Targeted disruption of ApoJ in microglia cells causes obesity

초록

Background The hypothalamus is a principal site of the brain that regulates body-weight homeostasis. Our work demonstrated that apolipoproteinJ (ApoJ, also known as clusterin) administration into the brain caused a significant reduction in food intake and body weight in mice, suggesting the anti-obesity effects of ApoJ. However, knowledge of the ApoJ’s anti-obesity action sites remains incomplete. Aim We thus investigated the physiological role of ApoJ in the development of obesity, with particular focus on the regulatory sites of ApoJ action. Method Mice bearing a loxP-flanked ApoJ allele (ApoJloxP/loxP mice) were generated. AAV-eGFP or AAV-Cre was injected into the mediobasal hypothalamus of ApoJloxP/loxP mice to delete ApoJ in the hypothalamic arcuate area of neurons. Using the Cre-LoxP system, mice lacking ApoJ in both microglia cells and hypothalamic neurons, including AgRP, POMC, and SF-1 neurons, were generated. Body weight, food intake, adiposity, and serum parameters from these mice were measured. Results After 14weeks of hypothalamic AAV injection, body weight was markedly increased by ~40% in AAV-Cre injected ApoJloxP/loxP mice compared to AAV-eGFP injected ApoJloxP/loxP mice. These effects are most likely due to increased food intake. However, selective deletion of ApoJ in hypothalamic arcuate neurons, including AgRP, POMC, and SF-1 neurons, does not affect body weight and adiposity, raising the possibility that sites other than hypothalamic neurons may be involved in ApoJ’s anti-obesity action. In fact, ApoJ’s effects on obesity are predominantly mediated by microglia cells (CX3CR1+), as evidenced by the fact that ApoJ deletion in microglia cells caused a remarkable increase in body weight and food intake. This weight gain was reflected by increases in fat mass measured by an MRI. Conclusion Our data demonstrate that ApoJ in microglia cells, but not in hypothalamic neurons, plays a significant role in regulating normal body-weight homeostasis and may offer a novel target for the treatment of obesity-related metabolic diseases.