Withindepot Sitespecific Properties And Obesity

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These data together clearly show that certain adipocytes have properties that are minimal or absent in samples from the standard perirenal or epi-didymal depots. Although indistinguishable in his-tological appearance from typical adipocytes, those around major lymph nodes are equipped to participate in local interactions with lymphoid cells, and seem to be at least partially exempt from contributing to whole-body supply during fasting. Bone marrow is another site where adipocytes are contiguous with lymphoid cells, and the combination is known to be capable of functioning like lymph nodes (45). At least in non-ruminants, these marrow adipocytes retain their storage lipid, and even the capacity to accumulate more, during prolonged starvation when those in the 'typical' depots are almost totally depleted (46). The mammalian immune system seems to have organized its own local supplies of the polyunsaturated fatty acids (and perhaps of other metabolites), thereby avoiding the need for their transportation through the general circulation, and competition with other tissues. Paracrine interactions between perinodal adipocytes and lymphoid cells would also allow ready access to large quantities of fatty acids, without the need for their accumulation inside rapidly dividing, metabolically active lymphocytes; this concept recalls that of Unger et al. (47) who suggested that adipocytes protect pancreatic islets (and by implication other types of cell) from toxic accumulation of triacylglycerols in obesity.

Converting adipocytes from fatty acid retention and controlled secretion to lipid oxidation is being considered as a therapy for obesity (48). If the interaction between lymph nodes and surrounding adipose tissue proves to be an integral part of the normal immune response, and I firmly believe that it is, drastic alteration of the metabolism of these adipocytes may not be physiologically desirable. By making immune responses slower or less efficient, such manipulation could make the animal or person more susceptible to infection and perhaps cancer.

Nothing is known of how permanent this specialized population of cells is, or how it is affected by expansion of the rest of the adipose tissue. There are indications that the lipid composition of the diet affects the interaction between lymphoid cells and adipocytes. In guinea-pigs (5), the capacity of lym-phoid cells to stimulate lipolysis in adipose tissue from around lymph nodes is significantly reduced after small quantities of suet (rich in saturated and monoenoic fatty acids) were added to the normal chow for several weeks, while spontaneous lipolysis from similar explants incubated alone is unaltered (Figure 13.6). The ability of adipose tissue explants to curtail mitogen-stimulated proliferation of lymphocytes is even more severely impaired (Figure 13.7), although the basic pattern of site-specific differences in triacylglycerol fatty acid composition remains unchanged. In assessing the roles of dietary lipids in immune function (49), the possibility that adipose tissue is intervening to sequester or release certain fatty acids selective cannot be disregarded.

Guinea-pigs are grazers, whose natural diet is very low in fat, and contains mostly unsaturated fatty acids, so this minor modification of the diet probably induced a major departure from the normal situation. These data suggest that circulating lipids affect local interactions between adipose tissue and lymphoid cells, though the mechanism remains unknown. A high fat diet or hyperlipidaemia may impair local immune responses, and reduce the sensitivity of adipocytes to cytokines. Such properties could be relevant to known associations between high fat diet, obesity and certain forms of cancer (42,50,51).

What lessons do these concepts have for the study of human obesity? In naturally lean wild animals, depots associated with lymph nodes are not readily depleted and are relatively massive and conspicuous. The omentum, mesentery and popliteal remain surprisingly small, even in very obese specimens, possibly because their specialized functions would be impaired by too little, or too much, 'whole-body storage'. In contrast to humans, the additional adipose tissue in naturally obese species such as polar bears, and subspecies of reindeer and arctic foxes accumulates in the perirenal and in superficial depots not associated with lymph nodes (9,12,44).

Figure 13.6 Means + SE of glycerol in the medium after incubation for 48 h of explants of adipose tissue taken from near a lymph node (or, in the case of perirenal, a knot of blood bessels) of four superficial (left group of bars), three intra-abdominal (centre) and two intermuscular (right) adipose depots of guinea-pigs fed on normal chow (plain bars; n= 10 guinea-pigs) or suet-enriched chow (striped bars; n = 7 guinea-pigs), either alone (pale bars) or with lipopolysaccharide-stimulated lymphoid cells (darker bars) (5). Asterisks refer to differences between measurements from incubations under similar conditions of homologous explants from guinea-pigs on the two different diets. *** Significantly different at P< 0.001; ** significantly different at P<0.01; * significantly different at P<0.05. Horizontal bracket refers to differences between homologous explants incubated with or without lymphoid cells. NS, not significant

