Dinamismo mitocondrial em resposta ao jejum de 24 horas em camundongos magros e com obesidade

Abstract

Introduction: Obesity is characterized by the accumulation of body fat determined, in part, by positive energy balance and various cellular dysfunctions, including mitochondrial dysfunction. Mitochondria are dynamic and essential organelles for the adipose tissue remodeling process, as they are responsible for oxidizing energy substrates and providing energy. Thus, during obesity, metabolic inflexibility can hinder the preferential oxidation of fat by mitochondria, which can directly compromise the remodeling of adipose tissue. However, it is not clear how mitochondria in tissues with high oxidative capacity or in adipose depots respond to weight loss strategies in the context of obesity. Therefore, in this work we evaluated how mitochondrial dynamics occur in different tissues and at different ages, faced with the challenge of 24-hour fasting in lean and obese mice. Methods: Male c57/bl6 mice were divided into lean and diet-induced obesity groups and into groups of young and adult mice. Subsequently, mice from both groups were fasted for 24 hours and then euthanized. We evaluated systemic metabolic markers, respiratory coefficient (RQ), biogenesis markers and mitochondrial dynamics in inguinal adipose tissue (IAT) and epididymal adipose tissue (EAT), liver and gastrocnemius. Furthermore, we examined mitochondrial ultrastructure and the interaction between mitochondria and endoplasmic reticulum (ER) using transmission electron microscopy (TEM). Results: Lean mice showed a reduction in weight and adipose tissue after fasting for 24 hours, which was not observed in obese mice and adult mice. Furthermore, obese mice and adults exhibited metabolic inflexibility as they did not change their RQ after fasting. Mitochondria from the IAT, liver and gastrocnemius of lean mice showed characteristic mitochondrial fusion after fasting, as well as increased ER-mitochondria interaction. In contrast, mitochondria from obese mice remained smaller and more circular after fasting, demonstrating less dynamism compared to lean mice. However, these findings were site specific since the opposite was observed in EAT, mitochondria with a fission phenotype. Furthermore, interestingly we saw that mitochondria from the IAT and liver of mice with obesity showed a slight increase in ER-mitochondria interaction, resembling the interaction pattern seen in lean mice. However, this stimulus did not occur in the same way in the gastrocnemius of mice with obesity. Conclusions: Our results suggest that both obesity and aging appear to compromise cellular homeostasis in such a way that both metabolic inflexibility and mitochondrial dysfunction are associated with less remodeling of adipose tissue in response to the 24-hour fasting challenge. On the other hand, acute fasting appears to be a stressful stimulus that partially restores ER-mitochondria communication in obesity in some sites.