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BACKGROUND: Mitochondrial dysfunction occurs in monocytes during obesity and contributes to a low-grade inflammatory state; therefore, maintaining good mitochondrial conditions is a key aspect of maintaining health. Dietary interventions are primary strategies for treating obesity, but little is known about their impact on monocyte bioenergetics. Thus, the aim of this study was to evaluate the effects of calorie restriction (CR), intermittent fasting (IF), a ketogenic diet (KD), and an ad libitum habitual diet (AL) on mitochondrial function in monocytes and its modulation by the gut microbiota. METHODS AND FINDINGS: A randomized controlled clinical trial was conducted in which individuals with obesity were assigned to one of the 4 groups for 1 month. Subsequently, the subjects received rifaximin and continued with the assigned diet for another month. The oxygen consumption rate (OCR) was evaluated in isolated monocytes, as was the gut microbiota composition in feces and anthropometric and biochemical parameters. Forty-four subjects completed the study, and those who underwent CR, IF and KD interventions had an increase in the maximal respiration OCR (p = 0.025, n2p = 0.159 [0.05, 0.27] 95% confidence interval) in monocytes compared to that in the AL group. The improvement in mitochondrial function was associated with a decrease in monocyte dependence on glycolysis after the IF and KD interventions. Together, diet and rifaximin increased the gut microbiota diversity in the IF and KD groups (p = 0.0001), enriched the abundance of Phascolarctobacterium faecium (p = 0.019) in the CR group and Ruminococcus bromii (p = 0.020) in the CR and KD groups, and reduced the abundance of lipopolysaccharide (LPS)-producing bacteria after CR, IF and KD interventions compared to the AL group at the end of the study according to ANCOVA with covariate adjustment. Spearman's correlation between the variables measured highlighted LPS as a potential modulator of the observed effects. In line with this findings, serum LPS and intracellular signaling in monocytes decreased with the three interventions (CR, p = 0.002; IF, p = 0.001; and KD, p = 0.001) compared to those in the AL group at the end of the study. CONCLUSIONS: We conclude that these dietary interventions positively regulate mitochondrial bioenergetic health and improve the metabolic profile of monocytes in individuals with obesity via modulation of the gut microbiota. Moreover, the evaluation of mitochondrial function in monocytes could be used as an indicator of metabolic and inflammatory status, with potential applications in future clinical trials. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov (NCT05200468).
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Restricción Calórica , Dieta Cetogénica , Microbioma Gastrointestinal , Mitocondrias , Monocitos , Obesidad , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Restricción Calórica/métodos , Dieta Cetogénica/métodos , Ayuno Intermitente , Lipopolisacáridos , Mitocondrias/metabolismo , Monocitos/metabolismo , Obesidad/dietoterapia , Obesidad/metabolismo , Consumo de Oxígeno , Transducción de SeñalRESUMEN
The post-nutritional intervention modulation of miRNA expression has been previously investigated; however, post-acute dietary-ingestion-related miRNA expression dynamics in individuals with obesity and insulin resistance (IR) are unknown. We aimed to determine the acute effects of protein ingestion from different dietary sources on the postprandial metabolic response, amino acid levels, and circulating miRNA expression in adults with obesity and IR. This clinical trial included adults with obesity and IR who consumed (1) animal-source protein (AP; calcium caseinate) or (2) vegetable-source protein (VP; soy protein isolate). Glycaemic, insulinaemic, and glucagon responses, amino acid levels, and exosomal microRNAs isolated from plasma were analysed. Post-AP ingestion, the area under the curve (AUC) of insulin (p = 0.04) and the plasma concentrations of branched-chain (p = 0.007) and gluconeogenic (p = 0.01) amino acids increased. The effects of different types of proteins on the concentration of miRNAs were evaluated by measuring their plasma circulating levels. Compared with the baseline, the AP group presented increased circulating levels of miR-27a-3p, miR-29b-3p, and miR-122-5p (p < 0.05). Subsequent analysis over time at 0, 30, and 60 min revealed the same pattern and differences between treatments. We demonstrated that a single dose of dietary protein has acute effects on hormonal and metabolic regulation and increases exosomal miRNA expression in individuals with obesity and IR.
