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Am J Physiol Endocrinol Metab 286: E697-E703, 2004. First published January 6, 2004; doi:10.1152/ajpendo.00502.2003
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Metabolomic analysis of adrenal lipids during hypoxia in the neonatal rat: implications in steroidogenesis

Eric D. Bruder,1 Ping C. Lee,2,3 and Hershel Raff1,4

1Endocrine Research Laboratory, St. Luke's Medical Center, Milwaukee 53215; and Departments of 2Pediatrics, 3Pharmacology and Toxicology, and 4Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

Submitted 6 November 2003 ; accepted in final form 27 December 2003


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The nursing rat pup exposed to hypoxia from birth exhibits ACTH-independent increases in corticosterone and renin/ANG II-independent increases in aldosterone. These increases are accompanied by significant elevation of plasma lipid concentrations in the hypoxic neonates. The purpose of the present study was to compare changes in the concentrations of specific fatty acid metabolites and lipid classes in serum and adrenal tissue from normoxic and hypoxic rat pups. We hypothesized that lipid alterations resulting from hypoxia may partly explain increases in steroidogenesis. Rats were exposed to normoxia or hypoxia from birth, and pooled serum and adrenal tissue from 7-day-old pups were subjected to metabolomic analyses. Hypoxia resulted in specific and significant changes in a number of fatty acid metabolites in both serum and the adrenal. Hypoxia increased the concentrations of oleic (18:1 n-9), eicosapentaenoic (EPA; 20:5 n-3), and arachidonic (20:4 n-6) acids in the triacylglyceride fraction of serum and decreased oleic and EPA concentrations in the cholesterol ester fraction. In the adrenal, hypoxia caused an increase in several n-6 fatty acids in the triacylglyceride fraction, including linoleic (18:2 n-6) and arachidonic acid. There was also an increase in the concentration of {alpha}-linolenic acid (18:3 n-3) in the triacylglyceride fraction of the hypoxic adrenal, along with an increase in linoleic acid concentration in the diacylglyceride fraction. We propose that specific changes in lipid metabolism in the adrenal, as a result of hypoxia, may partly explain the increased steroidogenesis previously observed. The mechanism responsible may involve alterations in cellular signaling and/or mitochondrial function. These cellular changes may be a mechanism by which the neonate can increase circulating adrenal steroids necessary for survival, therefore bypassing a relative insensitivity to normal stimuli.

NEONATAL HYPOXIA IS A COMMON CONDITION that results in serious morbidity and mortality in newborns (9, 19). The ability of the newborn to adapt to low O2 depends on a multitude of physiological changes. These changes include, but are not limited to, shifts in metabolic, hemodynamic, digestive, and cardiorespiratory function (2, 6, 10, 13, 14, 17, 21, 26, 35). It has also become evident that there exists a unique developmental aspect to the maturation of the adrenocortical response to stress in the neonatal rat (1, 33, 37, 38).

Neonatal rats exposed to hypoxia from birth to 7 days of age develop increased plasma levels of aldosterone and corticosterone compared with normoxic controls (30). Further studies on this phenomenon have measured small but significant increases in the expression of the steroidogenic acute regulatory (StAR) protein and the peripheral-type benzodiazepine receptor (PBR) protein in the hypoxic adrenal cortex (29). These changes occurred without a concomitant increase in plasma ACTH or plasma renin activity in the hypoxic pups (29, 30). Increases in plasma aldosterone and corticosterone could not be explained by changes in steroidogenic enzyme mRNA expression (30). Interestingly, chemical sympathectomy with guanethidine attenuated the increase in basal corticosterone and StAR protein in the hypoxic pups, but had no effect on aldosterone or ACTH-stimulated corticosterone production (31).

