In vivo evidence for the involvement of the adipose tissue surrounding lymph nodes in immune responses.

Spontaneous lipolysis in the adipocytes surrounding the popliteal lymph node rose within 1 h of its being activated with a subcutaneous injection of lipopolysaccharide (LPS), reached a peak after 6-9 h, then declined almost to basal levels after 24 h. The response of adipocytes from elsewhere in the same depot was delayed and smaller. Following the simulated immune challenge, perinodal adipocytes were consistently more sensitive to noradrenalin at 10(-8) and 10(-7) M than those elsewhere in the same depot, but the maximum lipolysis, in the presence of 10(-5) M noradrenalin, was similar in all popliteal samples. These effects were increased by incubating adipose tissue explants for 24 h in tissue culture medium, suggesting autocrine amplification of the initial stimuli. Incubation with interleukin-4 (IL-4, 10 ng/ml) abolished the increase in lipolysis in samples around the activated lymph node and depressed it to below control values in other adipocytes. In vivo stimulation of the popliteal node increased maximum lipolysis in the presence of 10(-5) M noradrenalin in samples from around mesenteric lymph nodes and after 24 h incubation, in omental perinodal adipocytes. No effects of any pre-treatments were detected in perirenal adipocytes. We conclude that the adipocytes surrounding lymph nodes are actively involved in local, transient immune responses. Their participation may explain why most major lymph nodes are embedded in adipose tissue.

The mechanical properties of the dentine and cement of the tusk of the narwhal Monodon monoceros compared with those of other mineralized tissues.

Values for Young's modulus of elasticity, ultimate and yield stresses, ultimate and yield strains, work under the stress-strain curve and work of fracture were obtained from tensile and bending tests on specimens of narwhal tusk dentine and cement, femoral bone from young and mature cattle, and reindeer antler. Compared with the cattle bone the narwhal tissues had low Young's moduli, low yield stresses, rather low ultimate stresses and high ultimate strains. In all these properties they were similar to reindeer antler. The calcium content and hardness of the narwhal tissues were compared with those of human and cattle dental tissues. The narwhal dentine was considerably softer and less mineralized than human and cattle dentine. Human cementum was softer and less mineralized than cattle cementum, and was like narwhal cementum. In general, the mechanical properties of the narwhal tusk tissues were as would be expected from their mineral content, except that the stiffness of the cementum was low. It is likely that narwhal dentine is not very similar to human and cattle dentine in its mechanical properties.

Site-specific differences in the fatty acid composition of human adipose tissue.

The fatty acid composition of triacylglycerols from fifteen distinct adipose depots taken from each of seven adult male human subjects was compared. Oleic, palmitic, linoleic, stearic, myristic, palmitoleic and vaccenic acids accounted for more than 90% of the triacylglycerol fatty acids in all sites from all subjects; a number of other fatty acids were also identified and quantified. There were large differences in the average fatty acid composition between individual subjects. There were no site-specific differences in the proportions of myristic (3.8-4.7% of triacylglycerol fatty acids), palmitic (23-29%), linoleic (6.7-9.8%) or vaccenic (4.1-4.7%) acids or in the proportions of any of the less abundant fatty acids. There were some significant site-specific differences in the proportions of palmitoleic, oleic and stearic acids. The calf depot contained more palmitoleic acid (6.41 +/- 1.09%) than the trapezius (3.12 +/- 0.55%), perirenal (3.59 +/- 0.50%) and mesenteric (3.70 +/- 0.43%) depots, more oleic acid (42.13 +/- 1.27%) than the trapezius (36.03 +/- 2.18%), perirenal (36.50 +/- 1.56%) and breast (37.13 +/- 1.55%) depots and less stearic acid (5.18 +/- 0.89%) than the trapezius (8.57 +/- 0.97%), perirenal (8.49 +/- 0.75%), mesenteric (7.87 +/- 0.42%), breast (8.02 +/- 0.75%) and clavicular (8.34 +/- 0.78%) depots. The buttock depot contained less stearic acid (6.06 +/- 0.65%) than the perirenal, mesenteric and clavicular depots, while the anterior thigh depot contained less stearic acid (6.07 +/- 0.70%) than the perirenal depot. These findings indicate that, while most human adipose depots differ little in fatty acid composition, some sites, in particular the calf, perirenal, trapezius and mesenteric depots, have site-specific properties.

