Short-term aerobic physical exercise and ApoJ action: the interorgan communications between liver and hypothalamus

Abstract

Obesity is one of the most common metabolic diseases worldwide and the hypothalamus is responsible for fine-regulation of hunger control and energy expenditure through a coordinated communication between hypothalamic neurons. Important understandings of the neural mechanisms responsible for hunger control and thermogenesis have been elucidated since the discovery of leptin. Furthermore, experimental studies have shown a leptin resistance in the hypothalamus of obese animals, impairing the crucial effects of leptin on energy homeostasis. In hypothalamic neurons, when leptin binds to its membrane receptor (LepRb), the proteins Janus kinase 2 (JAK2) and transcription factor Signal transducer and activator of transcription 3 (STAT-3) are phosphorylated, culminating in the synthesis of propionomelanocortin (POMC) and cocaine and amphetamine-related transcript (CART) which are important anorexigenic peptides responsible for energy control. Participating in this mechanism of hunger control, the glycoprotein clusterin or apoliprotein J (ApoJ) and its receptor - LDL receptor related protein 2 (LRP2) - have recently been suggested as co-regulators of leptin signaling, since LRP2 interacts with the LepRb receptor in the hypothalamus and therefore stimulates JAK2 phosphorylation and consequently STAT-3 phosphorylation. Studies with SH-SY5Y human neuronal cells showed that in the presence of ApoJ, the affinity of leptin for its receptor LepRb was significantly increased, indicating that ApoJ stimulates leptin binding to its receptor in neuronal cells. Moreover, ApoJ administration into hypothalamus reduces food intake, body weight and activates hypothalamic STAT3 in mice. On the other hand, inhibition of approximately 70% of the hypothalamic ApoJ action increases food intake, body weight and adiposity. Moreover, given the crucial role of leptin in controlling energy homeostasis, find new strategies to improve leptin signaling is of great importance. Regular physical exercise seems to be a possible way of ameliorating leptin signaling by regulating several proteins involved in its signal transduction pathway in the hypothalamus and altering the levels of orexigenic and anorexigenic neuropeptides. Several studies have shown that aerobic exercise is able to activate the leptin pathway on the hypothalamus and consequently reduce food intake. Preliminary data from Dr. Kim`s laboratory show that the liver is the main organ producing ApoJ. Moreover, researchers from the same laboratory observed that ApoJ levels increase in human serum during aerobic exercise. Given this information, we would like to know if the effects of aerobic exercise on controlling hunger by improving hypothalamic leptin signaling is dependent on hepatic ApoJ. To achieve this goal, central nervous system-specific ApoJ knockout mice will be submitted to a short-term aerobic exercise. At the end of the study, we hope to list ApoJ as an important hepatocin able to control food intake by enhancing hypothalamic leptin signaling of obese mice. (AU)