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Endocrinology, doi:10.1210/en.2006-1199
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Endocrinology Vol. 148, No. 5 2391-2397
Copyright © 2007 by The Endocrine Society

Depot-Specific Modulation of Rat Intraabdominal Adipose Tissue Lipid Metabolism by Pharmacological Inhibition of 11ß-Hydroxysteroid Dehydrogenase Type 1

Magalie Berthiaume, Mathieu Laplante, William Festuccia, Yves Gélinas, Sébastien Poulin, Josée Lalonde, Denis R. Joanisse, Rolf Thieringer and Yves Deshaies

Laval Hospital Research Center and Department of Anatomy and Physiology (M.B., M.L., W.F., Y.G., S.P., J.L., Y.D.) and Division of Kinesiology, Department of Social and Preventive Medicine (D.R.J.), Faculty of Medicine, Laval University, Quebec, Canada G1V 4G5; and Department of External Scientific Affairs (R.T.), Merck Research Laboratories, Rahway, New Jersey 07065

Address all correspondence and requests for reprints to: Dr. Yves Deshaies, Laval Hospital Research Center, Laval Hospital, 2725 Chemin Sainte-Foy Québec, Quebec, Canada G1V 4G5. E-mail: yves.deshaies{at}phs.ulaval.ca.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The metabolic consequences of visceral obesity have been associated with amplification of glucocorticoid action by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) in adipose tissue. This study aimed to assess in a rat model of diet-induced obesity the effects of pharmacological 11ß-HSD1 inhibition on the morphology and expression of key genes of lipid metabolism in intraabdominal adipose depots. Rats fed a high-sucrose, high-fat diet were treated or not with a specific 11ß-HSD1 inhibitor (compound A, 3 mg/kg·d) for 3 wk. Compound A did not alter food intake or body weight gain but specifically reduced mesenteric adipose weight (–18%) and adipocyte size, without significantly affecting those of epididymal or retroperitoneal depots. In mesenteric fat, the inhibitor decreased (to 25–50% of control) mRNA levels of genes involved in lipid synthesis (FAS, SCD1, DGAT1) and fatty acid cycling (lipolysis/reesterification, ATGL and PEPCK) and increased (30%) the activity of the fatty acid oxidation-promoting enzyme carnitine palmitoyltransferase 1. In striking contrast, in the epididymal depot, 11ß-HSD1 inhibition increased (1.5–5-fold) mRNA levels of those genes related to lipid synthesis/cycling and slightly decreased carnitine palmitoyltransferase 1 activity, whereas gene expression remained unaffected in the retroperitoneal depot. Compound A robustly reduced liver triacylglycerol content and plasma lipids. The study demonstrates that pharmacological inhibition of 11ß-HSD1, at a dose that does not alter food intake, reduces fat accretion specifically in the mesenterical adipose depot, exerts divergent intraabdominal depot-specific effects on genes of lipid metabolism, and reduces steatosis and lipemia.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
GLUCOCORTICOIDS (GCs) PLAY a pivotal role in modulating adipose tissue metabolism, function, and distribution. High serum GC levels promote visceral obesity, hyperlipidemia, and insulin resistance (1), as seen for instance in patients with Cushing’s syndrome (2). The deleterious metabolic consequences of visceral obesity have been associated with amplification of GC action by 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) in adipose tissue (3, 4). The enzyme, which locally converts inactive GC into bioactive forms such as cortisol in humans and corticosterone in rodents (5), is strongly expressed in the liver, brain, and adipose tissue (6), with expression levels reported to be higher in human omental than in sc fat (7, 8), although these findings are still under debate.

The importance of 11ß-HSD1-mediated local amplification of GC in the development of visceral obesity and its associated metabolic disturbances is being increasingly recognized (9, 10, 11) and is supported by the development of visceral obesity and the metabolic syndrome in mice overexpressing white adipose 11ß-HSD1 (10). In this model, fat accumulation is limited to the metabolically active, GC receptor (GR)-rich (12) intraabdominal fat, with marked hypertrophy of the mesenteric depot (MES), whereas peripheral fat is much less affected (10). Conversely, mice with whole-body invalidation of the 11ß-HSD1 gene display reduced visceral fat, are resistant to diet-induced visceral obesity, and present with an improved metabolic profile (13, 14, 15). Notably, both overexpression and knockout approaches point to regional specificity of action of 11ß-HSD1 on adipose tissue. Indeed, beyond specificity toward intraabdominal fat, manipulation of the 11ß-HSD1 gene appears to affect the mass of the MES but not that of epididymal fat (10, 15). This may bear significance to the metabolic consequences of such manipulation because of the different venous drainage (portal vs. caval) and different level of metabolic activity of these two intraabdominal depots (16).

