O papel da apolipoproteína J mediada pela micróglia e pelo exercício no metabolismo glicolítico e na sensibilidade à insulina em camundongos obesos induzidos por dieta

Author(s)

Kellen Cristina da Cruz Rodrigues

• Document type: Doctoral Thesis
• Press: Limeira, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Aplicadas
• Defense date: 2022-06-23

Examining board members

Leandro Pereira de Moura; Aykut Gokturk Uner; Ana Paula Pinto; Guilherme Zweig Rocha

• Advisor: Leandro Pereira de Moura; Young Bum Kim

Abstract

Obesity is one of the main public health problems in many countries, and understanding the pathophysiological mechanisms underlying the maintenance of energy and glucose homeostasis are essential for its treatment. The hypothalamus is responsible for modulating the neural responses that regulate the control of hunger and energy, and the microglia play an important role in the immune response and hypothalamic inflammation. Experimental studies have shown that obesity impairs leptin signaling in hypothalamic neurons, leading to leptin resistance. With regard to this, apolipoprotein J (ApoJ) and its receptor, LRP2, have recently been suggested as co-regulators of leptin signaling in the hypothalamus and therefore can be considered promising targets to treat obesity. Moreover, circulating ApoJ is positively associated with insulin resistance in obese and type 2 diabetes subjects. Synergistically, physical exercise is a non-pharmacological tool that is able to increase leptin sensitivity in the hypothalamus, and decrease the serum levels of ApoJ, which contributes to both reducing hyperphagia and insulin resistance. However, the effects of physical exercise on the hypothalamic ApoJ content are still unknown. This study aims to investigate the effects of short-term aerobic exercise on the hypothalamic ApoJ content as well as the metabolic profile of obese microglia ApoJ knockout mice. The study was divided into two phases; first, Swiss albino mice were divided into three groups lean controls, obese sedentary, and obese exercised. All obese exercised mice practiced aerobic exercise for seven consecutive days. The mice in obese groups received a high-fat diet. The obtained data revealed that sedentary obese mice reduced glucose sensitivity and increased serum levels of ApoJ, glucose, insulin, HOMA-IR, total cholesterol, and LDL. On the other hand, mice that practiced short-term aerobic exercise reduced food consumption and reversed the disturbances caused by obesity in glycemic homeostasis, which was concomitant to a reduction in circulating ApoJ levels. Interestingly, the exercised mice significantly increased the hypothalamic ApoJ protein content, which were negatively correlated with body weight and physiological parameters related to glycemic homeostasis. In the second phase of the study, we generated a mice strain lacking ApoJ in microglial cells (CX3CR1-Cre, ApoJflox/flox). In the first experiment with this strain, animals were fed a normal chow diet and a slight increase in body weight and serum leptin levels were observed. Then, mice were metabolically challenged with a high-fat diet and knockout mice showed insulin resistance, glucose intolerance, higher body fat mass as well as an increase in serum insulin and leptin levels. In addition, the results demonstrated a reduction of 60% of ApoJ mRNA levels in the hypothalamus of knockout animals compared to the controls. Serum ApoJ levels were not affected by ApoJ deletion in microglial cells whereas serum ApoJ was positively correlated with ApoJ content in several brain areas, liver, muscle, and white adipose tissue. Overall, the findings suggest that deletion of ApoJ in microglial cells severely worsens glucose intolerance and insulin resistance, and the practice of physical exercise might be an important non-pharmacological tool for the treatment of obesity (AU)

• FAPESP's process: 16/24406-4 - The role of physical exercise in pathways signaling of clusterin/leptin in hypothalamus of obese mice
• Grantee: Kellen Cristina da Cruz Rodrigues
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)