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Aminoácidos , MicroARN Circulante , Proteínas en la Dieta , Resistencia a la Insulina , Obesidad , Periodo Posprandial , Humanos , Proteínas en la Dieta/administración & dosificación , Masculino , Obesidad/sangre , Obesidad/dietoterapia , Obesidad/genética , Obesidad/metabolismo , Femenino , Adulto , MicroARN Circulante/sangre , MicroARN Circulante/genética , Aminoácidos/sangre , Persona de Mediana Edad , Insulina/sangre , Glucemia/metabolismo , MicroARNs/sangre , MicroARNs/genéticaRESUMEN
Immune mediators affect multiple biological functions of intestinal epithelial cells (IECs) and, like Paneth and Paneth-like cells, play an important role in intestinal epithelial homeostasis. IFN-γ a prototypical proinflammatory cytokine disrupts intestinal epithelial homeostasis. However, the mechanism underlying the process remains unknown. In this study, using in vivo and in vitro models we demonstrate that IFN-γ is spontaneously secreted in the small intestine. Furthermore, we observed that this cytokine stimulates mitochondrial activity, ROS production, and Paneth and Paneth-like cell secretion. Paneth and Paneth-like secretion downstream of IFN-γ, as identified here, is mTORC1 and necroptosis-dependent. Thus, our findings revealed that the pleiotropic function of IFN-γ also includes the regulation of Paneth cell function in the homeostatic gut.
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Sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin (Dapa), exhibited nephroprotective effects in patients with chronic kidney disease (CKD). We assessed the efficacy of short-term Dapa administration following acute kidney injury (AKI) in preventing CKD. Male Wistar rats were randomly assigned to Sham surgery, bilateral ischemia for 30 minutes (abbreviated as IR), and IR + Dapa groups. Daily treatment with Dapa was initiated just 24 hours after IR and maintained for only 10 days. Initially, rats were euthanized at this point to study early renal repair. After severe AKI, Dapa promptly restored creatinine clearance (CrCl) and significantly reduced renal vascular resistance compared with the IR group. Furthermore, Dapa effectively reversed the mitochondrial abnormalities, including increased fission, altered mitophagy, metabolic dysfunction, and proapoptotic signaling. To study this earlier, another set of rats was studied just 5 days after AKI. Despite persistent renal dysfunction, our data reveal a degree of mitochondrial protection. Remarkably, a 10-day treatment with Dapa demonstrated effectiveness in preventing CKD transition in an independent cohort monitored for 5 months after AKI. This was evidenced by improvements in proteinuria, CrCl, glomerulosclerosis, and fibrosis. Our findings underscore the potential of Dapa in preventing maladaptive repair following AKI, emphasizing the crucial role of early intervention in mitigating AKI long-term consequences.
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Lesión Renal Aguda , Insuficiencia Renal Crónica , Daño por Reperfusión , Animales , Humanos , Masculino , Ratas , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & control , Lesión Renal Aguda/metabolismo , Glucosa , Ratas Wistar , Insuficiencia Renal Crónica/tratamiento farmacológico , Daño por Reperfusión/complicaciones , Daño por Reperfusión/metabolismo , Sodio/metabolismo , Transportador 2 de Sodio-Glucosa/efectos de los fármacos , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Compuestos de Bencidrilo/farmacología , Compuestos de Bencidrilo/uso terapéuticoRESUMEN
Excessive consumption of fat and carbohydrates, together with a decrease in traditional food intake, has been related to obesity and the development of metabolic alterations. Ramon seed is a traditional Mayan food used to obtain Ramon flour (RF) with high biological value in terms of protein, fiber, micronutrients, and bioactive compounds such as polyphenols. However, few studies have evaluated the beneficial effects of RF. Thus, we aimed to determine the metabolic effects of RF consumption on a high-fat-diet-induced obesity mouse model. We divided male BALB/c mice into four groups (n = 5 each group) and fed them for 90 days with the following diets: Control (C): control diet (AIN-93), C + RF: control diet adjusted with 25% RF, HFD: high-fat diet + 5% sugar in water, and HFD + RF: high-fat diet adjusted with 25% RF + 5% sugar in water. The RF prevented the increase in serum total cholesterol (TC) and alanine transaminase (ALT) that occurred in the C and HFD groups. Notably, RF together with HFD increased serum polyphenols and antioxidant activity, and it promoted a decrease in the adipocyte size in white adipose tissue, along with lower hepatic lipid accumulation than in the HFD group. In the liver, the HFD + RF group showed an increase in the expression of ß-oxidation-related genes, and downregulation of the fatty acid synthase (Fas) gene compared with the HFD group. Moreover, the HFD + RF group had increased hepatic phosphorylation of AMP-activated protein kinase (AMPK), along with increased nuclear factor erythroid 2-related factor 2 (NRF2) and superoxide dismutase 2 (SOD2) protein expression compared with the HFD group. Thus, RF may be used as a nutritional strategy to decrease metabolic alterations during obesity.
