If there is an IRS activation in major depression, it was anticipated to find other indicators of IRS activation, such as lower serum zinc (Zn), and specific alterations in fatty acid metabolism and the erythron.
IRS activation is accompanied by a fall in serum Zn (Mussalo-Rauhamaa, Konttinen, Lehto, & Honkanen, 1988; Solomons, 1988; Srinivas, Braconier, Jeppsson, Abdulla, Akesson, & Ockerman, 1988). Zn is a trace element, which, in the plasma, is firmly bound to a2-macroglobulin (40%), while the remaining Zn is loosely bound to Alb (55%) or amino acids (5%).The loosely bound Zn fraction provides the Zn delivery to the tissues (Solomons, 1988). There is now evidence that depression is accompanied by lower serum Zn (Little, Castellanos, Humphries, & Austin, 1989; McLoughlin & Hodge, 1990; Maes, Scharpe, D'Haese, De Broe, & Cosyns, 1994d; Maes, Vandoolaeghe, Neels, Demedts, Wauters, Meltzer, Altamura, & Desnyder, 1997d).There are two factors which can explain lower serum Zn in depression. First, because IRS activation results in decreased serum Alb concentrations and Alb is the major Zn binding protein, there is potentially less Zn binding protein available, which could in part explain lower serum Zn (Giroux, Schechter, Schoun, and Sjoerdsma, 1977; Goldblum, Cohen, Jay, & McClain, 1987). However, we found that serum Alb and diagnostic classification had additive effects and independently from each other explained an important part of the variance in serum Zn (Maes et al., unpublished observations). These results suggest that lower serum Zn in depression is in part related to lowered concentrations of its "carrier" protein, Alb, and that another depression-related mech anism may play a role in lower serum Zn. Second, lowered serum Zn during IRS activation may be secondary to sequestration of the intracellular heavy metal binding protein metallothionein in the liver, which, in turn, may be related to an increased production of the proinflammatory cytokines, IL-1, and IL-6 (Cousins & Leinart, 1988; Morimoto, Murakami, Nakamori, Sakata, & Watanabe, 1989a; Morimoto, Sakata, Watanabe, & Murakami, 1989b; Van Miert, Van Duin, & Wensing, 1990). The decrease in serum Zn during IRS activation is associated with an increase in liver Zn contents (Dunn & Cousins, 1989). Reducing serum Zn concentrations during IRS activation could have an advantage to the host since more Zn could be made available for the increased acute phase protein synthesis in the liver (Solomons, 1988). We found significant inverse relationships between lower serum Zn and markers of IRS activation in depression, e.g. increased CD4+/CD8+ T cell ratio, serum neopterin, and increased serum IL-6 (Maes et al., 1994d; 1997d). Therefore, the relationships between serum Zn and IL-6 in depression, suggests that lower serum Zn is caused by increased production of IL-6 in that illness (Maes et al., 1997d).
Other hallmarks of IRS activation are lower serum total cholesterol, high-density-lipoprotein cholesterol (HDL-C), a lower esterified cholesterol: total cholesterol ratio, decreased activity of lecithin: cholesterol acyltransferase (LCAT; EC 22.214.171.124), and specific changes in polyunsaturated fatty acids (PUFAs). There is now some evidence that alterations in fatty acid metabolism and the composition of phospholipids in serum and membranes are involved in the pathophysiology of major depression (Horrobin, 1990; Smith, 1991; Maes, Delanghe, Meltzer, D'Hondt, & Cosyns, 1994a; Maes, Smith, Christophe, Cosyns, Desnyder, & Meltzer, 1996a; Maes, Vandoolaeghe, Neels, Demedts, Wauters, & Desnyder, 1997c; Hibbeln & Salem, 1995; Maes & Smith, 1998; Peet, Murphy, Shay, & Horrobin, 1998). Some (Morgan, Palinkas, Barrett-Connor, & Wingard, 1993; Glueck, Tieger, Kunkel, Hamer, Tracy, & Speirs, 1994), but not all authors (Swartz, 1990; McCallum, Simons, Simons, & Friedlander, 1994) reported an association between lower serum total cholesterol and major depression. Prevention trials designed to lower serum cholesterol levels by diet, drugs, or both were shown to increase the number of deaths due to suicide (review: Maes et al., 1997c). It was shown that men with low cholesterol or serum HDL-C were more likely to have ever made a medically serious suicide attempt (review: Maes et al., 1997c). Depressed patients exhibit significantly reduced esterified cholesterol and lowered HDL-C and HDLC/total cholesterol ratios (Maes et al., 1994a; 1997c). These results suggest an abnormal intake and/or metabolism of fatty acids and a decreased formation of cholesteryl esters in major depression (Maes et al., 1997c). The latter phenomenon may point toward decreased activity of LCAT, since most of the cholesteryl esters in man are formed in serum under the activity of LCAT, which reacts preferentially with free cholesterol of the HDL particles. Since in depression, lower serum HDL-C is related to indicators of IRS activation, such as the CD47CD8+ T cell ratio (negative), and serum Zn and Alb (both positively), we have hypothesized that the changes in HDL-C may be secondary to IRS activation.
