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1.
Nutr Neurosci ; 25(3): 567-580, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34000981

RESUMO

The energy-dense western diet significantly increases the risk of obesity, type 2 diabetes, cardiovascular episodes, stroke, and cancer. Recently more attention has been paid to the contribution of an unhealthy lifestyle on the development of central nervous system disorders. Exposure to long-lasting stress is one of the key lifestyle modifications associated with the increased prevalence of obesity and metabolic diseases. The main goal of the present study was to verify the hypothesis that exposure to chronic stress modifies alterations in the brain proteome induced by the western diet. Female adult rats were fed with the prepared chow reproducing the human western diet and/or subjected to chronic stress induced by social instability for 6 weeks. A control group of lean rats were fed with a standard diet. Being fed with the western diet resulted in an obese phenotype and induced changes in the serum metabolic parameters. The combination of the western diet and chronic stress exposure induced more profound changes in the rat cerebrocortical proteome profile than each of these factors individually. The down-regulation of proteins involved in neurotransmitter secretion (Rph3a, Snap25, Syn1) as well as in learning and memory processes (Map1a, Snap25, Tnr) were identified, while increased expression was detected for 14-3-3 protein gamma (Ywhag) engaged in the modulation of the insulin-signaling cascade in the brain. An analysis of the rat brain proteome reveals important changes that indicate that a combination of the western diet and stress exposure may lead to impairments of neuronal function and signaling.


Assuntos
Diabetes Mellitus Tipo 2 , Dieta Ocidental , Animais , Dieta Hiperlipídica , Dieta Ocidental/efeitos adversos , Feminino , Insulina , Obesidade/etiologia , Obesidade/metabolismo , Proteoma/metabolismo , Ratos
2.
Brain Behav Immun ; 96: 212-226, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34087424

RESUMO

OBJECTIVE: Obesity is a multidimensional condition that is treatable by the restoration of a lean phenotype; however, some obesity-related outcomes may persist after weight normalization. Among the organs of the human body, the brain possesses a relatively low regenerative capacity and could retain perturbations established as a result of developmental obesity. Calorie restriction (CR) or a restricted ketogenic diet (KD) are successfully used as weight loss approaches, but their impact on obesity-related effects in the brain have not been previously evaluated. METHODS: We performed a series of experiments in a rat model of developmental obesity induced by a 12-week cafeteria diet, followed by CR to implement weight loss. First, we assessed the impact of obesity on neurogenesis (BrdU incorporation into the hippocampus), cognitive function (water maze), and concomitant changes in hippocampal protein expression (GC/MS-MS, western blot). Next, we repeated these experiments in a rat model of weight loss induced by CR. We also measured mitochondrial enzyme activity in rats after weight loss during the fed or fasting state. This study was extended by additional experiments with restricted KD used as a weight loss approach in order to compare the efficacy of two different nutritional interventions used in the treatment of obesity on hippocampal functions. By using a modified version of the water maze we evaluated cognitive abilities in rats subjected to weight loss by CR or a restricted KD. RESULTS: In this study, obesity affected metabolic processes, upregulated hippocampal NF-κB, and induced proteomic differences which were associated with impaired cognition and neurogenesis. Weight loss improved neurogenesis and enhanced cognition. While the expression pattern of some proteins persisted after weight loss, most of the changes appeared de novo revealing metabolic adjustment by overactivation of citrate synthase and downregulation of ATP synthase. As a consequence of fasting, the activity of these enzymes indicated hippocampal adaptation to negative energy balance during the weight loss phase of CR. Moreover, the effects on cognitive abilities measured after weight loss were negatively correlated with the animal weight measured at the final stage of weight gain. This was alleviated by KD, which improved cognition when used as a weight loss approach. CONCLUSIONS: The study shows that cognition and mitochondrial metabolism in the hippocampus are affected by CR- or KD-induced weight loss.