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Amino acids have been extensively studied in nutrition, mainly as key elements for maintaining optimal protein synthesis in the body as well as precursors of various nitrogen-containing compounds. However, it is now known that amino acid catabolism is an important element for the metabolic control of different biological processes, although it is still a developing field to have a deeper understanding of its biological implications. The mechanisms involved in the regulation of amino acid catabolism now include the contribution of the gut microbiota to amino acid oxidation and metabolite generation in the intestine, the molecular mechanisms of transcriptional control, and the participation of specific miRNAs involved in the regulation of amino acid degrading enzymes. In addition, molecules derived from amino acid catabolism play a role in metabolism as they are used in the epigenetic regulation of many genes. Thus, this review aims to examine the mechanisms of amino acid catabolism and to support the idea that this process is associated with the immune response, abnormalities during obesity, in particular insulin resistance, and the regulation of thermogenesis.
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Resistencia a la Insulina , MicroARNs , Humanos , Epigénesis Genética , Aminoácidos/metabolismo , ObesidadRESUMEN
Genistein is an isoflavone present in soybeans and is considered a bioactive compound due to its widely reported biological activity. We have previously shown that intraperitoneal genistein administration and diet supplementation activates the thermogenic program in rats and mice subcutaneous white adipose tissue (scWAT) under multiple environmental cues, including cold exposure and high-fat diet feeding. However, the mechanistic insights of this process were not previously unveiled. Uncoupling protein 1 (UCP1), a mitochondrial membrane polypeptide responsible for dissipating energy into heat, is considered the most relevant thermogenic marker; thus, we aimed to evaluate whether genistein regulates UCP1 transcription. Here we show that genistein administration to thermoneutral-housed mice leads to the appearance of beige adipocyte markers, including a sharp upregulation of UCP1 expression and protein abundance in scWAT. Reporter assays showed an increase in UCP1 promoter activity after genistein stimulation, and in silico analysis revealed the presence of estrogen (ERE) and cAMP (CRE) response elements as putative candidates of genistein activation. Mutation of the CRE but not the ERE reduced genistein-induced promoter activity by 51%. Additionally, in vitro and in vivo ChIP assays demonstrated the binding of CREB to the UCP1 promoter after acute genistein administration. Taken together, these data elucidate the mechanism of genistein-mediated UCP1 induction and confirm its potential applications in managing metabolic disorders.
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Adipocitos Beige , Ratones , Ratas , Animales , Activación Transcripcional , Adipocitos Beige/metabolismo , Genisteína/farmacología , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Tejido Adiposo Blanco/metabolismo , Termogénesis/genética , Elementos de Respuesta , Tejido Adiposo Pardo/metabolismoRESUMEN
Hypothalamic circuits compute systemic information to control metabolism. Astrocytes residing within the hypothalamus directly sense nutrients and hormones, integrating metabolic information, and modulating neuronal responses. Nevertheless, the role of the astrocytic circadian clock on the control of energy balance remains unclear. We used mice with a targeted ablation of the core-clock gene Bmal1 within Gfap-expressing astrocytes to gain insight on the role played by this transcription factor in astrocytes. While this mutation does not substantially affect the phenotype in mice fed normo-caloric diet, under high-fat diet we unmasked a thermogenic phenotype consisting of increased energy expenditure, and catabolism in brown adipose and overall metabolic improvement consisting of better glycemia control, and body composition. Transcriptomic analysis in the ventromedial hypothalamus revealed an enhanced response to moderate cellular stress, including ER-stress response, unfolded protein response and autophagy. We identified Xbp1 and Atf1 as two key transcription factors enhancing cellular stress responses. Therefore, we unveiled a previously unknown role of the astrocytic circadian clock modulating energy balance through the regulation of cellular stress responses within the VMH.