Adipose tissue: quartermaster to the lymph node garrisons.

Why is mammalian adipose tissue always split into a few large depots and many small ones, widely scattered around the body? Recent research suggests that fat cells (adipocytes) in the minor depots that enclose lymph nodes could be specialised to supply immune cells with the fuel and materials they need to mount a prompt, effective response to foreign invasion. Eliminating them or disrupting their relationship with immune cells may have unforeseen consequences.

What are subcutaneous adipocytes really good for?

Our acute awareness of the cosmetic, psychosocial and sexual importance of subcutaneous adipose tissue contrasts dramatically with how poorly we have understood the biology of this massive, enigmatic, often ignored and much-abused skin compartment. Therefore, it is timely to recall the exciting, steadily growing, yet underappreciated body of evidence that subcutaneous adipocytes are so much more than just 'fat guys', hanging around passively to conspire, at most, against your desperate attempts to maintain ideal weight. Although the subcutis, quantitatively, tends to represent the dominant architectural component of human skin, conventional wisdom confines its biological key functions to those of energy storage, physical buffer, thermoregulation and thermoinsulation. However, already the distribution of human superficial adipose tissue, by itself, questions how justified the popular belief is that 'skin fat' (which actually may be more diverse than often assumed) serves primarily thermoinsulatory purposes. And although the metabolic complications of obesity are well appreciated, our understanding of how exactly subcutaneous adipocytes contribute to extracutaneous disease - and even influence important immune and brain functions! - is far from complete. The increasing insights recently won into subcutaneous adipose tissue as a cytokine depot that regulates innate immunity and cell growth exemplarily serve to illustrate the vast open research expanses that remain to be fully explored in the subcutis. The following public debate carries you from the evolutionary origins and the key functional purposes of adipose tissue, via adipose-derived stem cells and adipokines straight to the neuroendocrine, immunomodulatory and central nervous effects of signals that originate in the subcutis - perhaps, the most underestimated tissue of the human body. The editors are confident that, at the end, you shall agree: No basic scientist and no doctor with a serious interest in skin, and hardly anyone else in the life sciences, can afford to ignore the subcutaneous adipocyte - beyond its ample impact on beauty, benessence and body mass.

Adipose tissue, the immune system and exercise fatigue: how activated lymphocytes compete for lipids.

Adipose depots that contain lymph nodes, and probably intermuscular fat in skeletal and cardiac muscle, are specialized to provision adjacent tissue in a paracrine mode. Perinodal adipocytes respond selectively to various cytokines and incorporate proportionately more polyunsaturated fatty acids. Lipolysis in the adipocytes of node-containing depots can be stimulated via inflammation of the enclosed lymph nodes. Repeated immune stimulation elicits properties characteristic of perinodal adipocytes in those elsewhere in the same depot, and hours later in other node-containing depots, but not in nodeless depots. Such site-specific properties of adipose tissue enable partitioning of dietary and metabolic supplies of fatty acids between competing tissues. Local interactions emancipate the peripheral immune system from competing with other tissues for lipids during immune responses, and may be especially important during periods of high demand, such as strenuous exercise. Biopsies of subcutaneous adipose tissue from sites remote from lymph nodes do not adequately represent the composition of fatty acids available to the immune system in situ, and perhaps that supplied to other tissues. Intermuscular fat in skeletal and cardiac muscle may also indicate paracrine relationships between adipocytes and "end-user" tissues. The concept of paracrine interactions between certain adipocytes and "user" tissue may account for the widespread contiguity between these tissues in vivo.

Long-term changes in adipose tissue in human disease.

