enhanced basal Nrf2 activity, conferring a higher steady-state expression of NAD(P)H dehydrogenase, quinone 1 (Nqo1) to maintain mitochondrial membrane potential and, thereby, restrict excess oxidant generation. Together, the p62-Nrf2-Nqo1 cascade functions to assure mammalian longevity by stabilizing mitochondrial integrity.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas de Choque Térmico/metabolismo , Longevidade/fisiologia , Mamíferos/fisiologia , Mitocôndrias/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Animais , Autofagia , Feminino , Proteínas de Choque Térmico/deficiência , Proteína 1 Associada a ECH Semelhante a Kelch , Masculino , Camundongos , Oxirredução , Proteína Sequestossoma-1 , Transdução de SinaisRESUMO
Excessive phototransduction signaling is thought to be involved in light-induced and inherited retinal degeneration. Using knockout mice with defects in rhodopsin shut-off and transducin signaling, we show that two different pathways of photoreceptor-cell apoptosis are induced by light. Bright light induces apoptosis that is independent of transducin and accompanied by induction of the transcription factor AP-1. By contrast, low light induces an apoptotic pathway that requires transducin. We also provide evidence that additional genetic factors regulate sensitivity to light-induced damage. Our use of defined mouse mutants resolves some of the complexity underlying the mechanisms that regulate susceptibility to retinal degeneration.
Assuntos
Apoptose , Proteínas do Olho , Luz/efeitos adversos , Retina/efeitos da radiação , Animais , Arrestina/genética , Arrestina/metabolismo , Proteínas de Transporte , Dexametasona/metabolismo , Receptor Quinase 1 Acoplada a Proteína G , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mutação , Células Fotorreceptoras de Vertebrados/fisiologia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Proteínas/metabolismo , Retina/metabolismo , Retina/fisiopatologia , Rodopsina/metabolismo , Transdução de Sinais , Fator de Transcrição AP-1/antagonistas & inibidores , Fator de Transcrição AP-1/metabolismo , Transducina/metabolismo , cis-trans-IsomerasesRESUMO
Perilipin A is the most abundant phosphoprotein on adipocyte lipid droplets and is essential for lipid storage and lipolysis. Perilipin null mice exhibit diminished adipose tissue, elevated basal lipolysis, reduced catecholamine-stimulated lipolysis, and increased insulin resistance. To understand the physiological consequences of increased perilipin expression in vivo, we generated transgenic mice that overexpressed either human or mouse perilipin using the adipocyte-specific aP2 promoter/enhancer. Phenotypes of female transgenic and wild-type mice were characterized on chow and high-fat diets (HFDs). When challenged with an HFD, transgenic mice exhibited lower body weight, fat mass, and adipocyte size than wild-type mice. Expression of oxidative genes was increased and lipogenic genes decreased in brown adipose tissue of transgenic mice. Basal and catecholamine-stimulated lipolysis was decreased and glucose tolerance significantly improved in transgenic mice fed a HFD. Perilipin overexpression in adipose tissue protects against HFD-induced adipocyte hypertrophy, obesity, and glucose intolerance. Alterations in brown adipose tissue metabolism may mediate the effects of perilipin overexpression on body fat, although the mechanisms by which perilipin overexpression alters brown adipose tissue metabolism remain to be determined. Our findings demonstrate a novel role for perilipin expression in adipose tissue metabolism and regulation of obesity and its metabolic complications.