Neonatal hypoxia has profound effects on intermediary metabolism (2, 6, 13, 26, 27), including significant increases in plasma lipids (i.e., total cholesterol, free fatty acids, and triacylglycerides; see Ref. 27). It is well established that adrenocortical steroid synthesis is under the influence of many factors, including polyunsaturated fatty acids (PUFA) and their metabolites (3, 11, 12, 20, 34). Given this connection, it was of interest to determine whether changes in serum lipid concentrations resulting from hypoxia could affect lipid metabolism in the adrenal gland. This could provide further insight into possible mechanisms involved in the increased adrenal steroidogenesis during hypoxia in the neonatal rat.

Because previous studies were limited to measurements of only entire lipid classes in plasma, the present study sought a more powerful analytical tool. Metabolomic analysis is a method by which the concentrations of 40 different fatty acids, comprising 10 distinct lipid classes, can be quantitatively measured. The analysis allows a unique "profiling" of lipid metabolic pathways in the tissue of interest. The serum and adrenal lipid profiles of neonatal rats exposed to hypoxia for 7 days from birth (or normoxic controls) were measured. The goals of the present study were as follows: 1) compare changes in serum profiles with those found for the adrenal, 2) analyze the adrenal data as it pertains to specific fatty acid families, and 3) relate adrenal data to previously measured increases in plasma steroids.


   METHODS
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 METHODS
RESULTS
 DISCUSSION
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Animal treatment. All experimentation was approved by the Institutional Animal Care and Use Committees of the Medical College of Wisconsin and St. Luke's/Aurora Sinai Medical Center. Timed pregnant Sprague-Dawley rats (Harlan Sprague Dawley, Indianapolis, IN; n = 6) were obtained at 14 days gestation and were maintained on a standard sodium diet (Richmond Standard 5001, Brentwood, MO) and water ad libitum in a controlled environment (lights on, 0600–1800). Parturition usually occurred on the afternoon of gestational day 21, during which time rats were kept under observation. As soon as a litter was completely delivered, the dam and her pups (~13/litter) were immediately moved to an environment chamber and exposed to normobaric hypoxia (12% O2) or kept in room air as controls (21% O2; see Refs. 28, 32, 35). We have previously shown that this exposure leads to arterial PO2 levels in adults of ~50–55 Torr with sustained hypocapnia and alkalosis (28, 32).

Lactating dams were maintained with their litters for 7 days in a hypoxic or normoxic environment (35). Chambers were opened on day 4 to clean cages. At 0800 on day 7, dams were quickly removed from the chambers. Pups were quickly decapitated, and trunk blood was allowed to clot and was immediately centrifuged to obtain serum. Serum was pooled (3–4 pups/sample) and then immediately frozen in liquid N2. Adrenal glands were quickly removed, snap-frozen in liquid N2, and pooled (24 adrenals/sample). Four pooled serum and three pooled adrenal samples were subjected to metabolomic analysis.

Metabolomic analyses. All samples were subjected to metabolomic analysis (Lipomics Technologies, West Sacramento, CA). Lipids from serum and adrenal glands were extracted in the presence of internal standards by the method of Folch et al. (8), using chloroform-methanol (2:1 vol/vol). Individual lipid classes from each extract were separated by preparative TLC, as described previously (40, 41). Authentic lipid class standards were spotted on the two outside lanes of the TLC plate to enable localization of the sample lipid classes. Lipid fractions were scraped from the plate and trans-esterified in 3 N methanolic hydrochloride in a sealed vial under an N2 atmosphere at 100°C for 45 min. The resulting fatty acid methyl esters were extracted with hexane containing 0.05% butylated hydroxytoluene and prepared for gas chromatography by sealing the extracts under N2. Fatty acid methyl esters were separated and quantified by capillary gas chromatography using a gas chromatograph (model 6890; Hewlett-Packard, Wilmington, DE) equipped with a 30-m DB-225MS capillary column (J & W Scientific, Folsom, CA) and a flame-ionization detector, as described previously (40, 41). Fatty acid ratios were calculated from the sum of each fatty acid corrected for the number of fatty acids in each lipid class. Diacylglyceride, phosphatidylethanolamine, and phosphatidylcholine were multiplied by two, triacylglyceride by three, and cardiolipin by four. The ratio from each experiment was treated as one datum. Reproducibility was as follows: cholesterol ester (2.0%), diacylglyceride (5.5%), free fatty acid (3.5%), lysophosphatidylcholine (12.2%), phosphatidylcholine (5.0%), sphingomyelin (11.4%), phosphatidylethanolamine (13.0%), and triacylglyceride (0.4%).

