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Long-term hypercaloric diet consumption exacerbates age-induced metabolic dysfunction: Beneficial effects of CSN denervation
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RESUMO: A crescente incidência de distúrbios metabólicos, como resistência à insulina, diabetes
tipo 2 (T2D), dislipidemia, doença hepática gordurosa não alcoólica (NAFLD),
obesidade e síndrome metabólica (SM), atingiu proporções epidêmicas. A expectativa
de vida está a aumentar mundialmente e o envelhecimento está associado a uma alta
prevalência desses distúrbios, sendo crucial parar esta epidemia.
Os corpos carotídeos (CB) são quimiorreceptores periféricos, classicamente definidos
como sensores de O2 implicados na homeostase energética. Trabalhos anteriores
mostraram em animais jovens com 25 semanas de dietas hipercalóricas, que a abolição
da atividade do CB restaurava a sensibilidade à insulina e a tolerância à glucose.
Sabendo que a idade contribui para a resistência à insulina, o objetivo geral deste
trabalho foi investigar em ratos velhos o impacto de dietas hipercalóricas perlongadas e
abolição da atividade do CB, através da ressecção do nervo do seio carotídeo (CSN) na
homeostase da glucose. Sabendo que a NAFLD é uma das principais comorbidades
associadas ao dismetabolismo, focamos no metabolismo hepático. Ratos idosos foram
alimentados com dieta hipercalórica (HFHSu) por 44 semanas, após esse período,
metade foi submetido à ressecção do CSN e a outra à cirurgia sham. Os animais foram
acompanhados durante 9 semanas, avaliando-se a sensibilidade à insulina, tolerância à
glucose, glicemia em jejum, variação de peso e gordura. Após o procedimento terminal
o perfil lipídico, conteúdo lipídico hepático e análise hepatocelular foram avaliados. A
abolição da atividade CB/CSN em ratos idosos reduziu o ganho de peso, restaurou a
sensibilidade à insulina e a tolerância à glucose, diminuiu os triglicerídeos plasmáticos e
teve um impacto benéfico na função hepática.
Concluindo, este estudo demonstrou pela primeira vez que a modulação da atividade
do CB pode ser uma potencial intervenção terapêutica em disfunções metabólicas
induzidas pela idade, exacerbadas pela dieta, assim como dismetabolismo associado ao
fígado em animais jovens e velhos.
ABSTRACT: The increasing incidence of metabolic disorders, like insulin resistance, type 2 diabetes (T2D), dyslipidemia, non-alcoholic fatty liver disease (NAFLD), obesity and metabolic syndrome (MS), has reached epidemic proportions. Knowing that life expectancy is increasing worldwide and that ageing is associated with a high prevalence of these disorders, it is crucial to stop this epidemic. The carotid bodies (CB) are peripheral chemoreceptors, classically defined as O2 sensors, also implicated in energy homeostasis. Our previous work showed in young animals submitted to 25 weeks of hypercaloric diets that the abolition of the CB activity restored the insulin sensitivity and glucose tolerance. Knowing that age is associated with the development of insulin resistance, the general aim of this work was to investigate the impact of long-term hypercaloric diet consumption and the abolishment of CB activity, through the CB sensitive nerve resection, the carotid sinus nerve (CSN) on glucose homeostasis in older rats. Also, knowing that NAFLD is one of the core comorbidities associated with dysmetabolism, we have focus on liver metabolism. Aged rats were fed with high-fat high-sucrose (HFHSu) diet for 44 weeks and after this period half was submitted to CSN resection and the other to a sham surgery. Animals were followed-up during 9 weeks for insulin sensitivity, glucose tolerance, fasting plasma glucose, weight and fat variation. After a terminal experiment lipid profile, liver lipid content and hepatocellular analysis were assessed. Abolishment of the CB/CSN activity in old rats reduced weight gain, restored insulin sensitivity and glucose tolerance, decreased plasma triglycerides and had beneficial impact on liver function. Concluding, this study demonstrated for the first time that the modulation of the CB activity might be a potential therapeutic intervention in age-induced and diet exacerbated metabolic dysfunctions, as well in liver-associated metabolic dysfunction in young and old animals.
ABSTRACT: The increasing incidence of metabolic disorders, like insulin resistance, type 2 diabetes (T2D), dyslipidemia, non-alcoholic fatty liver disease (NAFLD), obesity and metabolic syndrome (MS), has reached epidemic proportions. Knowing that life expectancy is increasing worldwide and that ageing is associated with a high prevalence of these disorders, it is crucial to stop this epidemic. The carotid bodies (CB) are peripheral chemoreceptors, classically defined as O2 sensors, also implicated in energy homeostasis. Our previous work showed in young animals submitted to 25 weeks of hypercaloric diets that the abolition of the CB activity restored the insulin sensitivity and glucose tolerance. Knowing that age is associated with the development of insulin resistance, the general aim of this work was to investigate the impact of long-term hypercaloric diet consumption and the abolishment of CB activity, through the CB sensitive nerve resection, the carotid sinus nerve (CSN) on glucose homeostasis in older rats. Also, knowing that NAFLD is one of the core comorbidities associated with dysmetabolism, we have focus on liver metabolism. Aged rats were fed with high-fat high-sucrose (HFHSu) diet for 44 weeks and after this period half was submitted to CSN resection and the other to a sham surgery. Animals were followed-up during 9 weeks for insulin sensitivity, glucose tolerance, fasting plasma glucose, weight and fat variation. After a terminal experiment lipid profile, liver lipid content and hepatocellular analysis were assessed. Abolishment of the CB/CSN activity in old rats reduced weight gain, restored insulin sensitivity and glucose tolerance, decreased plasma triglycerides and had beneficial impact on liver function. Concluding, this study demonstrated for the first time that the modulation of the CB activity might be a potential therapeutic intervention in age-induced and diet exacerbated metabolic dysfunctions, as well in liver-associated metabolic dysfunction in young and old animals.
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Palavras-chave
Envelhecimento Corpo carotídeo Ressecção do nervo carotídeo Resistência à insulina Fígado Doenças metabólicas Doença hepática gordurosa não alcoólica Sistema nervoso simpático Diabetes tipo 2 Ageing Carotid body Carotid sinus nerve resection Dyslipidemia Insulin resistance Liver Metabolic diseases Non-alcoholic fatty liver disease Sympathetic nervous system Type 2 diabetes