Assuntos
Dieta/efeitos adversos , Obesidade/genética , Obesidade/prevenção & controle , Fosfoproteínas/genética , Adipócitos/metabolismo , Adipócitos/patologia , Animais , Proteínas de Transporte , Catecolaminas/farmacologia , Tamanho Celular , Gorduras na Dieta/efeitos adversos , Feminino , Expressão Gênica , Glucose/metabolismo , Homeostase/genética , Humanos , Insulina/metabolismo , Lipólise/efeitos dos fármacos , Lipólise/genética , Masculino , Camundongos , Camundongos Transgênicos , Obesidade/etiologia , Obesidade/metabolismo , Especificidade de Órgãos , Oxirredução , Perilipina-1 , Aumento de Peso/efeitos dos fármacos , Aumento de Peso/genéticaRESUMO
Menopause, the age-related loss of ovarian hormone production, promotes increased adiposity and associated metabolic pathology, but molecular mechanisms remain unclear. We previously reported that estrogen increases skeletal muscle PPARdelta expression in vivo, and transgenic mice overexpressing muscle-specific PPARdelta are reportedly protected from diet-induced obesity. We thus hypothesized that obesity observed in ovariectomized mice, a model of menopause, may result in part from abrogated expression of muscle PPARdelta and/or downstream mediators such as FoxO1. To test this hypothesis, we ovariectomized (OVX) or sham-ovariectomized (SHM) 10-week old female C57Bl/6J mice, and subsequently harvested quadriceps muscles 12weeks later for gene expression studies. Compared to SHM, muscle from OVX mice displayed significantly decreased expression of PPARdelta (3.4-fold), FoxO1 (4.5-fold), PDK-4 (2.3-fold), and UCP-2 (1.8-fold). Consistent with studies indicating PPARdelta and FoxO1 regulate muscle fiber type, we observed dramatic OVX-specific decreases in slow isoforms of the contractile proteins myosin light chain (11.1-fold) and troponin C (11.8-fold). In addition, muscles from OVX mice expressed 57% less myogenin (drives type I fiber formation), 2-fold more MyoD (drives type II fiber formation), and 1.6-fold less musclin (produced exclusively by type II fibers) than SHM, collectively suggesting a shift towards less type I oxidative fibers. Finally, and consistent with changes in PPARdelta and FoxO1 activity, we observed decreased expression of atrogin-1 (2.3-fold) and MuRF-1 (1.9-fold) in OVX mice. In conclusion, muscles from ovariectomized mice display decreased PPARdelta and FoxO1 expression, abrogated expression of downstream targets involved in lipid and protein metabolism, and gene expression profiles indicating less type I oxidative fibers.
Assuntos
Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Menopausa/metabolismo , Músculo Esquelético/metabolismo , Obesidade/genética , Ovário/metabolismo , PPAR delta/metabolismo , Animais , Feminino , Proteína Forkhead Box O1 , Metabolismo dos Lipídeos/genética , Menopausa/genética , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares de Contração Lenta/metabolismo , Proteína MyoD/genética , Miogenina/genéticaRESUMO
Adipose tissue (AT) inflammation promotes insulin resistance (IR) and other obesity complications. AT inflammation and IR are associated with oxidative stress, adipocyte death, and the scavenging of dead adipocytes by proinflammatory CD11c+ AT macrophages (ATMPhi). We tested the hypothesis that supplementation of an obesitogenic (high-fat) diet with whole blueberry (BB) powder protects against AT inflammation and IR. Male C57Bl/6j mice were maintained for 8 wk on 1 of 3 diets: low-fat (10% of energy) diet (LFD), high-fat (60% of energy) diet (HFD) or the HFD containing 4% (wt:wt) whole BB powder (1:1 Vaccinium ashei and V. corymbosum) (HFD+B). BB supplementation (2.7% of total energy) did not affect HFD-associated alterations in energy intake, metabolic rate, body weight, or adiposity. We observed an emerging pattern of gene expression in AT of HFD mice indicating a shift toward global upregulation of inflammatory genes (tumor necrosis factor-alpha, interleukin-6, monocyte chemoattractant protein 1, inducible nitric oxide synthase), increased M1-polarized ATMPhi (CD11c+), and increased oxidative stress (reduced glutathione peroxidase 3). This shift was attenuated or nonexistent in HFD+B-fed mice. Furthermore, mice fed the HFD+B were protected from IR and hyperglycemia coincident with reductions in adipocyte death. Salutary effects of BB on adipocyte physiology and ATMPhi gene expression may reflect the ability of BB anthocyanins to alter mitogen-activated protein kinase and nuclear factor-kappaB stress signaling pathways, which regulate cell fate and inflammatory genes. These results suggest that cytoprotective and antiinflammatory actions of dietary BB can provide metabolic benefits to combat obesity-associated pathology.