Redistribution of white adipose tissue is a long-term symptom of several chronic diseases. Although the roles of adipocytes in acute illness have been thoroughly studied, how or why short-term responses of adipose tissue to disease sometimes produce long-term redistribution, and the causal relationship between the anatomical changes and the associated metabolic syndromes are poorly understood. The present paper reviews explanations for the redistribution of adipose tissue after infection with HIV, and in Crohn's disease; both conditions that share the peculiarity of selective expansion of certain adipose depots while others are depleted. HIV adipose tissue redistribution syndrome (HARS) develops gradually after several months of infection with the HIV both in untreated patients and in those taking protease inhibitors and nucleoside reverse transcriptase inhibitors. Some current theories about the causes of HARS are critically assessed, and reasons presented for implicating local interactions between the immune system and perinodal adipocytes. Some evolutionary aspects of conspicuous long-term changes in the distribution of human adipose tissue are discussed. Adipose tissue acts as a social signal, indicating dietary history and previous exposure to pathogens. A distinctive symptom of Crohn's disease is selective enlargement of the mesenteric adipose tissue near the diseased lymph nodes and intestine. Perinodal adipocytes have site-specific properties not found in adipocytes from nodeless depots, such as perirenal and epididymal, that may equip them to interact locally with lymph-node lymphoid cells, making polyunsaturated fatty acids selectively and rapidly available to activated immune cells. Studies of the time course of activation of perinodal adipocytes via the lymph nodes they enclose indicate that prolonged or frequent stimulation recruits more adipocytes to control by immune cells, which may lead to selective enlargement of node-containing depots. These concepts suggest hypotheses about HARS and the anomalous development of mesenteric adipose tissue in Crohn's disease that could form the basis for further investigations.

Site-specific and sex differences in the rates of fatty acid/triacylglycerol substrate cycling in adipose, tissue and muscle of sedentary and exercised dwarf hamsters (Phodopus sungorus).

Site-specific and sex differences in fatty acid/triacylglycerol substrate cycling in adipose tissue and muscle were found in vivo in adult hamsters (Phodopus sungorus) fed ad libitum, both at rest and immediately after moderate exercise. In adipose tissue, rates of fatty acid/triacylglycerol cycling at rest were highest in two small intermuscular depots and lowest in the groin, behind forelimb, epididymal and kidney sites. Cycling rates were significantly higher in the groin and in the two depots around the forelimb in females. Following an hour of exercise in a hamster ball, the rates of fatty acid/triacylglycerol cycling rose significantly in the intermuscular and certain superficial adipose fatty depots of both sexes, but the increases were more uniform in males. In females only, cycling rates in the skeletal muscles also increased significantly. The rates of fatty acid/triacylglycerol cycling in adipose tissue correlate closely with the site-specific activities of hexokinase and phosphofructokinase, but not with mean adipocyte volume per se. The data are consistent with the hypotheses that adipose depots are depleted selectively during exercise and that there are sex differences in the pattern of lipid mobilization.

The effects of dietary restriction and exercise on the volume of adipocytes in two intra-orbital depots in the guinea-pig.

The volume of adipocytes in two intra-orbital sites and fourteen superficial and intra-abdominal sites, and the total adipocyte complement have been measured in virgin and reproductive guinea-pigs maintained on several different regimens of diet and exercise. The adipocytes around the ocular muscles at the back of the orbit (peripheral fat) are always larger than those just behind the eyeball (orbital fat). The adipocytes in both the intra-orbital sites are significantly larger in guinea-pigs whose total adipocyte complement is smaller than one standard deviation from the mean, than in those which have a normal-size or large adipocyte complement. The volume of intra-orbital adipocytes correlates very significantly with the volume of adipocytes in superficial and intra-abdominal sites in guinea-pigs which have large adipocyte complements, correlates weakly in those with normal adipocyte complements and not at all in those with small adipocyte complements. It is suggested that there may be fewer intra-orbital adipocytes in animals which have small adipocyte complements, and that, because the intra-orbital adipose tissue occupies a constant volume, the adipocytes in these sites become larger when they are less numerous.

The anatomy of adipose tissue in captive Macaca monkeys and its implications for human biology.

