RESUMO
Background: Obesity is associated with insulin resistance (IR) and metabolic dysfunction-associated steatotic liver disease (MASLD). Genistein, an isoflavone, is a promising natural compound for preventing and treating obesity and metabolic dysfunctions. We aimed to investigate the sex-specific protective effects of genistein on obesity, IR, and MASLD in a murine model of sex hormone deprivation with diet-induced obesity (DIO), mimicking postmenopausal women or aging men with metabolic syndrome. Methods: Gonadectomized and sham-operated C57BL/6NJcl mice were fed a high-fat high-sucrose diet for 4 weeks to induce obesity (7 mice per group). In gonadectomized mice, genistein (16 mg/kg/day) or vehicle (7.5% dimethyl sulfoxide) was orally administered for 45 days. We assessed glucose homeostasis parameters, hepatic histopathology, and hepatic gene expression to investigate the effects of gonadectomy and genistein treatment. Results: Gonadectomy exacerbated adiposity in both sexes. Ovariectomy diminished the protective effects of female gonadal hormones on the homeostatic model assessment for insulin resistance (HOMA-IR), serum alanine transaminase levels, hepatic steatosis score, and the expression of hepatic genes associated with MASLD progression and IR, such as Fasn, Srebf1, Saa1, Cd36, Col1a1, Pck1, and Ppargc1a. Genistein treatment in gonadectomized mice significantly reduced body weight gain and the hepatic steatosis score in both sexes. However, genistein treatment significantly attenuated HOMA-IR and the expression of the hepatic genes only in female mice. Conclusion: Genistein treatment mitigates DIO-related MASLD in both male and female gonadectomized mice. Regarding hepatic gene expression associated with MASLD and IR, the beneficial effect of genistein was significantly evident only in female mice. This study suggests a potential alternative application of genistein in individuals with obesity and sex hormone deprivation, yet pending clinical trials.
Assuntos
Dieta Hiperlipídica , Genisteína , Resistência à Insulina , Camundongos Endogâmicos C57BL , Obesidade , Ovariectomia , Animais , Genisteína/farmacologia , Genisteína/uso terapêutico , Masculino , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/metabolismo , Camundongos , Feminino , Dieta Hiperlipídica/efeitos adversos , Ovariectomia/efeitos adversos , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fatores SexuaisRESUMO
Excessive caloric intake and obesity due to high-fat (HFD) and high-disaccharide (HDD) diets have been recognized as major contributing factors to dyslipidemia and metabolic dysfunction-associated steatotic liver disease (MASLD). However, the effect of HFD and HDD without excessive caloric intake is obscure. The aim of the study was to evaluate the effect of physiological caloric intake delivered through HFD and HDD on liver and lipid profiles. The study was performed on 6-week-old male and female (50/50%) Sprague Dawley rats, receiving either a standard (controls, n = 16), HFD (n = 14) or HDD (n = 14) chow. All groups received the same, standard daily calorie rations, titrated weekly to the age of growing rats, for 12 weeks. A panel of metabolic in vivo measurement were performed, followed by histological, biochemical and molecular biology assays on tissues harvested from sacrificed rats. There was no significant difference between the groups in body weight. In contrast to controls, HFD and HDD groups showed metabolic dysfunction-associated steatohepatitis (MASH) characterized by liver steatosis, inflammation, ballooning of hepatocytes and fibrosis. These changes were more pronounced in the HFD than in the HDD group. The HFD group showed significantly higher serum LDL than controls or HDD rats. Furthermore, the HFD group had higher liver protein levels of low-density lipoprotein receptor (LDLR) but lower plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) than the controls or HDD group. There were no differences between sexes in evaluated parameters. The excessive caloric intake and obesity are not prerequisites for the development of MASH and dyslipidemia in rats. The liver changes induced by the HFD and HDD diets exhibit differences in severity, as well as in the expression patterns of LDLR and PCSK9. Notably, these effects are independent of the sex of the rats.