Assuntos
Adipócitos/efeitos dos fármacos , Antocianinas/farmacologia , Anti-Inflamatórios/farmacologia , Mirtilos Azuis (Planta) , Morte Celular/efeitos dos fármacos , Resistência à Insulina , Preparações de Plantas/farmacologia , Adiposidade/efeitos dos fármacos , Animais , Mirtilos Azuis (Planta)/química , Morte Celular/genética , Quimiocina CCL2/metabolismo , Dieta , Gorduras na Dieta/administração & dosagem , Frutas , Expressão Gênica/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Hiperglicemia/prevenção & controle , Interleucina-6/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/metabolismo , Preparações de Plantas/química , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismoRESUMO
In adipocytes, lipid droplet (LD) size reflects a balance of triglyceride synthesis (lipogenesis) and hydrolysis (lipolysis). Perilipin A (Peri A) is the most abundant phosphoprotein on the surface of adipocyte LDs and has a crucial role in lipid storage and lipolysis. Adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) are the major rate-determining enzymes for lipolysis in adipocytes. Each of these proteins (Peri A, ATGL, and HSL) has been demonstrated to regulate lipid storage and release in the adipocyte. However, in the absence of protein kinase A (PKA) stimulation (basal state), the lipases (ATGL and HSL) are located mainly in the cytoplasm, and their contribution to basal rates of lipolysis and influence on LD size are poorly understood. In this study, we utilize an adenoviral system to knockdown or overexpress ATGL and HSL in an engineered model system of adipocytes in the presence or absence of Peri A. We are able to demonstrate in our experimental model system that in the basal state, LD size, triglyceride storage, and fatty acid release are mainly influenced by the expression of ATGL. These results demonstrate for the first time the relative contributions of ATGL, HSL, and Peri A on determination of LD size in the absence of PKA stimulation.
Assuntos
Adipócitos/enzimologia , Hidrolases de Éster Carboxílico/metabolismo , Lipólise/fisiologia , Adenoviridae/genética , Adenoviridae/metabolismo , Animais , Proteínas de Transporte , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Lipase , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência , Perilipina-1 , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Esterol Esterase/metabolismoRESUMO
Recent discoveries, notably of the hormones leptin and adiponectin, have revised the notion that adipocytes are simply a storage depot for body energy. Instead, adipocytes are also endocrine organs, with multiple metabolic roles in regulating whole-body physiology. Small adipocytes in lean individuals promote metabolic homeostasis; the enlarged adipocytes of obese individuals recruit macrophages and promote inflammation and the release of a range of factors that predispose toward insulin resistance. Exercise activates the AMP-activated protein kinase (AMPK) in muscle and other tissues, a pathway that increases fat oxidation and glucose transport. Importantly, the adipocyte hormones leptin and adiponectin also activate AMPK; remarkably, the same pathway is activated by certain antidiabetic agents such as thiazolidinediones. Increasingly, our understanding of the adipocyte as an endocrine organ is leading to new insights into obesity and health.