In a sample of 31 sedentary, ad libitum-fed monkeys, most specimens had less than 5% adipose tissue by weight. Total fatness correlated closely with the number of adipocytes per kilogram lean body mass, but not at all with mean adipocyte volume, except in specimens below 5% fat. The total number of adipocytes per kilogram of lean body mass increased more than tenfold in the most obese specimens. These data suggest that, like humans but in contrast to laboratory rodents, adipocyte proliferation, not adipocyte enlargement, is the chief mechanism of adipose tissue expansion except in very lean monkeys. Adipose tissue was found in all the typical mammalian depots and in the superficial abdominal paunch, which enlarged disproportionately in obese specimens, forming an almost continuous layer over most of the body. Site-specific differences in the activities of some glycolytic enzymes were similar to those of other mammals. Adipocytes in the paunch depot showed biochemical properties in common with those in the groin depots. The distribution and cellularity of adipose tissue in normal humans were similar to those of exceptionally obese monkeys. Many of the interspecific and sex differences can be attributed to the much greater abundance of adipose tissue in humans, and may not be associated with hair reduction or aquatic habits. Some minor changes in the size or shape of certain adipose depots may have arisen recently under sexual selection. The relevance of laboratory rodents as animal models of human obesity is assessed from comparison of the cellular structure, anatomical distribution and enzyme profiles of adipose tissue in monkeys with those of human and other mammals.

Comparative aspects of hexokinase and phosphofructokinase activity in intermuscular adipose tissue.

1. The gross mass, mean adipocyte volume and activities of hexokinase (HK) and phosphofructokinase (PFK) were measured in adipose tissue from precisely identified intermuscular, superficial and intra-abdominal depots of 56 randomly collected wild and captive mammals and one bird. 2. In all intermuscular depots studied except that medial to the trapezius muscle, the activities of HK and PFK per adipocyte in adipose tissue in the centre of the depot were greater than in superficial and intra-abdominal depots of the same specimen. 3. These data are consistent with the suggestion that intermuscular adipose tissue may act as a local energy supply for adjacent muscles.

Biochemical correlates of the structural allometry and site-specific properties of mammalian adipose tissue.

1. The maximum activities of the glycolytic enzymes hexokinase (HK) and phosphofructokinase (PFK) were measured in defatted homogenates of adipose tissue from nine homologous depots of 57 wild and captive mammals belonging to 17 species and eight orders and differing in body mass by six orders of magnitude. 2. Site-specific differences in the enzyme activities were similar in all terrestrial species and were not consistently related to adipocyte volume. 3. The specimen-mean maximum activities of HK and PFK did not correlate with body mass, body composition or natural diet. 4. When specimens of different body composition and body mass were compared, glycolytic enzyme activity per adipocyte was directly proportional to adipocyte volume. 5. Site-specific differences in collagen content of adipose tissue did not correspond to those adipocyte volume. When homologous depots of different specimens were compared, the collagen content of adipose tissue was directly proportional to body mass. 6. Adipose tissue of large cetaceans contains more collagen than predicted from the allometric equations fitted to the data from terrestrial mammals. 7. Neither the scaling of the collagen content with body mass nor the site-specific differences in its abundance are consistent with a role as protection or support for adjacent tissues. 8. There are consistent site-specific differences in the extracellular components of adipose tissue as well as in the structure and metabolism of the adipocytes. 9. Adipose tissue differs from most other tissues in that its maximum metabolic capacities do not scale to body mass. 10. Adjustment of the biochemical activity of adipose tissue to changes in body mass and body composition must depend upon neural and endocrine controls, not upon intrinsic differences in its metabolic capabilities.

Site-specific properties of pericardial and epicardial adipose tissue: the effects of insulin and high-fat feeding on lipogenesis and the incorporation of fatty acids in vitro.

Lipogenesis and the rate of fatty acid incorporation in vitro were studied in the pericardial and epicardial adipose tissue of the guinea-pig heart and in the liver and two larger adipose depots. Both lipogenesis and the rate of fatty acid incorporation were higher in the cardiac depots than in any of the other tissues studied. The rate of fatty acid incorporation were unaffected by insulin (0.1 U/ml) in the cardiac depots in contrast to all other tissues examined, and lipogenesis was increased by insulin in the cardiac depots, but not in the other adipose depots or liver. High-fat feeding increased the rate of fatty acid incorporation in vitro in all tissues examined, but the rates of lipogenesis were unchanged except in perirenal adipose tissue (decrease) and liver (increase). The data are consistent with the hypothesis that epicardial adipose tissue may act as a local energy store for cardiac muscle and have a protective role against elevated levels of free fatty acid in the coronary circulation.

