Toward a Neuroimmunoendocrinology of Adipose Tissue.

Our understanding of the interactions between the different cell types populating endocrine organs has reached an unprecedented degree of complexity. This is particularly true of white adipose tissue, which until recently, was viewed as a passive lipid storage depot. The discovery of circulating factors secreted from adipocytes, including leptin (1), however, sparkled interest for adipose tissue as an endocrine organ that can modulate metabolic pathways at the organismal level (2, 3). Immunologists and neuroscientists also became increasingly interested in adipose tissue. In particular, there is a growing area of research concerned with the relations between adipocytes, resident macrophages and the sympathetic nervous system in the control of lipolysis, thermogenesis, insulin resistance, and the switch from white to brown fat (4–9). Moreover, ongoing research is trying to establish the functional relevance of brown adipose tissue in humans in situations of elevated sympathetic outflow (eg, cold) (10). Lastly, adding to the complexity of the aforementioned interactions and blurring the lines between conventional scientificdisciplines, adipocytes andadiposemacrophages have been discovered to release proinflammatory factors and neurotransmitters, respectively (11, 12). Therefore, adipose tissue is progressively being revisited as an important site of convergence for multiple regulatory systems, including, most notably, the nervous and immune systems. In this issue of Endocrinology, Tang et al (13) provided additional evidence of the complex interactions that exist between adipocytes, sympathetic nerves, and macrophages. Briefly, using a combination of in vivo and in vitro experiments, the authors established that norepinephrine derived from the sympathetic nervous system constitutively down-regulated the expression of TNFin mouse white and brown adipose tissues (Figure 1). More interestingly, using pharmacology and several knock-out models, they narrowed down the signaling pathways responsible for the immunosuppressive actions of norepinephrine (13). Specifically, the 2-adrenergic receptor and protein kinase A signaling pathways were shown to be required for the downregulation of TNFin adipose macrophages. In contrast, the 3-adrenergic receptor mediated norepinephrine-induced lipolysis. To the best of my knowledge, relatively few studies have examined the immunomodulatory role of the sympatheticnervoussystemonadipose tissue.However,one previous study (14) demonstrated that the administration of leptin in ob/ob mice was correlated with an adrenergic-dependent accumulation of antiinflammatory markers in adiposemacrophages.Overall, the2aforementionedstudiesare consistent with one another. In my view, the above results are not entirely surprising given the known immunosuppressive effects of the sympathetic nervous system when activated by psychogenic stressors (15). Interestingly, the aforementioned neuroimmune interactions appear to be under the control of the hypothalamic neuropeptide Agouti-related protein (AgRP) (Figure 1). Specifically, the acute intracerebroventricular administration of AgRP induced a 2-fold increase in the levels of TNFmRNA in white adipose tissue, but not in brown adipose tissue (13). Although fasting greatly stimulates the activity of AgRP neurons (16), it is also associated with a complex chain of events in white adipose tissue, including a transient rise in inflammatory markers, lipolysis, and infiltration of immune cells (17–19). In light of the data provided by Tang et al (13), altered sympathetic signaling in macrophages may contribute to the intraadipose adaptations seen in response to fasting. Of