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Relojes Circadianos , Ratones , Animales , Relojes Circadianos/genética , Astrocitos/metabolismo , Hipotálamo/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Metabolismo Energético/genéticaRESUMEN
The circadian clock is an endogenous time-tracking system that anticipates daily environmental changes. Misalignment of the clock can cause obesity, which is accompanied by reduced levels of the clock-controlled, rhythmic metabolite NAD+. Increasing NAD+ is becoming a therapy for metabolic dysfunction; however, the impact of daily NAD+ fluctuations remains unknown. Here, we demonstrate that time-of-day determines the efficacy of NAD+ treatment for diet-induced metabolic disease in mice. Increasing NAD+ prior to the active phase in obese male mice ameliorated metabolic markers including body weight, glucose and insulin tolerance, hepatic inflammation and nutrient sensing pathways. However, raising NAD+ immediately before the rest phase selectively compromised these responses. Remarkably, timed NAD+ adjusted circadian oscillations of the liver clock until completely inverting its oscillatory phase when increased just before the rest period, resulting in misaligned molecular and behavioral rhythms in male and female mice. Our findings unveil the time-of-day dependence of NAD+-based therapies and support a chronobiology-based approach.
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Relojes Circadianos , Enfermedades Metabólicas , Ratones , Masculino , Femenino , Animales , Ritmo Circadiano/fisiología , NAD/metabolismo , Dieta , Enfermedades Metabólicas/metabolismo , Hígado/metabolismoRESUMEN
Bile acids (BAs) are complex and incompletely understood enterohepatic-derived hormones that control whole-body metabolism. Here, we profiled postprandial BAs in the liver, feces, and plasma of 360 chow- or high-fat-diet-fed BXD male mice and demonstrated that both genetics and diet strongly influence BA abundance, composition, and correlation with metabolic traits. Through an integrated systems approach, we mapped hundreds of quantitative trait loci that modulate BAs and identified both known and unknown regulators of BA homeostasis. In particular, we discovered carboxylesterase 1c (Ces1c) as a genetic determinant of plasma tauroursodeoxycholic acid (TUDCA), a BA species with established disease-preventing actions. The association between Ces1c and plasma TUDCA was validated using data from independent mouse cohorts and a Ces1c knockout mouse model. Collectively, our data are a unique resource to dissect the physiological importance of BAs as determinants of metabolic traits, as underscored by the identification of CES1C as a master regulator of plasma TUDCA levels.
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Ácidos y Sales Biliares , Dieta Alta en Grasa , Animales , Ácidos y Sales Biliares/metabolismo , Hidrolasas de Éster Carboxílico/metabolismo , Homeostasis , Hormonas/metabolismo , Hígado/metabolismo , Masculino , Ratones , Análisis de Sistemas , Ácido TauroquenodesoxicólicoRESUMEN
SCOPE: Genistein increases whole body energy expenditure by stimulating white adipose tissue (WAT) browning and thermogenesis. G-Coupled receptor GPR30 can mediate some actions of genistein, however, it is not known whether it is involved in the activation of WAT-thermogenesis. Thus, the aim of the study is to determine whether genistein activates thermogenesis coupled to an increase in WAT browning and mitochondrial activity, in GPR30+/+ and GPR30-/- mice. METHODS AND RESULTS: GPR30+/+ and GPR30-/- mice are fed control or high fat sucrose diets containing or not genistein for 8 weeks. Body weight and composition, energy expenditure, glucose tolerance, and browning markers in WAT, and oxygen consumption rate, 3', 5'-cyclic adenosine monophosphate (cAMP) concentration and browning markers in adipocytes are evaluated. Genistein consumption reduces body weight and fat mass gain in a different extent in both genotypes, however, energy expenditure is lower in GPR30-/- compared to GPR30+/+ mice, accompanied by a reduction in browning markers, maximal mitochondrial respiration, cAMP concentration, and browning markers in cultured adipocytes from GPR30-/- mice. Genistein improves glucose tolerance in GPR30+/+ , but this is partially observed in GPR30-/- mice. CONCLUSION: The results show that GPR30 partially mediates genistein stimulation of WAT thermogenesis and the improvement of glucose tolerance.