Assuntos
Dieta Hiperlipídica , Dislipidemias , Ingestão de Energia , Obesidade , Ratos Sprague-Dawley , Animais , Dieta Hiperlipídica/efeitos adversos , Masculino , Dislipidemias/etiologia , Dislipidemias/metabolismo , Feminino , Ratos , Obesidade/metabolismo , Obesidade/etiologia , Fígado/metabolismo , Fígado/patologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Pró-Proteína Convertase 9/metabolismoRESUMO
BACKGROUND: Obesity is a global epidemic, and the low-grade chronic inflammation of adipose tissue in obese individuals can lead to insulin resistance and type 2 diabetes. Adipose tissue macrophages (ATMs) are the main source of pro-inflammatory cytokines in adipose tissue, making them an important target for therapy. While branched-chain amino acids (BCAA) have been strongly linked to obesity and type 2 diabetes in humans, the relationship between BCAA catabolism and adipose tissue inflammation is unclear. This study aims to investigate whether disrupted BCAA catabolism influences the function of adipose tissue macrophages and the secretion of pro-inflammatory cytokines in adipose tissue, and to determine the underlying mechanism. This research will help us better understand the role of BCAA catabolism in adipose tissue inflammation, obesity, and type 2 diabetes. METHODS: In vivo, we examined whether the BCAA catabolism in ATMs was altered in high-fat diet-induced obesity mice, and if BCAA supplementation would influence obesity, glucose tolerance, insulin sensitivity, adipose tissue inflammation and ATMs polarization in mice. In vitro, we isolated ATMs from standard chow and high BCAA-fed group mice, using RNA-sequencing to investigate the potential molecular pathway regulated by BCAA accumulation. Finally, we performed targeted gene silence experiment and used immunoblotting assays to verify our findings. RESULTS: We found that BCAA catabolic enzymes in ATMs were influenced by high-fat diet induced obesity mice, which caused the accumulation of both BCAA and its downstream BCKA. BCAA supplementation will cause obesity and insulin resistance compared to standard chow (STC) group. And high BCAA diet will induce pro-inflammatory cytokines including Interlukin-1beta (IL-1ß), Tumor Necrosis Factor alpha (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) secretion in adipose tissue as well as promoting ATMs M1 polarization (pro-inflammatory phenotype). Transcriptomic analysis revealed that a high BCAA diet would activate IFNGR1/JAK1/STAT1 pathway, and IFNGR1 specific silence can abolish the effect of BCAA supplementation-induced inflammation and ATMs M1 polarization. CONCLUSIONS: The obesity mice model reveals the catabolism of BCAA was disrupted which will cause the accumulation of BCAA, and high-level BCAA will promote ATMs M1 polarization and increase the pro-inflammatory cytokines in adipose tissue which will cause the insulin resistance in further. Therefore, reducing the circulating level of BCAA can be a therapeutic strategy in obesity and insulin resistance patients.
Assuntos
Aminoácidos de Cadeia Ramificada , Resistência à Insulina , Macrófagos , Obesidade , Fator de Transcrição STAT1 , Transdução de Sinais , Animais , Aminoácidos de Cadeia Ramificada/metabolismo , Aminoácidos de Cadeia Ramificada/administração & dosagem , Macrófagos/metabolismo , Camundongos , Masculino , Obesidade/metabolismo , Obesidade/etiologia , Fator de Transcrição STAT1/metabolismo , Janus Quinase 1/metabolismo , Dieta Hiperlipídica/efeitos adversos , Tecido Adiposo/metabolismo , Citocinas/metabolismo , Suplementos Nutricionais , Inflamação/metabolismo , Modelos Animais de DoençasRESUMO
Diet-induced obesity is associated with enhanced systemic inflammation that limits bone regeneration. HDAC inhibitors are currently being explored as anti-inflammatory agents. Prior reports show that myeloid progenitor-directed Hdac3 ablation enhances intramembranous bone healing in female mice. In this study, we determined if Hdac3 ablation increased intramembranous bone regeneration in mice fed a high-fat/high-sugar (HFD) diet. Micro-CT analyses demonstrated that HFD-feeding enhanced the formation of periosteal reaction tissue of control littermates, reflective of suboptimal bone healing. We confirmed enhanced bone volume within the defect of Hdac3-ablated females and showed that Hdac3 ablation reduced the amount of periosteal reaction tissue following HFD feeding. Osteoblasts cultured in a conditioned medium derived from Hdac3-ablated cells exhibited a four-fold increase in mineralization and enhanced osteogenic gene expression. We found that Hdac3 ablation elevated the secretion of several chemokines, including CCL2. We then confirmed that Hdac3 deficiency increased the expression of Ccl2. Lastly, we show that the proportion of CCL2-positve cells within bone defects was significantly higher in Hdac3-deficient mice and was further enhanced by HFD. Overall, our studies demonstrate that Hdac3 deletion enhances intramembranous bone healing in a setting of diet-induced obesity, possibly through increased production of CCL2 by macrophages within the defect.
Assuntos
Dieta Ocidental , Histona Desacetilases , Osteogênese , Animais , Feminino , Histona Desacetilases/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/deficiência , Camundongos , Dieta Ocidental/efeitos adversos , Osteoblastos/metabolismo , Dieta Hiperlipídica/efeitos adversos , Periósteo/metabolismo , Periósteo/patologia , Quimiocina CCL2/metabolismo , Quimiocina CCL2/genética , Regeneração Óssea , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo , Obesidade/etiologia , Obesidade/patologiaRESUMO
This study investigated the effects of ascochlorin (ASC), a natural compound derived from the fungus Ascochyta viciae, on adipogenesis and obesity. We determined the effects of ASC on 3T3-L1 preadipocytes and whether it ameliorated to mitigate high-fat diet (HFD)-induced obesity in C57BL/6J mice. We found that ASC significantly inhibited the differentiation of preadipocytes by modulating the Wnt/ß-catenin signaling pathway, a key regulator of adipogenic processes. Treatment with ASC not only reduced the mRNA and protein expression of key adipogenic transcription factors such as C/EBPα and PPARγ, but also reduced lipid accumulation both in vitro and in vivo. In addition, treatment HFD-fed mice with ASC significantly reduced their weight gain and adiposity vs. control mice. These results suggest that ASC has considerable potential as a therapeutic agent for obesity, owing to its dual action of inhibiting adipocyte differentiation and reducing lipid accumulation. Thus, ASC represents a promising candidate as a natural anti-obesity agent.