Assuntos
Proteômica , Redução de Peso , Animais , Restrição Calórica , Hipocampo , Obesidade/complicações , Ratos
3.
Postepy Biochem ; 67(2): 177-192, 2021 06 30.
Artigo em Polonês | MEDLINE | ID: mdl-34378895

RESUMO

Aging is a multifunctional process which is characterized by many changes on molecular, cellular and tissue levels. The chronic, sterile and low-grade inflammation process, that occurs during aging is referred to as 'inflammaging'. Inflammaging is mentioned as a risk factor for the onset and progression of chronic diseases, not only age-related. Inflammaging contributes to increased morbidity and mortality in elderly individuals, and also affects the lifespan and quality of life. Cell senescence and disturbances in the regulation of inflammasome activation, mitochondrial function, autophagy and mitophagy, ubiquitin-proteasome system and the response to DNA damage contribute to the development of inflammaging. The above processes interact with each other and are modulated by signaling pathways involved in the regulation of the inflammatory response, i.e. NF-kB, mTOR, RIG-I, Notch, TGF-b, Ras pathways, and regulation of sirtuin activity. The aim of the study is to present the processes and signaling pathways underlying inflammaging, including clinical and experimental studies.


Assuntos
Inflamação , Qualidade de Vida , Idoso , Envelhecimento , Senescência Celular , Humanos , Longevidade
4.
Postepy Biochem ; 66(2): 125-133, 2020 06 27.
Artigo em Polonês | MEDLINE | ID: mdl-32700505

RESUMO

Diet is an important modifiable lifestyle factor affecting the risk of developing of most non-communicable diseases. A properly selected diet protects against the development of many diseases or supports their treatment. Randomized clinical trials have shown that personalized nutrition is more effective than general nutritional advice in terms of changing eating habits and treating obesity. Depending on the degree of diversification of dietary recommendations and their adaptation to the individuals' needs, one can differentiate: stratified, personalized and precise nutrition. Metabolic phenotyping ­ grouping people based on their metabolic characteristics ­ is a relatively new research field which may have a great value in the development of personalized nutrition. Many studies have shown that people with different metabotypes react differently to a diet or specific nutritional interventions. This article reviews current studies regarding the possibility of using the metabolic phenotyping in stratified and personalized nutrition. The article presents methods for creating metabolic phenotypes, diagnostic and prognostic research involving metabotyping and research that use metabotyping for the delivery of targeted dietary advice conducted so far.


Assuntos
Dieta Saudável/métodos , Humanos , Individualidade , Estado Nutricional , Obesidade/terapia , Fenótipo
5.
Postepy Biochem ; 66(3): 270-286, 2020 09 30.
Artigo em Polonês | MEDLINE | ID: mdl-33315315

RESUMO

Ketogenic diet is a high fat and very low-carbohydrate nutritional approach that induces increased production of ketone bodies, which serve as an alternative to glucose energetic substrates. Since almost a century ketogenic diet has been used in the therapy of refractory epilepsy, especially in children. Because of the pleiotropic effect of ketogenic diet on physiology, including inflammation, oxidative stress, energy balance and signaling pathways, in recent years scientists have been intensively exploring the use of it in the treatment of other diseases. In the present article current clinical studies regarding the possibility of using the ketogenic diet in the treatment of obesity, diabetes, neurological disorders and cancer has been reviewed alongside with potential mechanisms responsible for the therapeutic effect of ketogenic diet in these diseases. The metabolic processes engaged in nutritional ketosis and practicals aspects of ketogenic dieting have been also discussed.


Assuntos
Diabetes Mellitus/dietoterapia , Dieta Cetogênica , Neoplasias/dietoterapia , Doenças do Sistema Nervoso/dietoterapia , Obesidade/dietoterapia , Humanos , Corpos Cetônicos/metabolismo , Cetose
6.
Brain Behav Immun ; 80: 247-254, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30885840

RESUMO

Methamphetamine (METH) abusers are prone to develop a variety of comorbidities, including cognitive disabilities, and the immunological responses have been recognized as an important component involved in the toxicity of this drug. Cytokines are among the key mediators between systemic inflammatory status and tissue responses. One of these, interleukin 1 (IL-1), has been hypothesized to be involved in cognitive functions and also appears to play a pivotal role among inflammatory molecules. In the present study, we demonstrate that exposure of mice to METH markedly increased the protein level of IL-1ß in hippocampal tissue. Additionally, METH administration induced a decline in spatial learning as determined by the Morris water maze test. We next evaluated the hypothesis that blocking IL-1ß signaling can protect against METH-induced loss of cognitive functioning. The results indicated that METH-induced impaired spatial learning abilities were attenuated by co-administration of mouse IL-1 Trap, a dimeric fusion protein that incorporates the extracellular domains of both of the IL-1 receptor components required for IL-1 signaling (IL-1 receptor type 1 and IL-1 receptor accessory protein), linked to the Fc portion of murine IgG2a. This effect was associated with a decrease in hippocampal IL-1ß level. The current study indicates for the first time that the loss of METH-related cognitive decline can be attenuated by neutralizing IL-1 signaling. Our findings suggest a potential new therapeutic pathway for treatment of altered cognitive abilities that occur in METH abusing individuals.