Assuntos
Adipócitos/fisiologia , Tecido Adiposo/metabolismo , Metabolismo Energético/fisiologia , Inflamação/metabolismo , Leptina/metabolismo , Obesidade/metabolismo , Adipócitos/metabolismo , Adiponectina , Tecido Adiposo/citologia , Animais , Humanos , Obesidade/complicaçõesRESUMO
Obesity is a risk factor for colorectal cancer (CRC), and alterations in the colonic microbiome and metabolome may be mechanistically involved in this relationship. The relative contribution of diet and obesity per se are unclear. We compared the effect of diet- and genetically-induced obesity on the intestinal microbiome and metabolome in a mouse model of CRC. Apc1638N mice were made obese by either high fat (HF) feeding or the presence of the Leprdb/db (DbDb) mutation. Intestinal tumors were quantified and stool microbiome and metabolome were profiled. Genetic obesity, and to a lesser extent HF feeding, promoted intestinal tumorigenesis. Each induced distinct microbial patterns: taxa enriched in HF were mostly Firmicutes (6 of 8) while those enriched in DbDb were split between Firmicutes (7 of 12) and Proteobacteria (5 of 12). Parabecteroides distasonis was lower in tumor-bearing mice and its abundance was inversely associated with colonic Il1b production (p<0.05). HF and genetic obesity altered the abundance of 49 and 40 fecal metabolites respectively, with 5 in common. Of these 5, adenosine was also lower in obese and in tumor-bearing mice (p<0.05) and its concentration was inversely associated with colonic Il1b and Tnf production (p<0.05). HF and genetic obesity differentially alter the intestinal microbiome and metabolome. A depletion of adenosine and P.distasonis in tumor-bearing mice could play a mechanistic role in tumor formation. Adenosine and P. distasonis have previously been shown to be anti-inflammatory in the colon and we postulate their reduction could promote tumorigenesis by de-repressing inflammation.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Fezes/química , Fezes/microbiologia , Metaboloma , Microbiota , Obesidade/genética , Receptores para Leptina/genética , Animais , Feminino , Neoplasias Intestinais/genética , Neoplasias Intestinais/metabolismo , Neoplasias Intestinais/microbiologia , Masculino , Metaboloma/efeitos dos fármacos , Metaboloma/genética , Camundongos , Microbiota/efeitos dos fármacos , Microbiota/genética , Mutação , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/microbiologia , Receptores para Leptina/deficiênciaRESUMO
Individuals with type 2 diabetes mellitus (T2DM) are at increased risk of developing cardiovascular disease (CVD), possibly associated with elevated plasma free fatty acid concentrations. Paradoxically, evidence suggests that unsaturated, compared to saturated fatty acids, suppress macrophage cholesterol efflux, favoring cholesterol accumulation in the artery wall. Murine bone marrow-derived macrophages (BMDM) were used to further explore the relationship between saturated and unsaturated fatty acids, and cholesterol efflux mediated by ATP-binding cassette transporters (ABCA1 and ABCG1) through transcription factors liver-x-receptor-alpha (LXR-α) and sterol receptor element binding protein (SREBP)-1. BMDM isolated from C57BL/6 mice were exposed to 100 µM linoleic acid (18:2) or palmitic acid (16:0) for 16 h, and 25 µg/mL oxidized low density lipoprotein for an additional 24 h. ABCA1 and ABCG1 mRNA expression was suppressed to a greater extent by 18:2 (60 % and 54 %, respectively) than 16:0 (30 % and 29 %, respectively) relative to the control (all p < 0.01). 18:2 decreased ABCA1 protein levels by 94 % and high density lipoprotein (HDL) mediated cholesterol efflux by 53 % (both p < 0.05), and had no significant effect on ABCG1, LXR-α or SREBP-1 protein levels. 16:0 had no effect on ABCA1, ABCG1, LXR-α or SREBP-1 protein expression or HDL-mediated cholesterol efflux. These results suggest that 18:2, relative to 16:0, attenuated macrophage HDL-mediated cholesterol efflux through down regulation of ABCA1 mRNA and protein levels but not through changes in LXR-α or SREBP-1 expression. The effect of 18:2 relative to 16:0 on macrophages cholesterol homeostasis may exacerbate the predisposition of individuals with T2DM to increased CVD risk.