Assuntos
Adipócitos , Adipogenia , Dieta Hiperlipídica , Obesidade , Via de Sinalização Wnt , Animais , Masculino , Camundongos , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Alcenos , Fármacos Antiobesidade/farmacologia , beta Catenina/metabolismo , Diferenciação Celular/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/etiologia , Fenóis/farmacologia , PPAR gama/metabolismo , PPAR gama/genética , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
Seasonal rhythms are gaining attention given their impact on metabolic disorders development such as obesity gut microbiota is emerging as a key factor in mediating this link. However, the underlying mechanisms are still poorly understood. In this regard, corticosterone may play a role as it has been shown to be affected by gut bacteria and seasonal rhythms, and has been linked to obesity. Thus, this study aimed to investigate if seasonal rhythms effects on corticosterone are influenced by gut microbiota in obese rats and whether this may be related to seasonal and clock genes expression in the pituitary gland and colon. Fischer 344 male rats fed with cafeteria diet (CAF) were housed under different photoperiods for 9 weeks and treated with an antibiotic cocktail (ABX) in drinking water during the last 4 weeks. Rats fed with standard chow and CAF-fed rats without ABX were included as controls. ABX altered gut microbiota, corticosterone levels and seasonal clock expression in the pituitary depending on photoperiod conditions. These results suggest a link between gut bacteria, seasonal rhythms and corticosterone and a novel nutrigenomic target for obesity.
Assuntos
Corticosterona , Microbioma Gastrointestinal , Obesidade , Fotoperíodo , Ratos Endogâmicos F344 , Estações do Ano , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Corticosterona/sangue , Corticosterona/metabolismo , Obesidade/metabolismo , Obesidade/microbiologia , Obesidade/etiologia , Masculino , Ratos , Hipófise/metabolismo , Colo/metabolismo , Colo/microbiologiaRESUMO
Endoplasmic reticulum (ER) homeostasis in the hypothalamus has been implicated in the pathogenesis of diet-induced obesity (DIO) and type 2 diabetes; however, the underlying molecular mechanism remain vague and debatable. Here we report that SEL1L-HRD1 protein complex of the highly conserved ER-associated protein degradation (ERAD) machinery in POMC-expressing neurons ameliorates diet-induced obesity and its associated complications, partly by regulating the turnover of the long isoform of Leptin receptors (LepRb). Loss of SEL1L in POMC-expressing neurons attenuates leptin signaling and predisposes mice to HFD-associated pathologies including fatty liver, glucose intolerance, insulin and leptin resistance. Mechanistically, nascent LepRb, both wildtype and disease-associated Cys604Ser variant, are misfolding prone and bona fide substrates of SEL1L-HRD1 ERAD. In the absence of SEL1L-HRD1 ERAD, LepRb are largely retained in the ER, in an ER stress-independent manner. This study uncovers an important role of SEL1L-HRD1 ERAD in the pathogenesis of central leptin resistance and leptin signaling.
Assuntos
Dieta Hiperlipídica , Degradação Associada com o Retículo Endoplasmático , Retículo Endoplasmático , Leptina , Neurônios , Obesidade , Pró-Opiomelanocortina , Receptores para Leptina , Transdução de Sinais , Ubiquitina-Proteína Ligases , Animais , Obesidade/metabolismo , Obesidade/genética , Obesidade/etiologia , Obesidade/patologia , Neurônios/metabolismo , Leptina/metabolismo , Receptores para Leptina/metabolismo , Receptores para Leptina/genética , Camundongos , Pró-Opiomelanocortina/metabolismo , Pró-Opiomelanocortina/genética , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Dieta Hiperlipídica/efeitos adversos , Masculino , Retículo Endoplasmático/metabolismo , Hipotálamo/metabolismo , Estresse do Retículo Endoplasmático , Camundongos Endogâmicos C57BL , Proteínas/metabolismo , Proteínas/genética , Camundongos Knockout , Humanos , Peptídeos e Proteínas de Sinalização IntracelularRESUMO
INTRODUCTION: Rapid growth in early childhood has been identified as a possible risk factor for long-term adiposity. However, there is a lack of studies quantifying this phenomenon only in healthy, full-term infants with appropriate birth weight for gestational age. This systematic review and meta-analysis aimed to investigate the association of rapid growth in full-term children up to 2 years of age with adiposity up to 18 years of age. METHODOLOGY: A systematic review of the literature was conducted in PubMed, EMBASE, and Web of Science. RESULTS: 14 studies were included. We were unable to find strong evidence that rapid growth in early childhood is a risk factor for long-term adiposity. Rapid growth in early childhood was associated with taller heights (standardized mean difference: 0.51 (CI: 0.25-0.77)) and higher body mass index (standardized mean difference: 0.50 (CI: 0.25-0.76)) and a higher risk of overweight under 18 years. CONCLUSION: Rapid growth in early childhood in term infants with appropriate birth weight is associated with higher growth, body mass index, and risk of being overweight up to age 18, but further work is needed to identify the associations between early rapid growth and obesity later in adulthood.