Assuntos
Estimulantes do Sistema Nervoso Central/administração & dosagem , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Hipocampo/efeitos dos fármacos , Interleucina-1beta/metabolismo , Metanfetamina/administração & dosagem , Animais , Hipocampo/metabolismo , Interleucina-1beta/antagonistas & inibidores , Locomoção/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Transdução de Sinais , Aprendizagem Espacial/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos
7.
Stress ; 20(6): 549-561, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28911267

RESUMO

The study aimed to test the hypotheses that chronic social instability stress (CSIS) alters behavioral and physiological parameters and expression of selected genes important for stress response and social behaviors. Adult female Sprague-Dawley rats were subjected to the 4-week CSIS procedure, which involves unpredictable rotation between phases of isolation and overcrowding. Behavioral analyses (Experiment 1) were performed on the same rats before and after CSIS (n = 16) and physiological and biochemical measurements (Experiment 2) were made on further control (CON; n = 7) and stressed groups (CSIS; n = 8). Behaviors in the open field test (locomotor and exploratory activities) and elevated-plus maze (anxiety-related behaviors) indicated anxiety after CSIS. CSIS did not alter the physiological parameters measured, i.e. body weight gain, regularity of estrous cycles, and circulating concentrations of stress hormones and sex steroids. QRT-PCR analysis of mRNA expression levels was performed on amygdala, hippocampus, prefrontal cortex (PFC), and hypothalamus. The main finding is that CSIS alters the mRNA levels for the studied genes in a region-specific manner. Hence, expression of POMC (pro-opiomelanocortin), AVPR1a (arginine vasopressin receptor), and OXTR (oxytocin receptor) significantly increased in the amygdala following CSIS, while in PFC and/or hypothalamus, POMC, AVPR1a, AVPR1b, OXTR, and ERß (estrogen receptor beta) expression decreased. CSIS significantly reduced expression of CRH-R1 (corticotropin-releasing hormone receptor type 1) in the hippocampus. The directions of change in gene expression and the genes and regions affected indicate a molecular basis for the behavior changes. In conclusion, CSIS may be valuable for further analyzing the neurobiology of stress-related disorders in females.


Assuntos
Ansiedade/genética , Comportamento Animal , Encéfalo/metabolismo , RNA Mensageiro/metabolismo , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Vasopressinas/genética , Estresse Psicológico/genética , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/metabolismo , Doença Crônica , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Expressão Gênica , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisário/metabolismo , Hipotálamo/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Córtex Pré-Frontal/metabolismo , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo , Receptores de Vasopressinas/metabolismo , Estresse Psicológico/metabolismo
8.
Postepy Hig Med Dosw (Online) ; 71(0): 825-841, 2017 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-28931747

RESUMO

Recently, the crosstalk between autophagy and apoptosis has attracted broader attention. Basal autophagy serves to maintain cell homeostasis, while the upregulation of this process is an element of stress response that enables the cell to survive under adverse conditions. Autophagy may also determine the fate of the cell through its interactions with cell death pathways. The protein networks that control the initiation and the execution phase of these two processes are highly interconnected. Several scenarios for the crosstalk between autophagy and apoptosis exist. In most cases, the activation of autophagy represents an attempt of the cell to cope with stress, and protects the cell from apoptosis or delays its initiation. Generally, the simultaneous activation of pro-survival and pro-death pathways is prevented by the mutual inhibitory crosstalk between autophagy and apoptosis. But in some circumstances, autophagy or the proteins of the core autophagic machinery may promote cellular demise through excessive self-digestion (so-called "autophagic cell death") or by stimulating the activation of other cell death pathways. It is controversial whether cells actually die via autophagy, which is why the term "autophagic cell death" has been under intense debate lately. This review summarizes the recent findings on the multilevel crosstalk between autophagy and apoptosis in aspects of common regulators, mutual inhibition of these processes, the stimulation of apoptosis by autophagy or autophagic proteins and finally the role of autophagy as a death-execution mechanism.