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Tejido Adiposo Pardo , Genisteína , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Animales , Peso Corporal , Metabolismo Energético , Genisteína/metabolismo , Genisteína/farmacología , Glucosa/metabolismo , Ratones , Ratones Endogámicos C57BL , Termogénesis/genéticaRESUMEN
The increase in incidence and prevalence of metabolic diseases, such as diabetes, obesity, and metabolic syndrome, is a health problem worldwide. Nutritional strategies that can impact on mitochondrial activity represent a novel and effective option to modulate energy expenditure and energetic metabolism in cells and tissues and could be used as adjuvant treatments for metabolic-associated disorders. Dietary bioactive compounds also known as "food bioactives" have proven to exert multiple health benefits and counteract metabolic alterations. In the last years, it has been consistently reported that the modulation of mitochondrial function represents one of the mechanisms behind the bioactive compounds-dependent health improvements. In this review, we focus on gathering, summarizing, and discussing the evidence that supports the effect of dietary bioactive compounds on mitochondrial activity and the relation of these effects in the pathological context. Despite the evidence presented here on in vivo and in vitro effects, more studies are needed to determine their effectiveness in humans.
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Alimentos Funcionales , Mitocondrias/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Alimentos Funcionales/análisis , Microbioma Gastrointestinal , Humanos , Mitocondrias/patología , Consumo de Oxígeno , Sirtuina 1/metabolismo , TermogénesisRESUMEN
Bile acids (BAs) are signalling molecules that mediate various cellular responses in both physiological and pathological processes. Several studies report that BAs can be detected in the brain1, yet their physiological role in the central nervous system is still largely unknown. Here we show that postprandial BAs can reach the brain and activate a negative-feedback loop controlling satiety in response to physiological feeding via TGR5, a G-protein-coupled receptor activated by multiple conjugated and unconjugated BAs2 and an established regulator of peripheral metabolism3-8. Notably, peripheral or central administration of a BA mix or a TGR5-specific BA mimetic (INT-777) exerted an anorexigenic effect in wild-type mice, while whole-body, neuron-specific or agouti-related peptide neuronal TGR5 deletion caused a significant increase in food intake. Accordingly, orexigenic peptide expression and secretion were reduced after short-term TGR5 activation. In vitro studies demonstrated that activation of the Rho-ROCK-actin-remodelling pathway decreases orexigenic agouti-related peptide/neuropeptide Y (AgRP/NPY) release in a TGR5-dependent manner. Taken together, these data identify a signalling cascade by which BAs exert acute effects at the transition between fasting and feeding and prime the switch towards satiety, unveiling a previously unrecognized role of physiological feedback mediated by BAs in the central nervous system.
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Ácidos y Sales Biliares/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Animales , Anorexia/etiología , Anorexia/metabolismo , Línea Celular , Ingestión de Alimentos , Regulación de la Expresión Génica , Hipotálamo/metabolismo , Hipotálamo/fisiopatología , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Neuronas/metabolismo , Neuropéptidos/metabolismo , Receptores Acoplados a Proteínas G/agonistasRESUMEN
SIRT7 is a NAD+ -dependent deacetylase that controls important aspects of metabolism, cancer, and bone formation. However, the molecular targets and functions of SIRT7 in the kidney are currently unknown. In silico analysis of kidney transcripts of the BXD murine genetic reference population revealed a positive correlation between Sirt7 and Slc12a7 mRNA expression, suggesting a link between the corresponding proteins that these transcripts encode, SIRT7, and the K-Cl cotransporter KCC4, respectively. Here, we find that protein levels and activity of heterologously expressed KCC4 are significantly modulated depending on its acetylation status in Xenopus laevis oocytes. Moreover, SIRT7 interacts with KCC4 in a NAD+ -dependent manner and increases its stability and activity in HEK293 cells. Interestingly, metabolic acidosis increases SIRT7 expression in kidney, as occurs with KCC4. In contrast, total SIRT7-deficient mice present lower KCC4 expression and an exacerbated metabolic acidosis than wild-type mice during an ammonium chloride challenge. Altogether, our data suggest that SIRT7 interacts with, stabilizes and modulates KCC4 activity through deacetylation, and reveals a novel role for SIRT7 in renal physiology.