Assuntos
Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Células da Medula Óssea/citologia , Colesterol/metabolismo , Ácido Linoleico/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Relação Estrutura-AtividadeRESUMO
OBJECTIVE: To investigate the role of TNF-like weak inducer of apoptosis (TWEAK) in pathological adipose tissue (AT) remodeling and complications of obesity. METHODS: Wild type (WT) and TWEAK knockout (KO) mice were fed normal diet (ND) or a high fat diet (HFD) for up to 17 weeks. Adipocyte death was induced using an established transgenic mouse model of inducible adipocyte apoptosis (FAT-ATTAC). Metabolic, biochemical, histologic, and flow cytometric analyses were performed. RESULTS: TWEAK and its receptor, fibroblast growth factor-inducible molecule 14 (Fn14) were upregulated in gonadal (g)AT of WT mice after HFD week 4 and 24 h after induction of adipocyte apoptosis. Phenotypes of KO and WT mouse were indistinguishable through HFD week 8. However, at week 17 obese KO mice had â¼30% larger gAT adipocytes and gAT mass than WT mice, coincident with reduced adipocyte death, enhanced insulin signaling, Th2/M2 immune skewing, fewer thick collagen fibers, and altered expression of extracellular matrix constituents and modulators that is consistent with reduced fibrosis and larger adipocytes. KO mice were less steatotic and became more insulin sensitive and glucose tolerant than WT mice after HFD week 12. CONCLUSION: TWEAK constrains "healthy" gAT expansion and promotes metabolic complications in severe obesity.
Assuntos
Tecido Adiposo/metabolismo , Apoptose/fisiologia , Deleção de Genes , Obesidade Mórbida/genética , Obesidade Mórbida/prevenção & controle , Fatores de Necrose Tumoral/genética , Adipócitos/metabolismo , Animais , Citocina TWEAK , Dieta Hiperlipídica , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/metabolismo , Transdução de Sinais , Receptor de TWEAK , Fatores de Necrose Tumoral/metabolismo , Regulação para CimaRESUMO
When humans eat more and exercise less, they tend to become obese and unhealthy. The molecular pathways that link obesity to serious diseases like Type 2 diabetes and cardiovascular disease have become a subject of intensive scientific investigation because the exploding prevalence of obesity worldwide represents a grave new threat to the health of hundreds of millions of people. However, obesity is not always destiny. Two important clinical populations have been valuable to understand the mechanisms behind this conundrum: individuals who exhibit metabolic dysfunction, diabetes and elevated cardiovascular disease risk despite a lean body type, and individuals who are relatively protected from these dangers despite significant obesity. Study of this second group of 'metabolically healthy obese' people in particular has been revealing because such individuals exhibit specific, identifiable, anatomic, cellular and molecular features that set them apart from the rest of us who suffer declining health with increasing weight. Here, we examine some of these features, including some mouse models that are informative of mechanism, and suggest hypotheses for further study, including the possibility that genes and pathways of the immune system might offer new diagnostic or therapeutic targets.
Assuntos
Obesidade/metabolismo , Adipócitos/citologia , Adipócitos/metabolismo , Tecido Adiposo/química , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Exercício Físico , Humanos , Inflamação/etiologia , Inflamação/fisiopatologia , Resistência à Insulina , Síndrome Metabólica/etiologia , Síndrome Metabólica/fisiopatologia , Camundongos , Obesidade/complicaçõesRESUMO
The human gut is densely populated by commensal and symbiotic microbes (the "gut microbiota"), with the majority of the constituent microorganisms being bacteria. Accumulating evidence indicates that the gut microbiota plays a significant role in the development of obesity, obesity-associated inflammation and insulin resistance. In this review we discuss molecular and cell biological mechanisms by which the microbiota participate in host functions that impact the development and maintenance of the obese state, including host ingestive behavior, energy harvest, energy expenditure and fat storage. We additionally explore the diverse signaling pathways that regulate gut permeability and bacterial translocation to the host and how these are altered in the obese state to promote the systemic inflammation ("metabolic endotoxemia") that is a hallmark of obesity and its complications. Fundamental to our discussions is the concept of "crosstalk", i.e., the biochemical exchange between host and microbiota that maintains the metabolic health of the superorganism and whose dysregulation is a hallmark of the obese state. Differences in community composition, functional genes and metabolic activities of the gut microbiota appear to distinguish lean vs obese individuals, suggesting that gut 'dysbiosis' contributes to the development of obesity and/or its complications. The current challenge is to determine the relative importance of obesity-associated compositional and functional changes in the microbiota and to identify the relevant taxa and functional gene modules that promote leanness and metabolic health. As diet appears to play a predominant role in shaping the microbiota and promoting obesity-associated dysbiosis, parallel initiatives are required to elucidate dietary patterns and diet components (e.g., prebiotics, probiotics) that promote healthy gut microbiota. How the microbiota promotes human health and disease is a rich area of investigation that is likely to generate fundamental discoveries in energy metabolism, molecular endocrinology and immunobiology and may lead to new strategies for prevention of obesity and its complications.