The effects of noradrenaline and insulin on lipolysis in adipocytes isolated from nine different adipose depots of guinea-pigs.

The rates of glycerol release in adipocytes isolated from nine identified adipose depots of sedentary or exercised guinea-pigs were measured in the presence of adenosine deaminase and 10(-9) to 10(-5) M noradrenaline and/or 1-1000 muunit/ml of bovine insulin. Twenty minutes of exercise increased the basal noradrenaline-stimulated rates of lipolysis in all depots, but these effects, and their interactions with in vitro application of the neurotransmitter differed between depots, showing that the long-lasting effects of exercise and the response to acute application of NA involve different mechanisms that may occur separately or together in different adipose depots. In general, large depots had the highest resting rates of lipolysis and the lowest responses to both noradrenaline and insulin, and lipolysis was only slightly different from the basal rate in adipocytes incubated with mixtures of the two agents. The two small intermuscular depots had the lowest unstimulated rates of lipolysis, but the fastest change and greatest maximum response to both agents. Noradrenaline-stimulated lipolysis was most effectively inhibited by small quantities of insulin in these depots. Different combinations of these properties were demonstrated in two smaller superficial depots, the mesenteric and omental depot, and in the cardiac depots. The data demonstrate the physiological inhomogeneity of both 'subcutaneous' and 'intra-abdominal' depots, and are consistent with the hypothesis that intermuscular adipose tissue interacts locally with adjacent muscle. Noradrenaline-stimulated lipolysis was more effectively inhibited by 100 muunit/ml insulin in adipocytes from the mesenteric and omental depot in those from any other site. A possible role for this property in the enlargement of this depot in hyperinsulinaemia in humans is proposed.

The effects of feeding suet-enriched chow on site-specific differences in the composition of triacylglycerol fatty acids in adipose tissue and its interactions in vitro with lymphoid cells.

The effects of diet on the composition and properties of adipose tissue in relation to lymph nodes were studied in adult guinea-pigs. The proportions of monoenoic triacylglycerol fatty acids were constant in all sites in adipose tissue of similarly fed guinea-pigs, but were substantially greater in samples from guinea-pigs fed on suet-enriched chow. Triacylglycerols in adipose tissue from near nodes contained significantly fewer saturated fatty acids, and significantly more 18:2n-6 and 18:3n-3 than those in samples from sites remote from nodes within the same depot. Depots that interact most strongly with lymphoid cells in vitro had the largest and most consistent within-depot differences. The gradients of triacylglycerol fatty acid composition with distance from lymph nodes in two small intermuscular depots were similar in guinea-pigs fed on plain or suet-enriched chow. These findings are consistent with the hypothesis that adipose tissue around lymph nodes is specialized for local interactions with the lymphoid cells therein, and help to explain the variability of serial or duplicate measurements of adipose tissue composition. When cultured alone, lipopolysaccharide-stimulated lymph node lymphoid cells from suet-fed guinea-pigs incorporated as much labelled thymidine as the controls. Adipose tissue explants from suet-fed guinea-pigs inhibited lymphocyte proliferation much less than those of the controls, although the site-specific differences were similar. The pattern of site-specific differences in glycerol released from explants incubated alone was generally similar for both dietary groups, but except in the popliteal depot, the increases following co-culturing with lymphoid cells were smaller for samples from suet-fed guinea-pigs. These experiments show that minor changes in the fatty acid composition of the diet can substantially alter the interactions between adipose tissue and lymphoid cells.

Adaptations of maternal adipose tissue to lactation.

The ability to store substantial amounts of energy as lipid in adipose tissue has allowed development of a variety of strategies in wild animals to meet the considerable metabolic challenge of lactation. The ability to use adipose tissue energy has also been critical for development of the exceptional rates of milk production achieved in the dairy cow. Lactation thus results in profound changes in adipose tissue metabolism, the molecular bases of which are beginning to be resolved in domestic ruminants and laboratory rodents. In addition to its role as an energy store, adipose tissue has a variety of other functions (e.g., modulation of mammary development, appetite, immune system function), some of which are important for lactation.