Figure 13.6 Means + SE of glycerol in the medium after incubation for 48 h of explants of adipose tissue taken from near a lymph node (or, in the case of perirenal, a knot of blood bessels) of four superficial (left group of bars), three intra-abdominal (centre) and two intermuscular (right) adipose depots of guinea-pigs fed on normal chow (plain bars; n= 10 guinea-pigs) or suet-enriched chow (striped bars; n = 7 guinea-pigs), either alone (pale bars) or with lipopolysaccharide-stimulated lymphoid cells (darker bars) (5). Asterisks refer to differences between measurements from incubations under similar conditions of homologous explants from guinea-pigs on the two different diets. *** Significantly different at P< 0.001; ** significantly different at P<0.01; * significantly different at P<0.05. Horizontal bracket refers to differences between homologous explants incubated with or without lymphoid cells. NS, not significant

The synergism between certain cytokines and the sympathetic nervous system agonist noradrenaline (Figure 13.3), and the fact that stimulation of the perinodal adipose tissue in one popliteal depot induces detectable changes in the mesenteric and omental adipose tissue (33), suggest that a pathway by which frequent activation of the immune system could promote lipolysis in the intra-abdominal depots. Repeated activation over many years could contribute to the development of intra-abdominal obesity, as does chronic overstimulation of the hy-pothalamo-pituitary-adrenal endocrine axis (52).

The omentum contains a large amount of lym-phoid tissue intimately interspersed with adipose tissue and has a high capacity for glutamine metab olism (3). Lipolysis in omental adipocytes is strongly influenced by lymphoid cells (Figures 13.1, 13.2 and 13.6), and amino acid metabolism may be as well. Its physiological functions are not firmly established, but in middle-aged people, especially men, living in Europe and the USA the omentum is often hypertrophied. Explanation for this effect, which can lead to metabolic disorders as well as being cosmetically unsatisfactory, relate mainly to lipid metabolism and endocrinological abnormalities (51). Digby (3) suggested that abnormalities of amino acid metabolism, perhaps triggered by the high protein content of the Western diet and/or excessive activation of omental lymphoid tissues, may also make an important contribution. This

Figure 13.7 Site-specific differences in the effects of adipose tissue (AT) explants from guinea-pigs fed on unmodified chow (plain bars: n = 10, 100% = 17 541 +470d.p.m.) or suet-enriched chow (striped bars: n = 7, 100% = 18 754 + 219d.p.m.) on lipopolysaccharide-stimulated proliferation of their lymphoid cells in culture (5). Means+ SE of cell proliferation, measured as incorporation of 3H-thymidine (% counts in aliquots cells from the same source incubated under identical conditions without any adipose tissue) into lymphocytes incubated with one explant of adipose tissue taken from away from lymph node(s) or, in the case of the perirenal depot, away from knots of blood vessels (light bars) and from near to lymph node(s) or near to knots of blood vessels (dark bars). Sets of samples were taken from four superficial (left group of bars), three intra-abdominal (centre) and two intermuscular (right) adipose depots. Asterisks refer to differences between data from incubations with adipose explants from 'near to' or 'away from' lymph nodes of the same depot of the same specimens. *** Significantly different at P< 0.001; ** significantly different at P<0.01; * significantly different at P<0.05

Figure 13.7 Site-specific differences in the effects of adipose tissue (AT) explants from guinea-pigs fed on unmodified chow (plain bars: n = 10, 100% = 17 541 +470d.p.m.) or suet-enriched chow (striped bars: n = 7, 100% = 18 754 + 219d.p.m.) on lipopolysaccharide-stimulated proliferation of their lymphoid cells in culture (5). Means+ SE of cell proliferation, measured as incorporation of 3H-thymidine (% counts in aliquots cells from the same source incubated under identical conditions without any adipose tissue) into lymphocytes incubated with one explant of adipose tissue taken from away from lymph node(s) or, in the case of the perirenal depot, away from knots of blood vessels (light bars) and from near to lymph node(s) or near to knots of blood vessels (dark bars). Sets of samples were taken from four superficial (left group of bars), three intra-abdominal (centre) and two intermuscular (right) adipose depots. Asterisks refer to differences between data from incubations with adipose explants from 'near to' or 'away from' lymph nodes of the same depot of the same specimens. *** Significantly different at P< 0.001; ** significantly different at P<0.01; * significantly different at P<0.05

suggestion again shifts the emphasis from energy storage and blood metabolites to specialized prope-ties of certain regions of the adipose mass.

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