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1.
FASEB J ; 36(10): e22546, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36106538

RESUMO

The tricarboxylic acid (TCA) cycle is the epicenter of cellular aerobic metabolism. TCA cycle intermediates facilitate energy production and provide anabolic precursors, but also function as intra- and extracellular metabolic signals regulating pleiotropic biological processes. Despite the importance of circulating TCA cycle metabolites as signaling molecules, the source of circulating TCA cycle intermediates remains uncertain. We observe that in mice, the concentration of TCA cycle intermediates in the portal blood exceeds that in tail blood indicating that the gut is a major contributor to circulating TCA cycle metabolites. With a focus on succinate as a representative of a TCA cycle intermediate with signaling activities and using a combination of gut microbiota depletion mouse models and isotopomer tracing, we demonstrate that intestinal microbiota is not a major contributor to circulating succinate. Moreover, we demonstrate that endogenous succinate production is markedly higher than intestinal succinate absorption in normal physiological conditions. Altogether, these results indicate that endogenous succinate production within the intestinal tissue is a major physiological source of circulating succinate. These results provide a foundation for an investigation into the role of the intestine in regulating circulating TCA cycle metabolites and their potential signaling effects on health and disease.


Assuntos
Microbioma Gastrointestinal , Ácido Succínico , Animais , Ciclo do Ácido Cítrico/fisiologia , Microbioma Gastrointestinal/fisiologia , Intestinos , Camundongos , Succinatos/metabolismo , Ácido Succínico/metabolismo
2.
Cell Rep ; 43(3): 113881, 2024 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-38442019

RESUMO

An intriguing effect of short-term caloric restriction (CR) is the expansion of certain stem cell populations, including muscle stem cells (satellite cells), which facilitate an accelerated regenerative program after injury. Here, we utilized the MetRSL274G (MetRS) transgenic mouse to identify liver-secreted plasminogen as a candidate for regulating satellite cell expansion during short-term CR. Knockdown of circulating plasminogen prevents satellite cell expansion during short-term CR. Furthermore, loss of the plasminogen receptor KT (Plg-RKT) is also sufficient to prevent CR-related satellite cell expansion, consistent with direct signaling of plasminogen through the plasminogen receptor Plg-RKT/ERK kinase to promote proliferation of satellite cells. Importantly, we are able to replicate many of these findings in human participants from the CALERIE trial. Our results demonstrate that CR enhances liver protein secretion of plasminogen, which signals directly to the muscle satellite cell through Plg-RKT to promote proliferation and subsequent muscle resilience during CR.


Assuntos
Plasminogênio , Receptores de Superfície Celular , Camundongos , Animais , Humanos , Plasminogênio/metabolismo , Receptores de Superfície Celular/metabolismo , Restrição Calórica , Fígado/metabolismo , Camundongos Transgênicos , Serina Proteases , Proliferação de Células , Músculos/metabolismo
3.
bioRxiv ; 2023 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-37131695

RESUMO

Objective: To investigate the effects of metformin on intestinal carbohydrate metabolism in vivo. Method: Male mice preconditioned with a high-fat, high-sucrose diet were treated orally with metformin or a control solution for two weeks. Fructose metabolism, glucose production from fructose, and production of other fructose-derived metabolites were assessed using stably labeled fructose as a tracer. Results: Metformin treatment decreased intestinal glucose levels and reduced incorporation of fructose-derived metabolites into glucose. This was associated with decreased intestinal fructose metabolism as indicated by decreased enterocyte F1P levels and diminished labeling of fructose-derived metabolites. Metformin also reduced fructose delivery to the liver. Proteomic analysis revealed that metformin coordinately down-regulated proteins involved carbohydrate metabolism including those involved in fructolysis and glucose production within intestinal tissue. Conclusion: Metformin reduces intestinal fructose metabolism, and this is associated with broad-based changes in intestinal enzyme and protein levels involved in sugar metabolism indicating that metformin's effects on sugar metabolism are pleiotropic.

4.
JCI Insight ; 8(1)2023 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-36413406

RESUMO

Carbohydrate response element-binding protein (ChREBP) is a carbohydrate-sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-Seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified hepatocyte growth factor activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone hepatocyte growth factor. We demonstrate that HGFAC-KO mice had phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhanced lipid and glucose homeostasis, which may be mediated in part through actions to activate hepatic PPARγ activity. Together, our studies show that ChREBP mediated an adaptive response to overnutrition via activation of HGFAC in the liver to preserve glucose and lipid homeostasis.