Assuntos
Peso ao Nascer , Desenvolvimento Infantil , Humanos , Recém-Nascido , Lactente , Pré-Escolar , Desenvolvimento Infantil/fisiologia , Fatores de Risco , Índice de Massa Corporal , Criança , Obesidade Infantil/etiologia , Obesidade Infantil/epidemiologia , Adiposidade , Feminino , Masculino , Obesidade/etiologia , Nascimento a Termo , AdolescenteRESUMO
More than two-thirds of women during childbearing years (20-39 years old) are overweight or obese in the United States, with protein intake among 20-49-year-old women being 1.6 times higher than recommended (75.4 g/day versus 46 g/day) that can be considered as a relatively high-protein diet (HPD). Both gestational obesity and HPDs during gestation adversely affect offspring health. This study investigates the impact of HPDs fed during gestation and lactation on obese mothers and their offspring in Wistar rats. Dams randomized to either a normal-protein diet (NPD) or HPD (n = 12/group). Pups from each maternal group were weaned to either NPD or HPD for 17 weeks (n = 12/group). No effect of maternal or weaning diet on food intake, body weight, or body fat/weight ratio was observed. However, NPD dams exhibited higher glucose area under the curve compared with HPD dams (p < 0.03). At weaning, offspring born to NPD dams showed higher fasting plasma glucose (P < 0.03) and insulin/glucose ratio (P = 0.05) than those born to HPD dams. The Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index was higher in offspring born to NPD dams (P < 0.04) and weaned to NPD (P < 0.05) at week 17. These findings underscore the role of high-protein maternal and weaning diets in pregnancy outcomes for obese mothers, particularly in glucose homeostasis, although gestational obesity may overshadow other parameters. Further research is needed to fully understand the impact on both maternal and offspring health and their underlying mechanisms in this context.
Assuntos
Dieta Rica em Proteínas , Ratos Wistar , Animais , Feminino , Gravidez , Ratos , Masculino , Dieta Rica em Proteínas/efeitos adversos , Dieta Rica em Proteínas/métodos , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/etiologia , Peso Corporal , Fenômenos Fisiológicos da Nutrição Materna , Ingestão de Alimentos/fisiologia , Obesidade/metabolismo , Obesidade/etiologia , Obesidade Materna/metabolismo , Composição Corporal , Proteínas Alimentares/administração & dosagem , Glucose/metabolismo , Glicemia/metabolismo , Glicemia/análiseRESUMO
Early life stress (ELS) and a Western diet (WD) promote mood and cardiovascular disorders, however, how these risks interact in disease pathogenesis is unclear. We assessed effects of ELS with or without a subsequent WD on behaviour, cardiometabolic risk factors, and cardiac function/ischaemic tolerance in male mice. Fifty-six new-born male C57BL/6J mice were randomly allocated to a control group (CON) undisturbed before weaning, or to maternal separation (3h/day) and early (postnatal day 17) weaning (MSEW). Mice consumed standard rodent chow (CON, n = 14; MSEW, n = 15) or WD chow (WD, n = 19; MSEW + WD, n = 19) from week 8 to 24. Fasted blood was sampled and open field test and elevated plus maze (EPM) tests undertaken at 7, 15, and 23 weeks of age, with hearts excised at 24 weeks for Langendorff perfusion (evaluating pre- and post-ischaemic function). MSEW alone transiently increased open field activity at 7 weeks; body weight and serum triglycerides at 4 and 7 weeks, respectively; and final blood glucose levels and insulin resistance at 23 weeks. WD increased insulin resistance and body weight gain, the latter potentiated by MSEW. MSEW + WD was anxiogenic, reducing EPM open arm activity vs. WD alone. Although MSEW had modest metabolic effects and did not influence cardiac function or ischaemic tolerance in lean mice, it exacerbated weight gain and anxiogenesis, and improved ischaemic tolerance in WD fed animals. MSEW-induced increases in body weight (obesity) in WD fed animals in the absence of changes in insulin resistance may have protected the hearts of these mice.
