Unraveling liver-derived signals against obesity and diabetes

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Metabolism is coordinated and regulated among different organs/tissues throughout the body. This coordinated metabolic regulation is apparently essential for maintaining systemic homeostasis, particularly glucose and energy metabolism. Therefore, communication among organs/tissues is extremely important and perturbation of this control system may lead to the development of metabolic disorders. During this decade, the versatility of adipose tissue as an endocrine organ and as a contributor to disease development has been established. However, a number of recent studies have shown that tissue-specific knockout mice exhibit unexpected phenotypes, suggesting the presence of many as yet unknown forms of cross-talk among organs/tissues.We have identified several systems consisting of autonomic nerve circuits, i.e. metabolic information highways, which play important roles in conveying inter-organ communication regarding metabolism. This is exemplified by the discovery of involvement of the afferent hepatic vagus in energy expenditure and fat accumulation. We expressed PPAR_γ in the liver, resulting in enhanced lipolysis in fat tissue and increased systemic energy expenditure. Thus, in response to lipid accumulation in the liver, hepatic vagal afferents transmit information regarding excess energy accumulation to the brain, thereby increasing sympathetic outflow to enhance energy expenditure.Our findings indicate that the brain obtains a variety of metabolic information from peripheral organs/tissues, resulting in cooperative metabolic regulation among tissues/organs throughout the body. Furthermore, these systems appear to contribute to pathological features of the metabolic syndrome under the condition of long-term excess calorie intake. Thus, elucidation of these regulatory systems may facilitate unraveling the mechanisms underlying metabolic homeostasis and those underlying development of the metabolic syndrome.