Assuntos
Apoptose/fisiologia , Autofagia/fisiologia , Reações Cruzadas , Animais , Homeostase , Humanos
9.
Front Nutr ; 11: 1322509, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38389795

RESUMO

As a journal page for full details. The ketogenic diet (KD) has been established as a treatment for epilepsy, but more recently it has been explored as an alternative or add-on therapy for many other diseases ranging from weight loss to neurological disorders. Animal models are widely used in studies investigating the therapeutic effects of the KD as well as underlying mechanisms. Especially in the context of neurological, psychiatric, and neurodevelopmental disorders essential endpoints are assessed by behavioral and motor tests. Here we summarized research evaluating the influence of the KD on cognition, depressive and anxiety-related behaviors, and social and nutritional behaviors of laboratory rodents. Each section contains a brief description of commonly used behavioral tests highlighting their limitations. Ninety original research articles, written in English, performed on mice or rats, providing measurement of blood beta-hydroxybutyrate (BHB) levels and behavioral evaluation were selected for the review. The majority of research performed in various disease models shows that the KD positively impacts cognition. Almost an equal number of studies report a reduction or no effect of the KD on depressive-related behaviors. For anxiety-related behaviors, the majority of studies show no effect. Despite the increasing use of the KD in weight loss and its appetite-reducing properties the behavioral evaluation of appetite regulation has not been addressed in preclinical studies. This review provides an overview of the behavioral effects of nutritional ketosis addressed to a broad audience of scientists interested in the KD field but not necessarily specializing in behavioral tests.

10.
Nat Metab ; 6(3): 448-457, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38418586

RESUMO

Insulin resistance is an early complication of diet-induced obesity (DIO)1, potentially leading to hyperglycaemia and hyperinsulinaemia, accompanied by adaptive ß cell hypertrophy and development of type 2 diabetes2. Insulin not only signals via the insulin receptor (INSR), but also promotes ß cell survival, growth and function via the insulin-like growth factor 1 receptor (IGF1R)3-6. We recently identified the insulin inhibitory receptor (inceptor) as the key mediator of IGF1R and INSR desensitization7. But, although ß cell-specific loss of inceptor improves ß cell function in lean mice7, it warrants clarification whether inceptor signal inhibition also improves glycaemia under conditions of obesity. We assessed the glucometabolic effects of targeted inceptor deletion in either the brain or the pancreatic ß cells under conditions of DIO in male mice. In the present study, we show that global and neuronal deletion of inceptor, as well as its adult-onset deletion in the ß cells, improves glucose homeostasis by enhancing ß cell health and function. Moreover, we demonstrate that inceptor-mediated improvement in glucose control does not depend on inceptor function in agouti-related protein-expressing or pro-opiomelanocortin neurons. Our data demonstrate that inceptor inhibition improves glucose homeostasis in mice with DIO, hence corroborating that inceptor is a crucial regulator of INSR and IGF1R signalling.


Assuntos
Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Camundongos , Masculino , Animais , Células Secretoras de Insulina/metabolismo , Glucose/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Obesidade/genética , Obesidade/metabolismo , Dieta , Insulina/metabolismo , Homeostase , Neurônios/metabolismo
11.
Mol Metab ; 83: 101915, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38492844

RESUMO

OBJECTIVE: The glucose-dependent insulinotropic polypeptide (GIP) decreases body weight via central GIP receptor (GIPR) signaling, but the underlying mechanisms remain largely unknown. Here, we assessed whether GIP regulates body weight and glucose control via GIPR signaling in cells that express the leptin receptor (Lepr). METHODS: Hypothalamic, hindbrain, and pancreatic co-expression of Gipr and Lepr was assessed using single cell RNAseq analysis. Mice with deletion of Gipr in Lepr cells were generated and metabolically characterized for alterations in diet-induced obesity (DIO), glucose control and leptin sensitivity. Long-acting single- and dual-agonists at GIPR and GLP-1R were further used to assess drug effects on energy and glucose metabolism in DIO wildtype (WT) and Lepr-Gipr knock-out (KO) mice. RESULTS: Gipr and Lepr show strong co-expression in the pancreas, but not in the hypothalamus and hindbrain. DIO Lepr-Gipr KO mice are indistinguishable from WT controls related to body weight, food intake and diet-induced leptin resistance. Acyl-GIP and the GIPR:GLP-1R co-agonist MAR709 remain fully efficacious to decrease body weight and food intake in DIO Lepr-Gipr KO mice. Consistent with the demonstration that Gipr and Lepr highly co-localize in the endocrine pancreas, including the ß-cells, we find the superior glycemic effect of GIPR:GLP-1R co-agonism over single GLP-1R agonism to vanish in Lepr-Gipr KO mice. CONCLUSIONS: GIPR signaling in cells/neurons that express the leptin receptor is not implicated in the control of body weight or food intake, but is of crucial importance for the superior glycemic effects of GIPR:GLP-1R co-agonism relative to single GLP-1R agonism.