Statistical analyses. All data obtained were quantitative (nmol fatty acid/g tissue or serum) and expressed as means ± SE. Significance of differences between the control (normoxic) and treatment (hypoxic) groups was assessed by unpaired Student's t-tests, with significance assumed at P < 0.05. This statistical approach has been validated for this type of metabolomic analysis (40, 41). Quantitative data were visualized using the Lipomics Surveyor software system. The system creates a "heat map" graph for significant differences between control and treatment groups. The heat map displays statistically significant percent increases from control values as green squares and statistically significant percent decreases from control values as red squares. The brightness of each individual square denotes the magnitude of the difference, as displayed above each of the heat maps.


   RESULTS
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DISCUSSION
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The heat map in Fig. 1 summarizes changes within entire fatty acid families for each lipid class. Pertinent data used to generate this heat map are summarized in Table 1. The most striking changes occurred in the cholesterol ester fraction of the serum. Serum from hypoxic neonates displayed significant decreases in nearly all fatty acid families measured in cholesterol ester. However, this was not reflected in the adrenal cholesterol ester fraction (no significant changes). A nearly 2.5-fold increase in the concentration of n-3 fatty acids was observed in the triacylglyceride fraction of serum, and there was a tendency for n-3 fatty acids to increase in the adrenal triacylglyceride fraction as well. There was a tendency for all fatty acid families in the adrenal to increase during hypoxia, although only differences in total PUFA and n-6 concentrations reached statistical significance. The total content of fatty acid in the diacylglyceride fraction of the adrenal was increased after hypoxia and could be attributed to small but insignificant increases in individual fatty acid families.



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  		Fig. 1. Effect of hypoxia on fatty acid concentrations, according to family, in different lipid fractions in serum and the adrenal gland. The concentration of each metabolite from normoxic and hypoxic samples was used to generate a heat map. Columns are the sum of all fatty acid metabolite concentrations for that particular family of fatty acids, and rows are individual lipid classes. The magnitude of the difference in the quantitative data, expressed as percent change from normoxic, is represented by color according to the legend. Differences not meeting P < 0.05 are shown in black. SAT, saturated fatty acid; PUFA, polyunsaturated fatty acid; MUFA, monounsaturated fatty acid.

 

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  		Table 1. Effects of hypoxia on fatty acid families in the adrenal and serum

 
Figure 2 represents the heat map generated for fatty acid metabolites grouped into five distinct families of fatty acids (columns) as they were measured in seven distinct lipid classes (rows). In general, the most profound changes were increases in the triacylglyceride fractions of both serum and adrenal tissue. The triacylglyceride fraction of serum from hypoxic pups displayed increases in each of the five fatty acid families measured. Relevant data for these serum measurements are represented in Table 2. Neonatal hypoxia led to significant increases in stearic (18:0), palmitoleic (16:1 n-7), oleic (18:1 n-9), eicosapentaenoic (20:5 n-3), and arachidonic (20:4 n-6) acids. Other significant changes in serum profiles not depicted in Table 2 include linoleic acid (18:2 n-6) in the diacylglyceride fraction (normoxic = 207 ± 12; hypoxic = 589 ± 49 nmol/g), 18:1 n-9 in the cholesterol ester fraction (normoxic = 167 ± 30; hypoxic = 102 ± 20 nmol/g), and 20:5 n-3 in the cholesterol ester fraction (normoxic = 29 ± 1; hypoxic = 20 ± 1 nmol/g). Hypoxia had no effect on fatty acid concentrations in the cardiolipin, lysophosphatidylcholine, or phosphatidylethanolamine fractions of either serum or the adrenal (data not shown).