Assuntos
Trato Gastrointestinal/microbiologia , Resistência à Insulina , Metagenoma , Obesidade/metabolismo , Animais , Endotoxemia/microbiologia , Endotoxemia/fisiopatologia , Ingestão de Energia , Metabolismo Energético , Trato Gastrointestinal/fisiopatologia , Humanos , Inflamação/microbiologia , Inflamação/fisiopatologia , Camundongos , Obesidade/microbiologia , Obesidade/fisiopatologia , Prebióticos/análise , Probióticos/administração & dosagem , Magreza/metabolismoRESUMO
Obesity is associated with increased risk in hepatocellular carcinoma (HCC) development and mortality. An important disease control strategy is the prevention of obesity-related hepatic inflammation and tumorigenesis by dietary means. Here, we report that apo-10'-lycopenoic acid (APO10LA), a cleavage metabolite of lycopene at its 9',10'-double bond by carotene-9',10'-oxygenase, functions as an effective chemopreventative agent against hepatic tumorigenesis and inflammation. APO10LA treatment on human liver THLE-2 and HuH7 cells dose dependently inhibited cell growth and upregulated sirtuin 1 (SIRT1), a NAD(+)-dependent protein deacetylase that may suppress hepatic carcinogenesis. This observed SIRT1 induction was associated with decreased cyclin D1 protein, increased cyclin-dependent kinase inhibitor p21 protein expression, and induced apoptosis. APO10LA supplementation (10 mg/kg diet) for 24 weeks significantly reduced diethylnitrosamine-initiated, high fat diet (HFD)-promoted hepatic tumorigenesis (50% reduction in tumor multiplicity; 65% in volume) and lung tumor incidence (85% reduction) in C57Bl/6J mice. The chemopreventative effects of APO10LA were associated with increased hepatic SIRT1 protein and deacetylation of SIRT1 targets, as well as with decreased caspase-1 activation and SIRT1 protein cleavage. APO10LA supplementation in diet improved glucose intolerance and reduced hepatic inflammation [decreased inflammatory foci, TNFα, interleukin (IL)-6, NF-κB p65 protein expression, and STAT3 activation] in HFD-fed mice. Furthermore, APO10LA suppressed Akt activation, cyclin D1 gene, and protein expression and promoted PARP protein cleavage in transformed cells within liver tumors. Taken together, these data indicate that APO10LA can effectively inhibit HFD-promoted hepatic tumorigenesis by stimulating SIRT1 signaling while reducing hepatic inflammation.