Assuntos
Peso Corporal , Ingestão de Alimentos , Polipeptídeo Inibidor Gástrico , Camundongos Knockout , Obesidade , Receptores dos Hormônios Gastrointestinais , Receptores para Leptina , Animais , Masculino , Camundongos , Polipeptídeo Inibidor Gástrico/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Glucose/metabolismo , Leptina/metabolismo , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Receptores dos Hormônios Gastrointestinais/metabolismo , Receptores dos Hormônios Gastrointestinais/genética , Receptores para Leptina/metabolismo , Receptores para Leptina/genética , Transdução de Sinais
12.
Nat Metab ; 5(12): 2075-2085, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37946085

RESUMO

The development of single-molecule co-agonists for the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) is considered a breakthrough in the treatment of obesity and type 2 diabetes. But although GIPR-GLP-1R co-agonism decreases body weight with superior efficacy relative to GLP-1R agonism alone in preclinical1-3 and clinical studies4,5, the role of GIP in regulating energy metabolism remains enigmatic. Increasing evidence suggests that long-acting GIPR agonists act in the brain to decrease body weight through the inhibition of food intake3,6-8; however, the mechanisms and neuronal populations through which GIP affects metabolism remain to be identified. Here, we report that long-acting GIPR agonists and GIPR-GLP-1R co-agonists decrease body weight and food intake via inhibitory GABAergic neurons. We show that acyl-GIP decreases body weight and food intake in male diet-induced obese wild-type mice, but not in mice with deletion of Gipr in Vgat(also known as Slc32a1)-expressing GABAergic neurons (Vgat-Gipr knockout). Whereas the GIPR-GLP-1R co-agonist MAR709 leads, in male diet-induced obese wild-type mice, to greater weight loss and further inhibition of food intake relative to a pharmacokinetically matched acyl-GLP-1 control, this superiority over GLP-1 vanishes in Vgat-Gipr knockout mice. Our data demonstrate that long-acting GIPR agonists crucially depend on GIPR signaling in inhibitory GABAergic neurons to decrease body weight and food intake.


Assuntos
Diabetes Mellitus Tipo 2 , Masculino , Camundongos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Polipeptídeo Inibidor Gástrico/metabolismo , Obesidade/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptores Acoplados a Proteínas G , Glucose , Neurônios GABAérgicos/metabolismo , Ingestão de Alimentos
13.
Nutrients ; 14(9)2022 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-35565902

RESUMO

The increasing consumption of highly processed foods with high amounts of saturated fatty acids and simple carbohydrates is a major contributor to the burden of overweight and obesity. Additionally, an unhealthy diet in combination with chronic stress exposure is known to be associated with the increased prevalence of central nervous system diseases. In the present study, the global brain proteome approach was applied to explore protein alterations after exposure to the Western diet and/or stress. Female adult rats were fed with the Western diet with human snacks and/or subjected to chronic stress induced by social instability for 12 weeks. The consumption of the Western diet resulted in an obese phenotype and induced changes in the serum metabolic parameters. Consuming the Western diet resulted in changes in only 5.4% of the proteins, whereas 48% of all detected proteins were affected by chronic stress, of which 86.3% were down-regulated due to this exposure to chronic stress. However, feeding with a particular diet modified stress-induced changes in the brain proteome. The down-regulation of proteins involved in axonogenesis and mediating the synaptic clustering of AMPA glutamate receptors (Nptx1), as well as proteins related to metabolic processes (Atp5i, Mrps36, Ndufb4), were identified, while increased expression was detected for proteins involved in the development and differentiation of the CNS (Basp1, Cend1), response to stress, learning and memory (Prrt2), and modulation of synaptic transmission (Ncam1, Prrt2). In summary, global proteome analysis provides information about the impact of the combination of the Western diet and stress exposure on cerebrocortical protein alterations and yields insight into the underlying mechanisms and pathways involved in functional and morphological brain alterations as well as behavioral disturbances described in the literature.