Interactions between adipose tissue around lymph nodes and lymphoid cells in vitro.

The functional relationships between lymphoid cells and the adipose tissue that surrounds lymph nodes were investigated in healthy adult guinea pigs. Lymphoid cells extracted from healthy adult guinea pigs were co-cultured for 48 h with adipose tissue explants from 18 sites defined by their anatomical relations to lymph nodes. Such explants from near a node suppressed lymphocyte proliferation stimulated with concanavalin A or lipopolysaccharide more than those from sites 5-10 mm from nodes. Inhibition was almost completely abolished by 500 microU insulin. The presence of lymphoid cells increased lipolysis (measured as glycerol release) in adipose tissue from all depots containing lymph nodes (i.e., except perirenal), especially in the presence of mitogens and with near-node samples from intermuscular and mesenteric depots. Inhibition of lymphocyte proliferation by adipose tissue was proportional to the additional lipolysis stimulated by the presence of lymphoid cells. For all depots except the mesenteric, glycerol release stimulated by lymphoid cells was inversely proportional to spontaneous lipolysis in adipose tissue cultured alone. These experiments demonstrate reciprocal interactions between lymphoid cells and adipose tissue, especially that around lymph nodes. The mediators of the action of adipose tissue on lymphoid cells probably include lipolytic products; mediators of the inverse effects are unknown.

Interactions of noradrenalin and tumour necrosis factor alpha, interleukin 4 and interleukin 6 in the control of lipolysis from adipocytes around lymph nodes.

The contributions of inflammatory and immunosuppressive cytokines and noradrenalin to the control of lipolysis in adipocytes surrounding and remote from lymph nodes were investigated in healthy adult guinea-pigs. A few hours after excision from fasting animals, spontaneous lipolysis in adipocytes from around the popliteal and mesenteric lymph nodes and omental "milky spots" was significantly lower than in those from elsewhere in the same depots, and much lower than in perirenal, epididymal or parametrial adipocytes. The perinodal adipocytes were consistently more sensitive to noradrenalin at 10(-8), 10(-7)and 10(-5) M, and their maximum rate of lipolysis was higher. They also responded more strongly to pre-incubation for 24 h with tumour necrosis factor alpha interleukin 6 and interleukin 4 than those elsewhere in the same depots. Tumour necrosis factor alpha and interleukin 6 applied alone stimulated lipolysis, but combined with interleukin 4, they suppressed glycerol release, especially in perinodal adipocytes, thereby creating large within-depot differences. These cytokines had minimal effects on lipolysis in perirenal or gonadal adipocytes. The authors conclude that adipocytes surrounding lymph nodes contribute little to whole-body energy supply during fasting, but are more sensitive than all others to cytokines and to noradrenalin, having higher maximum but lower minimum rates of lipolysis. These properties equip perinodal adipocytes for local interactions with lymphoid tissue.

Immunofluorescent localisation of tumour necrosis factor-alpha receptors on the popliteal lymph node and the surrounding adipose tissue following a simulated immune challenge.

We used immunohistochemical techniques to demonstrate the distribution of receptors for the cytokine tumour necrosis factor-alpha on the popliteal lymph node and the adipose tissue surrounding it for 5 d following a simulated immune challenge to one hind leg in the rat. We found different patterns of expression of receptors on adipocytes surrounding a lymph node to a distance of about 1 mm, and on those more remote from the node. Sites recognised by an antibody to type I tumour necrosis factor receptors appeared on the challenged node and the adipocytes surrounding it within 30 min of an injection of bacterial lipopolysaccharide, but appeared on adipocytes surrounding the unchallenged popliteal node only 24 h later. Adipocytes distant from the node, both within the same depot and in the contralateral depot, showed no response. Sites recognised by an antibody to type II tumour necrosis factor receptors were present at all times on lymph nodes and the adipocytes close to them, but appeared on more distant adipocytes only 24 h after immune challenge, in both challenged and unchallenged legs. These data support the proposal, based on in vitro studies, that the adipose tissue surrounding major lymph nodes is specialised to respond to cytokines derived from lymphoid cells, and participates in the immune responses of the adjacent node.