Adipose tissue and the immune system

Abstract

Adipocytes anatomically associated with lymph nodes (and omental milky spots) have many special properties including fatty acid composition and the control of lipolysis that equip them to interact locally with lymphoid cells. Lymph node lymphocytes and tissue dendritic cells acquire their fatty acids from the contiguous adipocytes. Lymph node-derived dendritic cells suppress lipolysis in perinodal adipocytes but those that permeate the adipose tissue stimulate lipolysis, especially after minor, local immune stimulation. Inflammation alters the composition of fatty acids incorporated into dendritic cells, and that of node-containing adipose tissue, counteracting the effects of dietary lipids. Thus these specialised adipocytes partially emancipate the immune system from fluctuations in the abundance and composition of dietary lipids.

Prolonged, low-level immune stimulation induces the local formation of more adipocytes, especially adjacent to the inflamed lymph node. This mechanism may contribute to hypertrophy of the mesentery and omentum in chronic inflammatory diseases such as HIV-infection, and in smokers. Paracrine interactions between adipose and lymphoid tissues are enhanced by diets rich in n-6 fatty acids and attentuated by fish oils. The latter improve immune function and body conformation in animals and people. The partitioning of adipose tissue in many depots, some specialised for local, paracrine interactions with other tissues, is a fundamental feature of mammals.

Introduction

Research into the functional association between adipose tissue and the immune system began in the early 1990s, when adipsin secreted from adipocytes was shown to be identical to complement factor D produced in the immune system [1], [2], [3]. Since then, many more protein secretions and/or cytokine receptors have been described [4]. In most cases, cytokines such as tumor necrosis factor-α (TNFα) and many interleukins were isolated first from the immune system and later found to be secreted by and/or taken up by adipocytes, but others, notably leptin [5], were identified first in adipose tissue and later shown to modulate immune function.

The possibility of using leptin or other appetite regulators as anti-obesity drugs has prompted intensive study of the metabolic interactions between the control of energy storage and immune function [6], [7]. Unfortunately much of the data come from mice, especially transgenics [8], and human biopsy samples. Mice and young rats are so small and lean that only the largest depots contain enough adipose tissue for most biochemical analyses. The choice is narrowed to the perirenal or gonadal (epididymal or parametrial) depots, both of which incorporate no lymphoid structures, and sometimes the inguinal, which contains a few nodes at the dorsal end. To avoid collateral damage, biopsy sites from humans and larger animals are always chosen for their surgical accessibility, which in practice means remoteness from lymph nodes and vessels, rather than for known site-specific properties. Consequently, information about the contributions of depots that incorporate lymphoid structures and those that are ‘pure’ adipose tissue is fragmentary, and does not readily suggest a coherent hypothesis.

Adipocytes in the omental, mesenteric and other depots that incorporate lymphoid structures synthesize much less leptin per unit mass than depots with little or no lymphoid tissue [9], [10], [11], [12]. As well as adipocytes, many other cell types are now known to secrete and/or respond to leptin [13] Bone marrow adipocytes produce a fair amount of leptin, at least in vitro [14], but so do the osteoblasts and chondrocytes themselves [15]. Leptin seems to be important for osteogenesis [16], [17]. No net uptake of leptin was measured in the human splanchnic or pulmonary regions, in spite of the presence of many lymph nodes and other lymphoid tissues in the spleen, omentum, mesentery, gut and lungs, although the legs, with relatively fewer lymph nodes, are net leptin exporters [18]. These observations are sufficient to show that conclusions that assume that the properties of large ‘pure adipose tissue’ depots or cell lines in vitro are representative of all adipose tissue can be misleading. Much of the confusion and paradoxical findings about the relationship between adipose stores and immune function can be clarified by taking account of site-specific properties of adipose tissue, and paracrine interactions between adipocytes and adjacent lymphoid cells.