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  		Fig. 2. Effect of hypoxia on individual fatty acid metabolites in different lipid fractions in serum and the adrenal gland. The concentration of each metabolite from normoxic and hypoxic samples was used to generate a heat map. Columns headers are the sum of all fatty acid metabolite concentrations for that particular family of fatty acids, and rows are individual lipid classes. The magnitude of the difference in the quantitative data, expressed as percent change from normoxic, is represented by color according to the legend. Differences not meeting P < 0.05 are shown in black. Hypoxia had no effect on fatty acid concentrations in the cardiolipin, lysophosphatidylcholine, and phosphatidylethanolamine fractions of either the adrenal or serum (data not shown).

 

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  		Table 2. Effects of hypoxia on fatty acid concentrations in the triacylglyceride fraction of serum

 
Table 3 lists data for increases in selected adrenal n-6 fatty acids depicted in Fig. 2. The concentrations of 18:2 n-6 were increased in three separate lipid classes in the adrenals of neonates exposed to hypoxia, with a nearly threefold increase in the triacylglyceride fraction. These increases were evident in metabolites of 18:2 n-6 up through 20:4 n-6. Conversely, 18:2 n-6 concentrations were increased in the diacylglyceride and sphingomyelin fractions of the hypoxic adrenal, but there were no significant changes in any downstream metabolites (i.e., 2 or more additional carbon atoms and/or 1 or more additional double bonds). Measurements of downstream products of 20:4 n-6 were low to undetectable in all fractions presented in Table 3.


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  		Table 3. Effects of hypoxia on n-6 fatty acids in the adrenal

 
The effect of hypoxia on n-3 and n-9 fatty acid concentrations in the triacylglyceride fraction of the adrenal is depicted in Table 4. There was a significant increase in {alpha}-linolenic acid (18:3 n-3) after hypoxia, and this was reflected in the increased amounts of downstream metabolites of this essential fatty acid in the hypoxic adrenal. Most n-9 fatty acids and their saturated precursors were increased after hypoxia, although none of these increases reached statistical significance. A nearly threefold increase in the concentration of 18:1 n-9 was measured, and this perhaps reflects the significant increase of this metabolite in the triacylglyceride fraction of hypoxic serum (Table 2). Low concentrations of downstream metabolites of both docosahexaenoic acid (22:6 n-3) and 18:1 n-9 were measured in the adrenal triacylglyceride fraction.


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  		Table 4. Effects of hypoxia on n-3 and n-9 fatty acids in the adrenal triacylglyceride fraction

 
Table 5 shows the ratios of some fatty acids in the adrenal gland. The ratio of 20:3 n-6 to 20:4 n-6 was significantly increased, whereas that for 18:0 to 18:1 n-9 tended to be decreased in the hypoxic adrenal gland. Other pertinent ratios, including those shown in Table 5, were not significantly altered by hypoxia.


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  		Table 5. Effects of hypoxia on the ratio of some fatty acids in the adrenal gland

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The present study demonstrates that neonatal rats exposed to hypoxia for 7 days from birth exhibit significant and specific changes in lipid metabolism. These findings amplify and extend previous studies that measured increases in total plasma lipids in the hypoxic pups (27). With the use of the power of metabolomic analysis, the results of previous studies have been greatly expanded to include a much broader range of quantitative data. Current results indicate an increase in the concentration of lipid in the hypoxic adrenal gland, with the greatest increases in the triacylglyceride fraction (~3-fold for all fatty acid families). The concentration of fatty acids present in the triacylglyceride fraction of both control and hypoxic adrenals was nearly 10-fold higher than that measured in the serum triacylglyceride fraction.