Assuntos
Glucose , Fatores de Transcrição , Animais , Humanos , Camundongos , Glucose/metabolismo , Homeostase , Lipídeos , Fatores de Transcrição/metabolismo
5.
Nutrients ; 13(10)2021 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-34684643

RESUMO

The metabolic syndrome (MetS), defined as the co-occurrence of disorders including obesity, dyslipidemia, insulin resistance, and hepatic steatosis, has become increasingly prevalent in the world over recent decades. Dietary and other environmental factors interacting with genetic predisposition are likely contributors to this epidemic. Among the involved dietary factors, excessive fructose consumption may be a key contributor. When fructose is consumed in large amounts, it can quickly produce many of the features of MetS both in humans and mice. The mechanisms by which fructose contributes to metabolic disease and its potential interactions with genetic factors in these processes remain uncertain. Here, we generated a small F2 genetic cohort of male mice derived from crossing fructose-sensitive and -resistant mouse strains to investigate the interrelationships between fructose-induced metabolic phenotypes and to identify hepatic transcriptional pathways that associate with these phenotypes. Our analysis indicates that the hepatic transcriptional pathways associated with fructose-induced hypertriglyceridemia and hyperinsulinemia are distinct from those that associate with fructose-mediated changes in body weight and liver triglyceride. These results suggest that multiple independent mechanisms and pathways may contribute to different aspects of fructose-induced metabolic disease.


Assuntos
Frutose/efeitos adversos , Hiperinsulinismo/complicações , Hipertrigliceridemia/complicações , Fígado/metabolismo , Análise de Sistemas , Triglicerídeos/metabolismo , Animais , Estudos de Coortes , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Haplótipos , Hiperinsulinismo/sangue , Hipertrigliceridemia/sangue , Insulina/sangue , Masculino , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Mutação de Sentido Incorreto/genética , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Triglicerídeos/sangue
6.
Mol Metab ; 32: 44-55, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32029229

RESUMO

OBJECTIVE: Glucose-dependent insulinotropic polypeptide is an intestinally derived hormone that is essential for normal metabolic regulation. Loss of the GIP receptor (GIPR) through genetic elimination or pharmacological antagonism reduces body weight and adiposity in the context of nutrient excess. Interrupting GIPR signaling also enhances the sensitivity of the receptor for the other incretin peptide, glucagon-like peptide 1 (GLP-1). The role of GLP-1 compensation in loss of GIPR signaling to protect against obesity has not been directly tested. METHODS: We blocked the GIPR and GLP-1R with specific antibodies, alone and in combination, in healthy and diet-induced obese (DIO) mice. The primary outcome measure of these interventions was the effect on body weight and composition. RESULTS: Antagonism of either the GIPR or GLP-1R system reduced food intake and weight gain during high-fat feeding and enhanced sensitivity to the alternative incretin signaling system. Combined antagonism of both GIPR and GLP-1R produced additive effects to mitigate DIO. Acute pharmacological studies using GIPR and GLP-1R agonists demonstrated both peptides reduced food intake, which was prevented by co-administration of the respective antagonists. CONCLUSIONS: Disruption of either axis of the incretin system protects against diet-induced obesity in mice. However, combined antagonism of both GIPR and GLP-1R produced additional protection against diet-induced obesity, suggesting additional factors beyond compensation by the complementary incretin axis. While antagonizing the GLP-1 system decreases weight gain, GLP-1R agonists are used clinically to target obesity. Hence, the phenotype arising from loss of function of GLP-1R does not implicate GLP-1 as an obesogenic hormone. By extension, caution is warranted in labeling GIP as an obesogenic hormone based on loss-of-function studies.


Assuntos
Fármacos Antiobesidade/uso terapêutico , Incretinas/uso terapêutico , Obesidade/tratamento farmacológico , Animais , Fármacos Antiobesidade/administração & dosagem , Dieta Hiperlipídica/efeitos adversos , Incretinas/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/induzido quimicamente , Obesidade/metabolismo , Aumento de Peso/efeitos dos fármacos
8.
J Clin Invest ; 128(2): 545-555, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29388924

RESUMO

Increased sugar consumption is increasingly considered to be a contributor to the worldwide epidemics of obesity and diabetes and their associated cardiometabolic risks. As a result of its unique metabolic properties, the fructose component of sugar may be particularly harmful. Diets high in fructose can rapidly produce all of the key features of the metabolic syndrome. Here we review the biology of fructose metabolism as well as potential mechanisms by which excessive fructose consumption may contribute to cardiometabolic disease.


Assuntos
Frutose/metabolismo , Síndrome Metabólica/metabolismo , Adiposidade , Animais , Frutose/química , Perfilação da Expressão Gênica , Glucose/química , Transportador de Glucose Tipo 2/metabolismo , Humanos , Hipertensão/metabolismo , Fígado/metabolismo , Síndrome Metabólica/genética , Fatores de Risco , Açúcares
9.
Cell Metab ; 27(6): 1281-1293.e7, 2018 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-29779826

RESUMO

Branched-chain amino acids (BCAA) are strongly associated with dysregulated glucose and lipid metabolism, but the underlying mechanisms are poorly understood. We report that inhibition of the kinase (BDK) or overexpression of the phosphatase (PPM1K) that regulates branched-chain ketoacid dehydrogenase (BCKDH), the committed step of BCAA catabolism, lowers circulating BCAA, reduces hepatic steatosis, and improves glucose tolerance in the absence of weight loss in Zucker fatty rats. Phosphoproteomics analysis identified ATP-citrate lyase (ACL) as an alternate substrate of BDK and PPM1K. Hepatic overexpression of BDK increased ACL phosphorylation and activated de novo lipogenesis. BDK and PPM1K transcript levels were increased and repressed, respectively, in response to fructose feeding or expression of the ChREBP-ß transcription factor. These studies identify BDK and PPM1K as a ChREBP-regulated node that integrates BCAA and lipid metabolism. Moreover, manipulation of the BDK:PPM1K ratio relieves key metabolic disease phenotypes in a genetic model of severe obesity.