Assuntos
Ansiedade , Dieta Ocidental , Camundongos Endogâmicos C57BL , Obesidade , Estresse Psicológico , Animais , Masculino , Camundongos , Dieta Ocidental/efeitos adversos , Obesidade/etiologia , Estresse Psicológico/complicações , Estresse Psicológico/fisiopatologia , Ansiedade/etiologia , Resistência à Insulina , Isquemia Miocárdica/etiologia , Privação MaternaRESUMO
AIMS: Obesity is a global public health issue, and some studies have linked it to an increased risk of prostatic diseases. This study aimed to evaluate the effects of a high-fat diet on metabolic parameters and prostate morphology in wild-type (WT) and adiponectin knockout (KO) mice. MAIN METHODS: Male WT and KO mice were fed a control diet (CD) or high-fat diet (HFD) for 6 months. Serum metabolic parameters, inflammatory cytokines in epididymal fat tissue, dorsal prostatic lobe morphometry and histopathology were analyzed. KEY FINDINGS: CD WT and CD KO mice did not exhibit altered metabolic or prostatic parameters. However, HFD WT mice showed altered glucose and insulin tolerance even without excessive weight gain. On the other hand, HFD KO mice developed obesity, with an increase in low-density lipoprotein (11.8 ± 5.1 vs. 31.4 ± 3.6 mg/dL), high-density lipoprotein (73.4 ± 7.4 vs. 103.4 ± 2.5 mg/dL), and total cholesterol levels (126.2 ± 16.1 vs. 294.6 ± 23.2 mg/dL), a decrease in insulin levels (28.7 ± 12.2 vs. 4.6 ± 2.3 µIU/mL), and glucose and insulin resistance. We also observed that HFD KO animals display an increase in inflammatory cytokines, such as IL6, IL1ß, and IL1RA. The dorsal prostate from HFD KO animals also presented significant increases in the mast cells (1.9 ± 0,7 vs. 5,3 ± 1.5 cells/field) and Ki67 index (2.91 ± 0.6 vs. 4.7 ± 0.4 %). SIGNIFICANCE: The above findings highlight the complex interactions between adiponectin, metabolism, malnutrition, and prostate health. Metabolic deregulation combined with adipose inflammation potentially induces a proliferative and inflammatory microenvironment in the prostate gland under conditions of low adiponectin production, potentially impairing prostate morphophysiology in the context of obesity and aging.
Assuntos
Adiponectina , Citocinas , Dieta Hiperlipídica , Camundongos Knockout , Obesidade , Próstata , Animais , Masculino , Dieta Hiperlipídica/efeitos adversos , Adiponectina/metabolismo , Adiponectina/sangue , Camundongos , Citocinas/metabolismo , Próstata/patologia , Próstata/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Obesidade/etiologia , Camundongos Endogâmicos C57BL , Resistência à Insulina , Inflamação/metabolismo , Inflamação/patologiaRESUMO
Obesity, a complex condition that involves genetic, environmental, and behavioral factors, is a non-infectious pandemic that affects over 650 million adults worldwide with a rapidly growing prevalence. A major contributor is the consumption of high-fat diets, an increasingly common feature of modern diets. Maternal obesity results in an increased risk of offspring developing obesity and related health problems; however, the impact of maternal diet on the adipose tissue composition of offspring has not been evaluated. Here, we designed a generational diet-induced obesity study in female C57BL/6 mice that included maternal cohorts and their female offspring fed either a control diet (10% fat) or a high-fat diet (45% fat) and examined the visceral adipose proteome. Solubilizing proteins from adipose tissue is challenging due to the need for high concentrations of detergents; however, the use of a detergent-compatible sample preparation strategy based on suspension trapping (S-Trap) enabled label-free quantitative bottom-up analysis of the adipose proteome. We identified differentially expressed proteins related to lipid metabolism, inflammatory disease, immune response, and cancer, providing valuable molecular-level insight into how maternal obesity impacts the health of offspring. Data are available via ProteomeXchange with the identifier PXD042092.