It has been established that hypoxia leads to significant increases in plasma aldosterone and corticosterone concentrations (30). These increases occur without an increase in plasma ACTH. Furthermore, the corticosterone response to exogenous ACTH is augmented in hypoxic pups (29). None of these changes could be explained by increased expression of genes encoding the steroidogenic enzymes, or by changes in the expression of the hypoxia-inducible transcription factor-1{alpha} (29, 30). The present results offer a possible link between neonatal hypoxia and its affect on adrenocortical steroidogenesis.

The present analyses were performed on whole adrenal glands. The zona fasciculata/reticularis (ZF/R) comprises nearly 95% of the cortex, so changes in the zona glomerulosa (ZG) would be very difficult to discern. With the current technology, we could not generate enough ZG tissue to perform zonal comparisons. Therefore, changes in the adrenal lipid metabolome were likely because of changes in the ZF/R. Discussion of changes in the ZG metabolome resulting from hypoxia, and how they may relate to changes in basal aldosterone production, would only be speculative.

The concentrations of 18:2 n-6 and homo-{gamma}-linolenic acid (20:3 n-6) were significantly increased in the adrenal diacylglyceride fraction. One role of diacylglyceride in adrenocortical cells is as a mediator of the intracellular signaling pathway involving phospholipase C and calcium mobilization (22). The concentration of diacylglyceride measured in the hypoxic adrenal in the present study was increased. The type of fatty acids linked to a diacylglyceride molecule may have significant effects on cell signaling, and diacylglyceride-derived metabolites of 20:4 n-6 have been shown to increase aldosterone synthesis in glomerulosa cells (22). It is possible that the increase in diacylglyceride-linked n-6 fatty acids caused an increase in basal and ACTH-stimulated steroidogenesis.

The ratio of 20:3 n-6 to 20:4 n-6, an indicator of delta-5 desaturase activity, was increased in the adrenal gland during hypoxia. An increase in this ratio may be the result of partial inhibition of the delta-5 desaturase or may be the result of increased production of 20:4 n-6 metabolites in the hypoxic adrenal, which would lower the concentration of 20:4 n-6. The concentrations of 18:2 n-6, 20:2 n-6 (eicosadienoic acid), 20:3 n-6, and 20:4 n-6 were significantly increased in the triacylglyceride fraction of the hypoxic adrenal. Lipoxygenase and cyclooxygenase metabolites of 20:4 n-6 (leukotrienes and prostaglandins, respectively) have been implicated in the control of ACTH-stimulated steroidogenesis and may also be involved in the rate-limiting transport of cholesterol to the inner mitochondrial membrane (4, 16, 20). In addition, both StAR gene and protein expression were modulated by these metabolites (16). An oxidized metabolite of 18:2 n-6 has been shown to stimulate basal aldosterone production in ZG cells (11, 12), as well as augment basal and ACTH-stimulated corticosterone production in ZF/R cells (3, 12). StAR and PBR proteins are significantly increased in the hypoxic adrenal (29), and the involvement of lipids in this process seems quite plausible given these previous findings.

Recent studies have begun to shine new light on the process of cholesterol transport in adrenocortical cells (16). Mitochondrial free fatty acids are now believed to be pivotal for optimized delivery of cholesterol to the inner membrane (25). Fatty acyl-CoA molecules, including those released from hydrolyzed cholesterol ester, appear to accumulate near the inner mitochondrial membrane and are essential for optimal StAR activity (20). Fatty acyl-CoA has also been implicated in the activation of the PBR in adrenocortical cells (24). The increased concentrations of PUFA in the hypoxic adrenal, along with the measured increase in steroid output, are consistent with these findings. An increase in membrane fluidity caused by PUFA-laden triacylglyceride may very well affect adrenocortical mitochondrial dynamics, favoring interactions between StAR and P450scc and increases in steroidogenesis (15, 25).