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Sirtuinas , Simportadores , Acetilación , Animales , Células HEK293 , Humanos , Riñón , Ratones , Sirtuinas/genética , Sirtuinas/metabolismo , Simportadores/genética , Simportadores/metabolismo , Cotransportadores de K ClRESUMEN
The preservation of body proteins is essential to guarantee their functions in organisms. Therefore, the utilization of amino acids as energy substrates is regulated by a precise fine-tuned mechanism. Recent evidence suggests that the transcription factors peroxisome proliferator-activated receptor alpha (PPARα) and hepatocyte nuclear factor 4 alpha (HNF4α) are involved in this regulatory mechanism. Thus, the aim of this study was to determine how these transcription factors interact to regulate the expression of amino acid catabolism genes. In vivo studies using PPARα-knockout mice (Pparα-null) fed different amounts of dietary protein showed that in the absence of PPARα, there was a significant increase in HNF4α abundance in the liver, which corresponded with an increase in amino acid catabolizing enzyme (AACE) expression and the generation of increased amounts of postprandial urea. Moreover, this effect was proportional to the increase in dietary protein consumed. Chromatin immunoprecipitation assays showed that HNF4α can bind to the promoter of AACE serine dehydratase (SDS), an effect that was potentiated by dietary protein in the Pparα-null mice. The mechanistic studies revealed that the presence of retinoid X receptor alpha (RXRα) is essential to repress HNF4α activity in the presence of PPARα, and this interaction accelerates HNF4α degradation via the proteasome pathway. These results showed that PPARα can downregulate liver amino acid catabolism in the presence of RXRα by inhibiting HNF4α activity.
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Aminoácidos/metabolismo , Factor Nuclear 4 del Hepatocito/metabolismo , Hígado/metabolismo , PPAR alfa/fisiología , Receptor alfa X Retinoide/fisiología , Animales , Regulación hacia Abajo/genética , Células HEK293 , Células Hep G2 , Humanos , Masculino , Metabolismo/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , PPAR alfa/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Unión Proteica , Proteolisis , Receptor alfa X Retinoide/genéticaRESUMEN
SCOPE: The aim of this study is to assess whether the long-term addition of genistein to a high-fat diet can ameliorate the metabolic and the cognitive alterations and whether the changes can be associated with modifications to the gut microbiota. METHODS AND RESULTS: C57/BL6 mice were fed either a control (C) diet, a high-fat (HF) diet, or a high-fat diet containing genistein (HFG) for 6 months. During the study, indirect calorimetry, IP glucose tolerance tests, and behavioral analyses were performed. At the end of the study, plasma, liver, brain, and fecal samples were collected. The results showed that mice fed the HFG diet gained less weight, had lower serum triglycerides, and an improvement in glucose tolerance than those fed an HF diet. Mice fed the HFG diet also modified the gut microbiota that was associated with lower circulating levels of lipopolysaccharide (LPS) and reduced expression of pro-inflammatory cytokines in the liver compared to those fed HF diet. The reduction in LPS by the consumption of genistein was accompanied by an improvement of the cognitive function. CONCLUSIONS: Genistein is able to regulate the gut microbiota, reducing metabolic endotoxemia and decreasing the neuroinflammatory response despite the consumption of a HF diet.
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Cognición/efectos de los fármacos , Endotoxemia/prevención & control , Microbioma Gastrointestinal/efectos de los fármacos , Genisteína/administración & dosificación , Glucosa/metabolismo , Animales , Dieta Alta en Grasa , Homólogo 4 de la Proteína Discs Large/análisis , Metabolismo Energético , Inflamación/prevención & control , Lípidos/sangre , Lipopolisacáridos/sangre , Masculino , Ratones , Ratones Endogámicos C57BL , Aumento de PesoRESUMEN
Remodelling of energy storing white fat into energy expending beige fat could be a promising strategy to reduce adiposity. Here, we show that the bile acid-responsive membrane receptor TGR5 mediates beiging of the subcutaneous white adipose tissue (scWAT) under multiple environmental cues including cold exposure and prolonged high-fat diet feeding. Moreover, administration of TGR5-selective bile acid mimetics to thermoneutral housed mice leads to the appearance of beige adipocyte markers and increases mitochondrial content in the scWAT of Tgr5 +/+ mice but not in their Tgr5 -/- littermates. This phenotype is recapitulated in vitro in differentiated adipocytes, in which TGR5 activation increases free fatty acid availability through lipolysis, hence fuelling ß-oxidation and thermogenic activity. TGR5 signalling also induces mitochondrial fission through the ERK/DRP1 pathway, further improving mitochondrial respiration. Taken together, these data identify TGR5 as a druggable target to promote beiging with potential applications in the management of metabolic disorders.