Assuntos
Dieta Ocidental , Proteoma , Animais , Proteínas de Ligação a Calmodulina/metabolismo , Proteínas do Citoesqueleto/metabolismo , Dieta Hiperlipídica , Dieta Ocidental/efeitos adversos , Fast Foods , Feminino , Proteínas do Tecido Nervoso/metabolismo , Obesidade/metabolismo , Proteoma/metabolismo , Ratos , Lobo Temporal/metabolismo
14.
Nat Metab ; 4(8): 1071-1083, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35995995

RESUMO

Dual agonists activating the peroxisome proliferator-activated receptors alpha and gamma (PPARɑ/ɣ) have beneficial effects on glucose and lipid metabolism in patients with type 2 diabetes, but their development was discontinued due to potential adverse effects. Here we report the design and preclinical evaluation of a molecule that covalently links the PPARɑ/ɣ dual-agonist tesaglitazar to a GLP-1 receptor agonist (GLP-1RA) to allow for GLP-1R-dependent cellular delivery of tesaglitazar. GLP-1RA/tesaglitazar does not differ from the pharmacokinetically matched GLP-1RA in GLP-1R signalling, but shows GLP-1R-dependent PPARɣ-retinoic acid receptor heterodimerization and enhanced improvements of body weight, food intake and glucose metabolism relative to the GLP-1RA or tesaglitazar alone in obese male mice. The conjugate fails to affect body weight and glucose metabolism in GLP-1R knockout mice and shows preserved effects in obese mice at subthreshold doses for the GLP-1RA and tesaglitazar. Liquid chromatography-mass spectrometry-based proteomics identified PPAR regulated proteins in the hypothalamus that are acutely upregulated by GLP-1RA/tesaglitazar. Our data show that GLP-1RA/tesaglitazar improves glucose control with superior efficacy to the GLP-1RA or tesaglitazar alone and suggest that this conjugate might hold therapeutic value to acutely treat hyperglycaemia and insulin resistance.


Assuntos
Diabetes Mellitus Tipo 2 , PPAR alfa , Alcanossulfonatos , Animais , Peso Corporal , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1 , Glucose , Masculino , Camundongos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , PPAR alfa/agonistas , PPAR alfa/uso terapêutico , Fenilpropionatos
15.
Front Endocrinol (Lausanne) ; 12: 568197, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33716957

RESUMO

Obesity cardiomyopathy increases the risk of heart failure and death. Obesity is curable, leading to the restoration of the heart phenotype, but it is not clear if there are any after-effects of obesity present after weight loss. We characterize the proteomic landscape of obesity cardiomyopathy with an evaluation of whether the cardiac phenotype is still shaped after weight loss. Cardiomyopathy was validated by cardiac hypertrophy, fibrosis, oversized myocytes, and mTOR upregulation in a rat model of cafeteria diet-induced developmental obesity. By global proteomic techniques (LC-MS/MS) a plethora of molecular changes was observed in the heart and circulation of obese animals, suggesting abnormal utilization of metabolic substrates. This was confirmed by increased levels of cardiac ACSL-1, a key enzyme for fatty acid degradation and decreased GLUT-1, a glucose transporter in obese rats. Calorie restriction and weight loss led to the normalization of the heart's size, but fibrosis was still excessive. The proteomic compositions of cardiac tissue and plasma were different after weight loss as compared to control. In addition to morphological consequences, obesity cardiomyopathy involves many proteomic changes. Weight loss provides for a partial repair of the heart's architecture, but the trace of fibrotic deposition and proteomic alterations may occur.


Assuntos
Cardiomiopatias , Obesidade , Redução de Peso/fisiologia , Animais , Restrição Calórica , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Modelos Animais de Doenças , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Miocárdio/ultraestrutura , Obesidade/complicações , Obesidade/dietoterapia , Obesidade/metabolismo , Obesidade/patologia , Proteoma/análise , Proteoma/metabolismo , Proteômica , Ratos , Ratos Long-Evans
16.
Front Cell Neurosci ; 15: 733607, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34456688