Hormone-sensitive lipase (HSL) present in the adrenal also acts as a cholesterol esterase, and lack of HSL activity significantly decreases ACTH-stimulated corticosterone production (7, 18). HSL activity is modulated through hormonal/neuronal mechanisms (e.g., free fatty acid release from adipocytes). It is possible that hypoxia-induced changes in adrenergic activity cause an upregulation of adrenal HSL activity (36). Concerted action between fatty acid release via HSL and increased cholesterol availability (e.g., increased serum cholesterol) may partly explain the observed increases in plasma corticosterone and aldosterone in the present study. An argument against this could be made because of the lack of change in cholesterol ester or free fatty acid concentrations in the hypoxic adrenal. Prolonged hypoxic stress in adult rats has been shown to increase cholesterol reserves and steroid output in adrenocortical cells without causing hypertrophy (5). This does not seem evident in hypoxic neonates, nor can increased steroidogenesis be explained by changes in mitochondrial density or distribution (30).

The points raised above along with the current data suggest that increased steroidogenesis in the adrenal cortex of hypoxic neonates could be the result of changes in lipid metabolism. Increases in aldosterone and corticosterone production could potentially be explained by modulation of cellular signaling pathways and/or increases in cholesterol metabolism and transport into the mitochondria. The increased expression of both StAR and PBR protein in hypoxic adrenocortical cells likely plays a role (29) but may be a secondary effect of hypoxia manifested through changes in fatty acid concentrations. The fact that sympathectomy in hypoxic pups attenuates the increase in StAR protein and basal corticosterone lends support to this fatty acid mechanism quite possibly because of a decrease in adrenal HSL activity (31).

In summary, the present study has shown that exposing neonatal rats to hypoxia from birth has significant effects on lipid metabolism in the adrenal gland. With the use of metabolomic analyses, increases in a variety of specific fatty acids in at least three separate lipid classes were measured in hypoxic serum and adrenal tissue. Most significant of these increases were those of n-6 metabolites in the triacylglyceride fraction of the adrenal. We hypothesize that increased concentrations of plasma aldosterone and corticosterone and increased ACTH-stimulated corticosterone production in hypoxic neonates is at least partly explained by these alterations in lipid profiles. The mechanism may involve changes in mitochondrial membrane characteristics and cellular signaling events, leading to an increase in cholesterol transport into the mitochondria.

Chronic hypoxia in the newborn may be caused by a variety of common heart and lung diseases and requires intensive medical attention (9, 10, 19). Chronic hypoxia in the neonatal rat has been used as a model of neonatal hypoxia in humans (21, 35). The timing of the hypoxic episode is a critical factor, as it has been shown that neonatal rats go through a period of stress hyporesponsiveness at the level of the hypothalamic-pituitary-adrenal (HPA) axis (33, 36–38). It has been hypothesized that this period, characterized by diminished adrenal sensitivity to ACTH, allows for normal brain development by keeping plasma glucocorticoid concentrations at a steady level (33). Neonatal hypoxia also causes shifts in intermediary metabolism, including hyperlipidemia and fatty liver (2, 6, 9, 13, 17). Specific changes in plasma lipids may bypass the hyporesponsiveness of the HPA axis, stimulating steroidogenesis and increasing plasma concentrations of both mineralocorticoids and glucocorticoids. This survival mechanism could arise to maintain blood volume/vascular tone (aldosterone) and to meet increased metabolic needs (glucocorticoids), while sacrificing developmental processes such as neurogenesis. A greater understanding of the adrenal response to neonatal hypoxia may give insight into treatment of this common condition and may help reduce possible long-term effects still not fully appreciated in the clinical setting.


   GRANTS
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 ABSTRACT
 METHODS
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 GRANTS
REFERENCES
 
This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grant DK-54685 to H. Raff.


   ACKNOWLEDGMENTS
 
We thank Barbara Jankowski, Peter Homar, and Mark Struve for expert technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: H. Raff, Endocrinology, St. Luke's Physician's Office Bldg., 2801 W. KK River Pky, Suite 245, Milwaukee, WI 53215 (E-mail: hraff{at}mcw.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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