Assuntos
Carcinoma Hepatocelular/prevenção & controle , Carotenoides/uso terapêutico , Transformação Celular Neoplásica/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Dietilnitrosamina/toxicidade , Ácidos Graxos Insaturados/uso terapêutico , Inflamação/prevenção & controle , Neoplasias Hepáticas/prevenção & controle , Alquilantes/toxicidade , Animais , Apoptose/efeitos dos fármacos , Western Blotting , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Carotenoides/metabolismo , Proliferação de Células/efeitos dos fármacos , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/patologia , Ciclina D1/genética , Ciclina D1/metabolismo , Feminino , Teste de Tolerância a Glucose , Humanos , Inflamação/induzido quimicamente , Inflamação/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/patologia , Licopeno , Camundongos , Camundongos Endogâmicos C57BL , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Menopause promotes central obesity, adipose tissue (AT) inflammation, and insulin resistance (IR). Both obesity and the loss of estrogen can activate innate and adaptive immune cells (macrophages, T cells). The respective impacts of weight gain and loss of ovarian hormones on AT inflammation and IR are poorly understood. Here we determined the temporal kinetics of fat accretion, AT inflammation, and IR over a 26-wk time course in ovariectomized (OVX) mice, a model of menopause. OVX and sham-operated (SHM) C57BL6 mice were fed a normal chow diet. Weight, body composition (magnetic resonance imaging), total and regional adiposity, activity, food intake, AT crown-like structures, biohumoral measures, and insulin sensitivity (insulin tolerance testing and homeostatic model assessment) were determined at wk 12, 20, and 26. Macrophages and T cells from perigonadal AT were immunophenotyped by fluorescence-associated cell sorting, and perigonadal adipose tissue (PGAT) gene expression was quantified by quantitative PCR. OVX mice (≈ 31 g) became fatter than SHM mice (≈ 26 g) by wk 12, but mice were equally insulin sensitive. PGAT of OVX mice contained more T cells but expressed higher levels of M2-MΦ (arginase-1) and T cell-regulatory (cytotoxic T-lymphocyte antigen 4) genes. At wk 20, both OVX and SHM mice weighed approximately 35 g and were equally insulin sensitive with comparable amounts of PGAT and total body fat. OVX mice became less insulin sensitive than SHM mice by wk 26, coincident with the down-regulation of PGAT arginase-1 (-20-fold) and cytotoxic T-lymphocyte antigen 4 (2-fold) and up-regulation of M1/Th1 genes CD11c (+2-fold), IL12p40 (+2-fold), and interferon-γ (+78-fold). Ovarian hormone loss in mice induces PGAT inflammation and IR by mechanisms that can be uncoupled from OVX-induced obesity.
Assuntos
Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Adiposidade/fisiologia , Resistência à Insulina/imunologia , Ovariectomia , Animais , Composição Corporal/fisiologia , Peso Corporal/fisiologia , Feminino , Citometria de Fluxo , Imuno-Histoquímica , Camundongos , Reação em Cadeia da PolimeraseRESUMO
OBJECTIVE: Obesity-associated low-grade systemic inflammation resulting from increased adipose mass is strongly related to the development of insulin resistance and type 2 diabetes as well as other metabolic complications. Recent studies have demonstrated that the obese metabolic state can be improved by ablating certain inflammatory signaling pathways. Tumor progression locus 2 (TPL2), a kinase that integrates signals from Toll receptors, cytokine receptors, and inhibitor of κ-B kinase-ß is an important regulator of inflammatory pathways. We used TPL2 knockout (KO) mice to investigate the role of TPL2 in mediating obesity-associated inflammation and insulin resistance. RESEARCH DESIGN AND METHODS: Male TPL2KO and wild-type (WT) littermates were fed a low-fat diet or a high-fat diet to investigate the effect of TPL2 deletion on obesity, inflammation, and insulin sensitivity. RESULTS: We demonstrate that TPL2 deletion does not alter body weight gain or adipose depot weight. However, hyperinsulinemic euglycemic clamp studies revealed improved insulin sensitivity with enhanced glucose uptake in skeletal muscle and increased suppression of hepatic glucose output in obese TPL2KO mice compared with obese WT mice. Consistent with an improved metabolic phenotype, immune cell infiltration and inflammation was attenuated in the adipose tissue of obese TPL2KO mice coincident with reduced hepatic inflammatory gene expression and lipid accumulation. CONCLUSIONS: Our results provide the first in vivo demonstration that TPL2 ablation attenuates obesity-associated metabolic dysfunction. These data suggest TPL2 is a novel target for improving the metabolic state associated with obesity.