RESUMO

Experimental and clinical data support the neuroprotective properties of the ketogenic diet and ketone bodies, but there is still a lot to discover to comprehensively understand the underlying mechanisms. Autophagy is a key mechanism for maintaining cell homeostasis, and therefore its proper function is necessary for preventing accelerated brain aging and neurodegeneration. Due to many potential interconnections, it is possible that the stimulation of autophagy may be one of the mediators of the neuroprotection afforded by the ketogenic diet. Recent studies point to possible interconnections between ketone body metabolism and autophagy. It has been shown that autophagy is essential for hepatic and renal ketogenesis in starvation. On the other hand, exogenous ketone bodies modulate autophagy both in vitro and in vivo. Many regional differences occur between brain structures which concern i.e., metabolic responses and autophagy dynamics. The aim of the present study was to evaluate the influence of the ketogenic diet on autophagic markers and the ketone body utilizing and transporting proteins in the hippocampus and frontal cortex. C57BL/6N male mice were fed with two ketogenic chows composed of fat of either animal or plant origins for 4 weeks. Markers of autophagosome formation as well as proteins associated with ketolysis (BDH1-3-hydroxybutyrate dehydrogenase 1, SCOT/OXCT1-succinyl CoA:3-oxoacid CoA transferase), ketone transport (MCT1-monocarboxylate transporter 1) and ketogenesis (HMGCL, HMGCS2) were measured. The hippocampus showed a robust response to nutritional ketosis in both changes in the markers of autophagy as well as the levels of ketone body utilizing and transporting proteins, which was also accompanied by increased concentrations of ketone bodies in this brain structure, while subtle changes were observed in the frontal cortex. The magnitude of the effects was dependent on the type of ketogenic diet used, suggesting that plant fats may exert a more profound effect on the orchestrated upregulation of autophagy and ketone body metabolism markers. The study provides a foundation for a deeper understanding of the possible interconnections between autophagy and the neuroprotective efficacy of nutritional ketosis.

17.
J Nutr Biochem ; 93: 108620, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33705944

RESUMO

Many of the metabolic effects evoked by the ketogenic diet mimic the actions of fasting and the benefits of the ketogenic diet are often attributed to these similarities. Since fasting is a potent autophagy inductor in vivo and in vitro it has been hypothesized that the ketogenic diet may upregulate autophagy. The aim of the present study was to provide a comprehensive evaluation of the influence of the ketogenic diet on the hepatic autophagy. C57BL/6N male mice were fed with two different ketogenic chows composed of fat of either animal or plant origin for 4 weeks. To gain some insight into the time frame for the induction of autophagy on the ketogenic diet, we performed a short-term experiment in which animals were fed with ketogenic diets for only 24 or 48 h. The results showed that autophagy is upregulated in the livers of animals fed with the ketogenic diet. Moreover, the size of the observed effect was likely dependent on the diet composition. Subsequently, the markers of regulatory pathways that may link ketogenic diet action to autophagy were measured, i.e., the activity of mTORC1, activation of AMPK, and the levels of SIRT1, p53, and FOXO3. Overall, observed treatment-specific effects including the upregulation of SIRT1 and downregulation of FOXO3 and p53. Finally, a GC/MS analysis of the fatty acid composition of animals' livers and the chows was performed in order to obtain an idea about the presence of specific compounds that may shape the effects of ketogenic diets on autophagy.


Assuntos
Autofagia/fisiologia , Dieta Cetogênica , Gorduras na Dieta/farmacologia , Cetose/metabolismo , Fígado/fisiologia , Regulação para Cima/efeitos dos fármacos , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Gorduras na Dieta/análise , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plantas , Transdução de Sinais , Sirtuína 1/genética , Sirtuína 1/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
18.
Nutrients ; 13(12)2021 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-34959794

