Obesity and associated health consequences comprise the greatest public health challenge of our time. Worldwide, ~1.5 billion people tip the scales as overweight, 300-500 million of whom are obese, placing nearly a quarter of humanity at dramatically increased risk for diabetes, cardiovascular disease, and many types of cancer [1
]. While our considerable scientific investments have barely begun to slow the expansion of our waistlines, they have already yielded unexpected physiologic insights, perhaps the greatest of which is the discovery of the unprecedented level of cooperation between parenchymal cells and leukocytes necessary for proper function in metabolic tissues.
For almost two centuries, the stereotyped appearances of basic human tissues have been staples of medical textbooks [3
]. Despite this well-worn familiarity, it was not until recently that cellular inventory of these tissues revealed remarkable numbers of macrophages and other leukocytes tucked away among the more familiar parenchymal cells. However, rather than being randomly distributed, these leukocytes were arranged in stereotyped, reproducible patterns that were tissue-specific [4
]. For example, liver samples consistently harbored similar numbers of macrophages (also known as Kupffer cells) arranged in the same peri-sinusoidal pattern, whereas brain tissues demonstrated similarly constant complements of microglia (resident macrophages of the central nervous system). Indeed, macrophage representation is significant and similar (~5-15%) across nearly every tissue and remarkably well conserved across vertebrate species [6
]. Perhaps most interesting of all, however, is that depletion of macrophages from any given tissue results not in permanent loss, haphazard recolonization, or encroachment by other leukocyte lineages, but in rapid and precise restoration of the original macrophage complement in both spatial and numerical terms [8
While the macrophage's infiltrative penchant has long been appreciated, the precision and rigidity of their arrangements in healthy tissues, the conservation of these patterns across vertebrate species, and their rapid and precise re-establishment following depletion suggest that specific set points exist for ensuring an appropriate complement of leukocytes in each tissue. Furthermore, the temporal stability and aggressive re-establishment of macrophage-parenchyma relationships suggest that active mechanisms exist to maintain this interaction within specific parameters [7
]. Indeed, recent work has begun to unearth the complex recruitment and retention networks dedicated to the maintenance and survival of resident leukocyte/macrophage populations, e.g. recruitment and survival of CX3
monocytes by tissue-derived CX3
CL1 and Csf1 [4
]. Needless to say, such sophisticated arrangements — especially in tissues with little risk of infection — are not easily explained by traditional theories of host defense. Why then would parenchymal cells go to such lengths to accoutre themselves with macrophages? In answer, numerous studies have now demonstrated that resident macrophages shoulder critical, non-immunologic tissue functions: for example, microglia are required for proper synapse formation and function [10
], resident intestinal macrophages are necessary to maintain gut epithelial integrity [11
], and bone marrow resident macrophages act as critical components of the hematopoietic stem cell niche [12
]. Together, these observations suggest that, as a general principle, vertebrate tissues are critically dependent on resident tissue macrophages to perform their primary functions. In this review, we will explore these concepts as they operate within white and brown adipose tissue physiology. Specifically, we will review recent findings demonstrating novel and non-redundant roles for resident leukocytes in adipose tissue metabolism and discuss how alterations in leukocyte “set points” (numbers and activation status) contribute to the pathogenesis of metabolic disease.