Assuntos
3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/metabolismo , ATP Citrato (pro-S)-Liase/metabolismo , Aminoácidos de Cadeia Ramificada/metabolismo , Lipogênese , Obesidade/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Modelos Animais de Doenças , Feminino , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Fosfatase 2C , Ratos , Ratos Wistar , Ratos Zucker
10.
JCI Insight ; 2(24)2017 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-29263303

RESUMO

Increased sugar consumption is a risk factor for the metabolic syndrome including obesity, hypertriglyceridemia, insulin resistance, diabetes, and nonalcoholic fatty liver disease (NAFLD). Carbohydrate responsive element-binding protein (ChREBP) is a transcription factor that responds to sugar consumption to regulate adaptive metabolic programs. Hepatic ChREBP is particularly responsive to fructose and global ChREBP-KO mice are intolerant to diets containing fructose. It has recently been suggested that ChREBP protects the liver from hepatotoxicity following high-fructose diets (HFrDs). We directly tested this hypothesis using tissue-specific ChREBP deletion. HFrD increased adiposity and impaired glucose homeostasis in control mice, responses that were prevented in liver-specific ChREBP-KO (LiChKO) mice. Moreover, LiChKO mice tolerated chronic HFrD without marked weight loss or hepatotoxicity. In contrast, intestine-specific ChREBP-KO (IChKO) mice rapidly lost weight after transition to HFrD, and this was associated with dilation of the small intestine and cecum, suggestive of malabsorption. These findings were associated with downregulation of the intestinal fructose transporter, Slc2a5, which is essential for fructose tolerance. Altogether, these results establish an essential role for intestinal, but not hepatic, ChREBP in fructose tolerance.


Assuntos
Intolerância à Frutose/metabolismo , Frutose/toxicidade , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Proteínas Nucleares/fisiologia , Fatores de Transcrição/fisiologia , Animais , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Colesterol/metabolismo , Regulação para Baixo/fisiologia , Feminino , Intolerância à Frutose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Transportador de Glucose Tipo 5 , Lipogênese/efeitos dos fármacos , Masculino , Camundongos Knockout , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Fatores de Transcrição/deficiência , Fatores de Transcrição/genética , Redução de Peso/fisiologia
11.
Diab Vasc Dis Res ; 14(6): 516-524, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28868898

RESUMO

The genomic CDKN2A/B locus, encoding p16INK4a among others, is linked to an increased risk for cardiovascular disease and type 2 diabetes. Obesity is a risk factor for both cardiovascular disease and type 2 diabetes. p16INK4a is a cell cycle regulator and tumour suppressor. Whether it plays a role in adipose tissue formation is unknown. p16INK4a knock-down in 3T3/L1 preadipocytes or p16INK4a deficiency in mouse embryonic fibroblasts enhanced adipogenesis, suggesting a role for p16INK4a in adipose tissue formation. p16INK4a-deficient mice developed more epicardial adipose tissue in response to the adipogenic peroxisome proliferator activated receptor gamma agonist rosiglitazone. Additionally, adipose tissue around the aorta from p16INK4a-deficient mice displayed enhanced rosiglitazone-induced gene expression of adipogenic markers and stem cell antigen, a marker of bone marrow-derived precursor cells. Mice transplanted with p16INK4a-deficient bone marrow had more epicardial adipose tissue compared to controls when fed a high-fat diet. In humans, p16INK4a gene expression was enriched in epicardial adipose tissue compared to other adipose tissue depots. Moreover, epicardial adipose tissue from obese humans displayed increased expression of stem cell antigen compared to lean controls, supporting a bone marrow origin of epicardial adipose tissue. These results show that p16INK4a modulates epicardial adipose tissue development, providing a potential mechanistic link between the genetic association of the CDKN2A/B locus and cardiovascular disease risk.


Assuntos
Adipócitos/metabolismo , Adipogenia , Tecido Adiposo/metabolismo , Medula Óssea/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p18/metabolismo , Obesidade/metabolismo , Células-Tronco/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/patologia , Adipogenia/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Adiposidade , Adulto , Idoso , Animais , Transplante de Medula Óssea , Estudos de Casos e Controles , Inibidor p16 de Quinase Dependente de Ciclina/deficiência , Inibidor p16 de Quinase Dependente de Ciclina/genética , Modelos Animais de Doenças , Feminino , Genótipo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/patologia , Obesidade/fisiopatologia , PPAR gama/agonistas , PPAR gama/metabolismo , Fenótipo , Interferência de RNA , Receptores de LDL/genética , Receptores de LDL/metabolismo , Rosiglitazona , Transdução de Sinais , Células-Tronco/efeitos dos fármacos , Tiazolidinedionas/farmacologia , Transfecção
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