RESUMO

BACKGROUND: In the pathogenesis of central nervous system disorders (e.g., neurodegenerative), an important role is attributed to an unhealthy lifestyle affecting brain energy metabolism. Physical activity in the prevention and treatment of lifestyle-related diseases is getting increasing attention. METHODS: We performed a series of assessments in adult female Long Evans rats subjected to 6 weeks of Western diet feeding and wheel-running training. A control group of lean rats was fed with a standard diet. In all experimental groups, we measured physiological parameters (animal weights, body composition, serum metabolic parameters). We assessed the impact of simultaneous exposure to a Western diet and wheel-running on the cerebrocortical protein expression (global proteomic profiling), and in the second part of the experiment, we measured the cortical levels of protein related to brain metabolism (Western blot). RESULTS: Western diet led to an obese phenotype and induced changes in the serum metabolic parameters. Wheel-running did not reduce animal weights or fat mass but significantly decreased serum glucose level. The global proteome analysis revealed that the altered proteins were functionally annotated as they were involved mostly in metabolic pathways. Western blot analysis showed the downregulation of the mitochondrial protein-Acyl-CoA dehydrogenase family member 9, hexokinase 1 (HK1)-enzyme involved in principal glucose metabolism pathways and monocarboxylate transporter 2 (MCT2). Wheel-running reversed this decline in the cortical levels of HK1 and MCT2. CONCLUSION: The cerebrocortical proteome is affected by a combination of physical activity and Western diet in female rats. An analysis of the cortical proteins involved in brain energy metabolism provides a valuable basis for the deeper investigation of changes in the brain structure and function induced by simultaneous exposure to a Western diet and physical activity.


Assuntos
Encéfalo/metabolismo , Dieta Ocidental/efeitos adversos , Metabolismo Energético/fisiologia , Condicionamento Físico Animal/fisiologia , Animais , Feminino , Redes e Vias Metabólicas/fisiologia , Obesidade/fisiopatologia , Proteoma/metabolismo , Proteômica , Ratos , Ratos Long-Evans
19.
Mol Brain ; 13(1): 62, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32303271

RESUMO

Physical activity impacts brain functions, but the direct mechanisms of this effect are not fully recognized or understood. Among multidimensional changes induced by physical activity, brain fatty acids (FA) appear to play an important role; however, the knowledge in this area is particularly scarce. Here we performed global metabolomics profiling of the hippocampus and the frontal cortex (FC) in a model of voluntary running in mice. Examined brain structures responded differentially to physical activity. Specifically, the markers of the tricarboxylic acid (TCA) cycle were downregulated in the FC, whereas glycolysis was enhanced in the hippocampus. Physical activity stimulated production of myristic, palmitic and stearic FA; i.e., the primary end products of de novo lipogenesis in the brain, which was accompanied by increased expression of hippocampal fatty acid synthase (FASN), suggesting stimulation of lipid synthesis. The changes in the brain fatty acid profile were associated with reduced anxiety level in the running mice. Overall, the study examines exercise-related metabolic changes in the brain and links them to behavioral outcomes.


Assuntos
Ansiedade/metabolismo , Encéfalo/metabolismo , Ácidos Graxos/biossíntese , Condicionamento Físico Animal , Animais , Comportamento Animal , Metabolismo Energético , Hipocampo/fisiologia , Masculino , Metaboloma , Metabolômica , Camundongos Endogâmicos C57BL , Modelos Animais
20.
Appl Physiol Nutr Metab ; 43(2): 203-210, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29045796

RESUMO

The high-fat and low-carbohydrate ketogenic diet (HFKD) is extensively studied within the fields of numerous diseases, including cancer and neurological disorders. Since most studies incorporate animal models, ensuring the quality of ketogenic rodent diets is important, both in the context of laboratory animal welfare as well as for the accuracy of the obtained results. In this study we implemented a modification to a commonly used ketogenic rodent chow by replacing non-resorbable cellulose with wheat bran. We assessed the effects of month-long treatment with either the unmodified or the modified HFKD on the growth and development of young male rats. Daily body weight, functional performance, and brain morphometric parameters were assessed to evaluate the influence of both applied diets on rodent development. Our results revealed that the unmodified ketogenic chow induced strong side effects that included weakness, emaciation, and brain undergrowth concomitant to growth inhibition. However, application of the ketogenic chow supplemented with wheat bran suppressed these adverse side effects, which was associated with the restoration of insulin-like growth factor 1 and a decrease in corticosterone levels. We have also shown that the advantageous results of the modified HFKD are not species- or sex-specific. Our data indicate that the proposed HFKD modification even allows for its application in young animals, without causing detrimental side effects.


Assuntos
Dieta Cetogênica/efeitos adversos , Transtornos do Crescimento/dietoterapia , Ácido 3-Hidroxibutírico/sangue , Animais , Glicemia/metabolismo , Peso Corporal , Corticosterona/sangue , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Fibras na Dieta/administração & dosagem , Proteínas Alimentares/administração & dosagem , Modelos Animais de Doenças , Transtornos do Crescimento/etiologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Ratos , Ratos Long-Evans
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