Assuntos
Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Obesidade , Proteoma , Animais , Feminino , Dieta Hiperlipídica/efeitos adversos , Obesidade/metabolismo , Obesidade/etiologia , Camundongos , Gravidez , Omento/metabolismo , Obesidade Materna/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Tecido Adiposo/metabolismo , Metabolismo dos Lipídeos , Proteômica/métodos , Gordura Intra-Abdominal/metabolismoRESUMO
Angiotensin converting enzyme 2 (ACE2) presents pleiotropic actions. It hydrolyzes angiotensin I (AngI) and angiotensin II (AngII) into angiotensin-(1-9) (Ang-(1-9)) and angiotensin-(1-7) (Ang-(1-7)), respectively, as well as participates in tryptophan uptake in the gut and in COVID-19 infection. Our aim was to investigate the metabolic effect of ACE2 deletion in young adults and elderly mice under conditions of high calorie intake. Male C57Bl/6 (WT) and ACE2-deficient (ACE2-/y) mice were analyzed at the age of 6 and 12 months under standard diet (StD) and high-fat diet (HFD). Under StD, ACE2-/y showed lower body weight and fat depots, improved glucose tolerance, enhanced insulin sensitivity, higher adiponectin, and lower leptin levels compared to WT. This difference was even more pronounced after HFD in 6-month-old mice, but, interestingly, it was blunted at the age of 12 months. ACE2-/y presented a decrease in adipocyte diameter and lipolysis, which reflected in the upregulation of lipid metabolism in white adipose tissue through the increased expression of genes involved in lipid regulation. Under HFD, both food intake and total energy expenditure were decreased in 6-month-old ACE2-/y mice, accompanied by an increase in liquid intake, compared to WT mice, fed either StD or HFD. Thus, ACE2-/y mice are less susceptible to HFD-induced obesity in an age-dependent manner, as well as represent an excellent animal model of human lipodystrophy and a tool to investigate new treatments.
Assuntos
Enzima de Conversão de Angiotensina 2 , Dieta Hiperlipídica , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade , Animais , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/genética , Dieta Hiperlipídica/efeitos adversos , Obesidade/metabolismo , Obesidade/etiologia , Obesidade/genética , Obesidade/patologia , Masculino , Camundongos , Resistência à Insulina , Metabolismo dos Lipídeos , Envelhecimento/metabolismo , COVID-19/metabolismo , COVID-19/genética , Leptina/metabolismo , Fatores Etários , Peso CorporalRESUMO
The biological clocks of the circadian timing system coordinate cellular and physiological processes and synchronize them with daily cycles. While the central clock in the suprachiasmatic nucleus (SCN) is mainly synchronized by the light/dark cycles, the peripheral clocks react to other stimuli, including the feeding/fasting state, nutrients, sleep-wake cycles, and physical activity. During the disruption of circadian rhythms due to genetic mutations or social and occupational obligations, incorrect arrangement between the internal clock system and environmental rhythms leads to the development of obesity. Desynchronization between the central and peripheral clocks by altered timing of food intake and diet composition leads to uncoupling of the peripheral clocks from the central pacemaker and to the development of metabolic disorders. The strong coupling of the SCN to the light-dark cycle creates a situation of misalignment when food is ingested during the "wrong" time of day. Food-anticipatory activity is mediated by a self-sustained circadian timing, and its principal component is a food-entrainable oscillator. Modifying the time of feeding alone greatly affects body weight, whereas ketogenic diet (KD) influences circadian biology, through the modulation of clock gene expression. Night-eating behavior is one of the causes of circadian disruption, and night eaters have compulsive and uncontrolled eating with severe obesity. By contrast, time-restricted eating (TRE) restores circadian rhythms through maintaining an appropriate daily rhythm of the eating-fasting cycle. The hypothalamus has a crucial role in the regulation of energy balance rather than food intake. While circadian locomotor output cycles kaput (CLOCK) expression levels increase with high-fat diet-induced obesity, peroxisome proliferator-activated receptor-alpha (PPARα) increases the transcriptional level of brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1 (BMAL1) in obese subjects. In this context, effective timing of chronotherapies aiming to correct SCN-driven rhythms depends on an accurate assessment of the SCN phase. In fact, in a multi-oscillator system, local rhythmicity and its disruption reflects the disruption of either local clocks or central clocks, thus imposing rhythmicity on those local tissues, whereas misalignment of peripheral oscillators is due to exosome-based intercellular communication.Consequently, disruption of clock genes results in dyslipidemia, insulin resistance, and obesity, while light exposure during the daytime, food intake during the daytime, and sleeping during the biological night promote circadian alignment between the central and peripheral clocks. Thus, shift work is associated with an increased risk of obesity, diabetes, and cardiovascular diseases because of unusual eating times as well as unusual light exposure and disruption of the circadian rhythm.
Assuntos
Ritmo Circadiano , Comportamento Alimentar , Obesidade , Obesidade/fisiopatologia , Obesidade/metabolismo , Obesidade/etiologia , Ritmo Circadiano/fisiologia , Humanos , Animais , Comportamento Alimentar/fisiologia , Núcleo Supraquiasmático/metabolismo , Núcleo Supraquiasmático/fisiologia , Núcleo Supraquiasmático/fisiopatologia , Dieta Cetogênica/efeitos adversos , Relógios Circadianos/fisiologia , Relógios Circadianos/genéticaRESUMO
Obesity represents a global health concern, affecting individuals of all age groups across the world. The prevalence of excess weight and obesity has escalated to pandemic proportions, leading to a substantial increase in the incidence of various comorbidities, such as cardiovascular diseases, type 2 diabetes, and cancer. This chapter seeks to provide a comprehensive exploration of the pathways through which endocrine-disrupting chemicals can influence the pathophysiology of obesity. These mechanisms encompass aspects such as the regulation of food intake and appetite, intestinal fat absorption, lipid metabolism, and the modulation of inflammation. This knowledge may help to elucidate the role of exogenous molecules in both the aetiology and progression of obesity.