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Tejido Adiposo Beige/metabolismo , Tejido Adiposo Blanco/metabolismo , Dinámicas Mitocondriales , Receptores Acoplados a Proteínas G/metabolismo , Células 3T3-L1 , Adipocitos Beige/metabolismo , Adipocitos Blancos/metabolismo , Tejido Adiposo Beige/citología , Tejido Adiposo Blanco/citología , Animales , Diferenciación Celular/genética , Línea Celular , Ácidos Grasos no Esterificados/metabolismo , Humanos , Ratones , Ratones Noqueados , Receptores Acoplados a Proteínas G/genética , Transducción de Señal/genética , Grasa Subcutánea/citología , Grasa Subcutánea/metabolismo , TemperaturaRESUMEN
Identifying genetic and environmental factors that impact complex traits and common diseases is a high biomedical priority. Here, we developed, validated, and implemented a series of multi-layered systems approaches, including (expression-based) phenome-wide association, transcriptome-/proteome-wide association, and (reverse-) mediation analysis, in an open-access web server (systems-genetics.org) to expedite the systems dissection of gene function. We applied these approaches to multi-omics datasets from the BXD mouse genetic reference population, and identified and validated associations between genes and clinical and molecular phenotypes, including previously unreported links between Rpl26 and body weight, and Cpt1a and lipid metabolism. Furthermore, through mediation and reverse-mediation analysis we established regulatory relations between genes, such as the co-regulation of BCKDHA and BCKDHB protein levels, and identified targets of transcription factors E2F6, ZFP277, and ZKSCAN1. Our multifaceted toolkit enabled the identification of gene-gene and gene-phenotype links that are robust and that translate well across populations and species, and can be universally applied to any populations with multi-omics datasets.
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Perfilación de la Expresión Génica/métodos , Genómica/métodos , Proteómica/métodos , Animales , Carnitina O-Palmitoiltransferasa/genética , Carnitina O-Palmitoiltransferasa/fisiología , Bases de Datos Genéticas , Estudio de Asociación del Genoma Completo , Genotipo , Ratones , Ratones Endogámicos/genética , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo , Proteínas Ribosómicas/genética , Proteínas Ribosómicas/fisiología , Biología de Sistemas/métodos , TranscriptomaRESUMEN
SCOPE: Hyperglucagonemia contributes to hyperglycemia in type 2 diabetes (T2D). Previously, we have found that soy protein normalized fasting hyperglucagonemia in obese Zucker (fa/fa) rats, sensitizing the HSL-lipolytic signaling pathway in white adipose tissue (WAT), however the mechanism remains unknown. METHODS AND RESULTS: Zucker (fa/fa) rats were fed casein or soy protein diet in combination with soybean or coconut oil. Glucagon receptor (GR) was increased at the plasma membrane of adipocytes of rats fed soy protein compared to those fed casein, without changes in total GR abundance. The protein abundance of Rab4, a GTPase involved in GR fast recycling, was dramatically up-regulated in adipocytes of rats fed soy protein. The proportion of GR bound to Rab4 or to RAMP2, involved in promoting GR ligand-binding and G protein selectivity, increased when soy protein was combined with soybean oil as fat source. In rats fed soy protein with coconut oil, Rab11 levels, a protein involved in the slow recycling of GR, was also increased. CONCLUSION: Soy protein increases GR recycling to the membrane of adipocytes and its ligand-binding and G protein selectivity, suggesting, it could be used in T2D dietary treatment to reestablish glucagon sensitivity in WAT, leading to the regulation of circulating glucagon levels.