PUFAs have important effects on inflammatory processes since they are precursors of eicosanoids (C20: 4to6 or arachidonic acid is the most abundant eicosanoid precursor in people consuming a Western diet) and can affect eicosanoid and cytokine formation. It has been shown that an imbalance of co6 to a)3 PUFAs may lead to an overproduction of cytokines (Endres, 1993). Supplements of linoleic (C18:2(o6) oil increases IL-1 and TNFa secretion (Meydani, Endres, Woods, Goldin, Soo, Morrill-Laborde, Dinarello, & Gorbach, 1991; Soyland, Lea, Sandstad, & Drevon, 1994). co3 PUFAs, e.g. C20:50)3 or eicosapentaenoic acid, inhibit the synthesis of eicosanoids such as prostaglandin E2 (Meydani et al., 1991) and reduce the production of proinflammatory cytokines and other signs of IRS activation (Meydani et al., 1991; Espersen, Grunnet, Lervang, Nielsen, Thomsen, Faarvang, Dyerberg, & Ernst, 1992; Endres, 1993; Soyland et al., 1994). Recently, it has been shown that depressed patients show alterations in the co6/cd3 ratio, i) Our laboratory was the first to report that depressed patients show an increased C20: 4w6/C20: 5a>3 ratio in serum phospholipids and cho-lesteryl esters and significantly decreased total (I)co3, C18:3co3 and C20:5ct>3 fractions in serum cholesteryl esters (Maes et al., 1996a). In a recent study, these findings were replicated (Maes et al., unpublished data): major depression was associated with increased C20:4(o6/C20: 5a)3 and C22: 5co6/C22: 6a>3 ratios, but lowered C20:5®3 and C22:5(o3 fractions in phospholipids; and increased C20: 4co6/C20: 5co3 and Xo>6/L(o3 ratios, but lowered C18:3a)3, C20:5co3, and total (Z)o)3 FA fractions in cholesteryl esters, ii) Adams, Lawson, Sanigorski, & Sinclair (1996) detected a significant positive relationship between severity of illness and the C20: 4co6/C20: 5a>3 ratio in serum phospholipids and in RBC membranes of depressed patients, iii) Peet et al. (1998) reported significantly depleted Za)3 PUFAs and, in particular C22:6co3, in cell membranes from RBC of depressive patients. In conclusion, these results show that, in major depression, there is a deficiency of a>3 PUFAs in phospholipids. Therefore, it has been suggested that the increased C20:4co6/C20:5co3 ratio and the imbalance in a>6/o)3 PUFAs in major depression may be related to the increased production of proinflammatory cytokines and eicosanoids in that illness (Maes et al., 1996a; Maes & Smith, 1998). Most importantly, there were significant and positive correlations between serum Zn and C20: 5co3 and C22: 6o>3 fractions in phospholipids; and significant inverse correlations between serum Zn and the L(o6/So)3, C20:4cd6/C20:5cd3, and C22:5co6/C22:6co3 ratios in phospholipids (Maes et al., unpublished data). In the rodent, lowered intake of Zn does not affect food intake or weight gain but reduces whole-body accumulation of desaturated and elongated products of linoleic acid (C18:2(o6) and a-linolenic acid (C18:3oo3) (Cunnane, Yang, & Chen, 1993). Desaturase enzymes require Zn as cofactor (Russo, Olivieri, Girelli, Guarini, Pasquallini, Azzini, & Corrocher, 1997). Thus, depletion of long-chain ©3 PUFAs in depression could be related to lower serum Zn, which, in turn is an indicator of IRS activation in that illness. The results suggest that i) there is a metabolic disorder in the elongation and desaturation of fatty acids; and ii) the fatty acid alterations in depression are related to IRS activation in that illness.
IRS activation is also characterized by alterations in the erythron (Lee, 1983; Fairbanks and Beutler, 1988; Brock, 1994). The specific changes are decreased serum iron (Fe) and Tf and normal or increased ferritin levels, and a reduced number of red blood cells (RBC), lowered hematocrit (Htc), and hemoglobin (Hb) (Lee, 1983; Fairbanks, & Beutler, 1988; Brock, 1994). It has been shown that patients with major depression have significantly lower serum Fe and Tf, and a significantly lower number of RBC, lower Htc and Hb, and a significantly increased number of reticulocytes than normal controls (Maes, Van de Vyvere, Vandoolaeghe, Bril, Demedts, Wauters, & Neels, 1996b; Van-doolaeghe, DeVos, DeSchouwer, Neels, & Maes, 1999). Significant relationships were reported between erythron variables and indicators of IRS activation. For example, there are significant and positive correlations between serum Zn and number of RBC, Htc, Hb (all positive), and serum ferritin (negative), and between serum Alb and RBC, Htc and Hb (all positive).There are also significant correlations between serum Zn and Fe and serum Tf (positive), serum Alb and Fe (positive), serum Alb and Tf (positive), and the a!-globulin fraction and Fe (negative). Finally, there were significant and positive correlations between the number of reticulocytes and number of leukocytes and neutrophils and the arglobulin fraction (Maes et al., 1996b; Vandoolaeghe et al., 1999). Proinflammatory cytokines, such as IL-1 and IL-6 modulate iron metabolism and the erythron through increased storage of Fe, reduced release of Fe from the reticuloendothelial cells, increased Fe incorporation into ferritin, increased ferritin synthesis, failure to deliver Fe to the erythron and a reduction in erythrocyte life span (review: Maes et al., 1996b). The physiological function of the alterations in Fe metabolism during the acute phase response is still a matter of debate. It is interesting to note that one hypothesis is that hypoferremia may serve to increase the activity of IFNy (Weiss, Fuchs, Hausen, Reibnegger, Werner, Werner-Felmayer, & Wachter, 1992), which has been reported to occur in depression. Therefore, we have hypothesized that disorders in the erythron indicate IRS activation in major depression (Maes et al., 1996b; Vandoolaeghe et al., 1999).
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