Assuntos
Resistência à Insulina/fisiologia , MAP Quinase Quinase Quinases/metabolismo , Obesidade/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Animais , Western Blotting , Células da Medula Óssea , Células Cultivadas , Gorduras na Dieta/efeitos adversos , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Inflamação/genética , Inflamação/fisiopatologia , Resistência à Insulina/genética , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fígado/metabolismo , Fígado/patologia , MAP Quinase Quinase Quinases/genética , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Obesidade/induzido quimicamente , Obesidade/genética , Proteínas Proto-Oncogênicas/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Triglicerídeos/metabolismoRESUMO
Lipid droplets (LDs) are intracellular organelles that store neutral lipids within cells. Over the last two decades there has been a dramatic growth in our understanding of LD biology and, in parallel, our understanding of the role of LDs in health and disease. In its simplest form, the LD regulates the storage and hydrolysis of neutral lipids, including triacylglycerol and/or cholesterol esters. It is becoming increasingly evident that alterations in the regulation of LD physiology and metabolism influence the risk of developing metabolic diseases such as diabetes. In this review we provide an update on the role of LD-associated proteins and LDs in metabolic disease.
Assuntos
Tecido Adiposo/fisiopatologia , Lipídeos/fisiologia , Doenças Metabólicas/fisiopatologia , Vacúolos/fisiologia , Adipócitos/fisiologia , Adipócitos/ultraestrutura , Animais , Diabetes Mellitus/fisiopatologia , Metabolismo Energético/fisiologia , Ácidos Graxos/efeitos adversos , Ácidos Graxos/metabolismo , Fígado Gorduroso/fisiopatologia , Humanos , Resistência à Insulina , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Lipólise/fisiologia , Camundongos , Camundongos Mutantes , Músculo Esquelético/metabolismo , Hepatopatia Gordurosa não Alcoólica , Obesidade/fisiopatologia , Transdução de Sinais/fisiologia , Triglicerídeos/metabolismoRESUMO
The role of adaptive immunity in obesity-associated adipose tissue (AT) inflammation and insulin resistance (IR) is controversial. We employed flow cytometry and quantitative PCR to assess T-cell recruitment and activation in epididymal AT (eAT) of C57BL/6 mice during 4-22 weeks of a high-fat diet (HFD (60% energy)). By week 6, eAT mass and stromal vascular cell (SVC) number increased threefold in mice fed HFD, coincident with onset of IR. We observed no increase in the proportion of CD3(+) SVCs or in gene expression of CD3, interferon-γ (IFN-γ), or regulated upon activation, normal T-cell expressed and secreted (RANTES) during the first 16 weeks of HFD. In contrast, CD11c(+) macrophages (MΦ) were enriched sixfold by week 8 (P < 0.01). SVC enrichment for T cells (predominantly CD4(+) and CD8(+)) and elevated IFN-γ and RANTES gene expression were detected by 20-22 weeks of HFD (P < 0.01), coincident with the resolution of eAT remodeling. HFD-induced T-cell priming earlier in the obesity time course is suggested by (i) elevated (fivefold) interleukin-12 (IL-12)p40 gene expression in eAT by week 12 (P ≤ 0.01) and (ii) greater IFN-γ secretion from phorbol myristate acetate (PMA)/ionophore-stimulated eAT explants at week 6 (onefold, P = 0.08) and week 12 (fivefold, P < 0.001). In conclusion, T-cell enrichment and IFN-γ gene induction occur subsequent to AT macrophage (ATMΦ) recruitment, onset of IR and resolution of eAT remodeling. However, enhanced priming for IFN-γ production suggests the contribution of CD4(+) and/or CD8(+) effectors to cell-mediated immune responses promoting HFD-induced AT inflammation and IR.