Assuntos
Disruptores Endócrinos , Obesidade , Humanos , Disruptores Endócrinos/efeitos adversos , Disruptores Endócrinos/toxicidade , Obesidade/induzido quimicamente , Obesidade/fisiopatologia , Obesidade/metabolismo , Obesidade/etiologia , Animais , Metabolismo dos Lipídeos/efeitos dos fármacos , Inflamação/induzido quimicamente , Transdução de Sinais/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Regulação do Apetite/efeitos dos fármacosRESUMO
BACKGROUND: While intermittent fasting leads to weight loss and improved glucose metabolism, food insecurity, the insufficient access to food for a healthy life, is associated with obesity and adverse cardiometabolic health, especially in women. We aimed to characterize the effects of intermittently restricted feeding on energy balance and glucose tolerance in female mice. METHODS: Female C57BL/6J mice were fed a high-fat, high-sucrose diet and intermittently food restricted to 60% of control littermates' ad libitum intake, starting at weaning and until week 19. Restricted mice were subsequently allowed ad libitum access to the same diet. Body composition and energy balance were measured at weeks 18.5, 19, 30, and 40. At week 42, mice underwent an intraperitoneal glucose tolerance test and plasma appetitive hormones measurements after nutrient gavage. RESULTS: During the food restriction phase, restricted mice accrued lower weight and fat mass than controls despite periodic ad libitum food access. Reintroduction of continuous ad libitum food caused increased food intake during the light phase and increased body mass in restricted mice. Minor differences in body composition-adjusted energy expenditure between groups were observed at week 40. At week 42, glucose tolerance was impaired in restricted mice compared to controls, and trends toward lower levels of postprandial anorexigenic hormones glucagon-like peptide-1 and pancreatic polypeptide were observed. CONCLUSION: Our findings suggest that repeated intermittent food restriction leads to changes in eating behavior that predispose to glucose intolerance when food is freely available. Future studies are needed to elucidate the specific mechanisms underlying these changes.
Assuntos
Composição Corporal , Dieta Hiperlipídica , Metabolismo Energético , Camundongos Endogâmicos C57BL , Animais , Feminino , Dieta Hiperlipídica/efeitos adversos , Camundongos , Teste de Tolerância a Glucose , Intolerância à Glucose/etiologia , Intolerância à Glucose/metabolismo , Sacarose Alimentar/administração & dosagem , Restrição Calórica , Obesidade/metabolismo , Obesidade/etiologiaRESUMO
We investigated the effects of a single and simultaneous intake of allitol and d-allulose on body fat accumulation and cecal short-chain fatty acid (SCFA) production and accurately assessed the contribution of rare sugars to body fat in rats fed a high-fat diet that led to obesity. Thirty-two male 3-week-old Wistar rats were randomly divided into four groups: control, allitol, d-allulose, and allitol + d-allulose. The rats were fed experimental diets and water ad libitum for 11 weeks. High doses of allitol or d-allulose can induce diarrhea in rat; hence, each group of rats was acclimated to 1-5% allitol and d-allulose incrementally for the initial 20 days. After the feeding period, all rats were euthanized and collected tissues. Perirenal, mesenteric, and total intra-abdominal adipose tissue weights were significantly reduced by dietary d-allulose, whereas dietary allitol tended to decrease these adipose tissue weights. Both allitol and d-allulose significantly decreased carcass and total body fat mass. We confirmed that both dietary allitol and d-allulose inhibited body fat accumulation; however, d-allulose did not inhibit hepatic lipogenesis and no synergy was observed between dietary allitol and d-allulose in terms of anti-obesity effects. Dietary allitol significantly increased cecal SCFA levels and these effects were more potent than those of dietary d-allulose. The antiobesity effect of allitol may be due to the action of SCFAs, especially butyric acid, produced by the gut microbiota. Many of the effects of allitol as an alternative sweetener remain unknown, and further research is required.
Assuntos
Tecido Adiposo , Ceco , Dieta Hiperlipídica , Ácidos Graxos Voláteis , Frutose , Ratos Wistar , Álcoois Açúcares , Animais , Masculino , Ceco/metabolismo , Ceco/efeitos dos fármacos , Ácidos Graxos Voláteis/metabolismo , Dieta Hiperlipídica/efeitos adversos , Frutose/administração & dosagem , Álcoois Açúcares/farmacologia , Álcoois Açúcares/administração & dosagem , Tecido Adiposo/metabolismo , Tecido Adiposo/efeitos dos fármacos , Obesidade/metabolismo , Obesidade/etiologia , Ratos , Lipogênese/efeitos dos fármacosRESUMO
The skeleton has been suggested to function as an endocrine organ controlling whole organism energy balance, however the mediators of this effect and their molecular links remain unclear. Here, utilizing Schnurri-3-/- (Shn3-/-) mice with augmented osteoblast activity, we show Shn3-/-mice display resistance against diet-induced obesity and enhanced white adipose tissue (WAT) browning. Conditional deletion of Shn3 in osteoblasts but not adipocytes recapitulates lean phenotype of Shn3-/-mice, indicating this phenotype is driven by skeleton. We further demonstrate osteoblasts lacking Shn3 can secrete cytokines to promote WAT browning. Among them, we identify a C-terminal fragment of SLIT2 (SLIT2-C), primarily secreted by osteoblasts, as a Shn3-regulated osteokine that mediates WAT browning. Lastly, AAV-mediated Shn3 silencing phenocopies the lean phenotype and augmented glucose metabolism. Altogether, our findings establish a novel bone-fat signaling axis via SHN3 regulated SLIT2-C production in osteoblasts, offering a potential therapeutic target to address both osteoporosis and metabolic syndrome.
Assuntos
Tecido Adiposo Branco , Osso e Ossos , Dieta Hiperlipídica , Peptídeos e Proteínas de Sinalização Intercelular , Camundongos Knockout , Obesidade , Osteoblastos , Animais , Masculino , Camundongos , Adipócitos/metabolismo , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/metabolismo , Osso e Ossos/metabolismo , Dieta Hiperlipídica/efeitos adversos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Obesidade/metabolismo , Obesidade/genética , Obesidade/etiologia , Osteoblastos/metabolismo , Transdução de Sinais , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismoRESUMO
OBJECTIVES: The obesity prevalence in South Korea in 2021 stood at 38.4%. South Korea faces unique challenges in providing essential and emergency guidelines for weight management because of stepping into an aging society. We aimed to determine the daily diet patterns among the general Korean population and to investigate the association between such patterns and different obesity. STUDY DESIGN: Longitudinal prospective cohort study. METHODS: A total of 6539 adult participants (mean age 50.8 years, 52.9% male) with normal-weight adults were included from the Ansan-Ansung cohort of 10,030 Korean adults aged 40 or older and followed for an average of 11 years. Obesity was defined according to the criteria from the Korean Society for The Study of Obesity. Baseline dietary intake was assessed using a validated 103-item food frequency questionnaire. Dietary patterns were derived from k-means cluster analysis. RESULTS: In the multivariate analysis, referring to white rice + baechu kimchi, participants from multigrain rice + baechu kimchi showed lower HR for obesity development (waist circumference defined-obesity; HR: 0.87, 95% CI: 0.79, 0.95; body fat percentage defined-obesity; HR: 0.89, 95% CI: 0.80, 0.98). Further analysis documented that except for body fat percentage defined-obesity, consuming milk or dairy products was linked to a reduced incidence of the other three obesity (body mass index defined-obesity; HR: 0.84, 95% CI: 0.72, 0.99; waist circumference defined-obesity; HR: 0.82, 95% CI: 0.71, 0.94; waist-to-hip ratio defined-obesity; HR: 0.75, 95% CI: 0.61, 0.91). CONCLUSIONS: Following a diet that includes multigrain rice, fermented baechu kimchi, and dairy products is linked to a decreased risk of obesity in Korean adults. Public health programs and policies could incorporate these dietary recommendations, targeting specific population groups such as schoolchildren, adults, and the elderly. Additionally, further research is needed to explore the synergistic effects of various foods and their interactions within dietary patterns on obesity outcomes.
Assuntos
Padrões Dietéticos , Obesidade , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Longitudinais , Obesidade/epidemiologia , Obesidade/etiologia , Obesidade/prevenção & controle , Estudos Prospectivos , República da Coreia/epidemiologiaRESUMO
Obesity poses a public health threat, reaching epidemic proportions. Our hypothesis suggests that some of this epidemic stems from its transmission across generations via paternal epigenetic mechanisms. To investigate this possibility, we focused on examining the paternal transmission of CpG methylation. First-generation male Wistar rats were fed either a high-fat diet (HF) or chow and were mated with females fed chow. We collected sperm from these males. The resulting offspring were raised on a chow diet until day 35, after which they underwent a dietary challenge. Diet-induced obese (DIO) male rats passed on the obesogenic trait to both male and female offspring. We observed significant hypermethylation of the Pomc promoter in the sperm of HF-treated males and in the hypothalamic arcuate nucleus (Arc) of their offspring at weaning. However, these differences in Arc methylation decreased later in life. This hypermethylation is correlated with increased expression of DNMT3B. Further investigating genes in the Arc that might be involved in obesogenic transgenerational transmission, using reduced representation bisulfite sequencing (RRBS) we identified 77 differentially methylated regions (DMRs), highlighting pathways associated with neuronal development. These findings support paternal CpG methylation as a mechanism for transmitting obesogenic traits across generations.