The above gene manipulation studies have clearly highlighted the impact of 11ß-HSD1 on adipose tissue metabolism and whole-body metabolic health and render pharmacological 11ß-HSD1 inhibition an attractive approach for the treatment of the metabolic consequences of visceral obesity. Although a few studies have reported on the metabolic effects of specific 11ß-HSD1 inhibition (17, 18, 19, 20), little is known about its impact on adipose tissue, one of its major sites of action. In addition, previous studies used compounds at doses that elicited a reduction in food intake, a major confounding factor. The present study aimed at assessing whether clinically relevant selective pharmacological 11ß-HSD1 inhibition recapitulates the beneficial effects of lifelong gene invalidation on intraabdominal fat distribution and function. The study also aimed at extending the investigation of the consequences of 11ß-HSD1 inhibition to the depot-specific expression of key adipose lipid metabolism genes, particularly some (FAS, SCD1, DGAT1, ATGL, PEPCK, CPT1), documented or not as direct GC targets, whose importance in the modulation of fat mass and lipid handling has been highlighted recently (21).


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and treatments
Male Sprague Dawley rats (10 per protocol, three protocols) initially weighing 150–175 g were purchased from Charles River Laboratories (St. Constant, Quebec, Canada) and housed individually in stainless steel cages in a room kept at 23 ± 1 C with a 12-h light, 12-h dark cycle (lights on at 0700 h). The animals were cared for and handled in conformance with the Canadian Guide for the Care and Use of Laboratory Animals, and the protocols were approved by our institutional animal care committee. For the first 5 d, rats had free access to tap water and a stock diet (Charles River Rodent Diet no. 5075, Ralston Products, Woodstock, Canada; digestible energy content, 12.9 kJ/g). Rats were then switched to a purified high-sucrose, high-fat diet (19.44 kJ/g, 41% energy from carbohydrates, 39% from fat, and 20% from protein). Half of the animals were given the 11ß-HSD1 inhibitor [compound A, a 4-heteroarylbicyclo[2.2.2]octyltriazole (22)] as an adjunct to their diet at a daily dose of 3 mg/kg for the entire feeding period of 3 wk. Plasma levels achieved with this dose were nearly identical with those of a pilot study in which compound A, given to rats as an adjunct to rodent chow for 7 d, was found to inhibit 97 ± 3% of 11ß-HSD1 activity in epididymal adipose tissue and liver, as quantified by a [3H]-cortisone to cortisol conversion assay (20). The dose used has the advantage of not altering food intake, which is significantly lowered at higher doses. The amount of 11ß-HSD1 inhibitor was adjusted every other day to the average food consumption so as to provide the same amount per unit body weight throughout treatment. At the end of the treatment period, food was removed at 0730 h, and rats were killed by decapitation at 1330 h.

Serum and tissue sampling
Truncal blood was collected, centrifuged (1500 x g, 15 min at 4 C), and serum was stored at –20 C until later biochemical measurements. Adrenal glands were removed and weighed as an index of long-term hypothalamic-pituitary-adrenal (HPA) axis activation. The intraabdominal MES, retroperitoneal adipose depot (RET), and epididymal adipose depot (EPI) were excised, weighed, and prepared for further analysis as described below. A sample of liver was immediately frozen and stored at –80 C for later quantification of triacylglycerol (TAG) content in total lipid extracts (23).

Serum/tissue determinations
Serum glucose concentrations were measured by the glucose oxidase method with the Beckman glucose analyzer. Insulin was determined by RIA using a reagent kit from Linco Research (St. Charles, MO) with rat insulin as standard. TAG concentrations in serum and liver lipid extracts were measured by an enzymatic method using a reagent kit (Roche Diagnostics, Montreal, Canada). Serum nonesterified fatty acid (FA) levels were measured by an enzymatic method using reagents from Wako Chemicals (Richmond, VA).

Adipocyte morphology by light microscopy
Samples of MES, RET, and EPI were fixed in 0.1 mM PBS (pH 7.3) containing 4% paraformaldehyde and embedded in paraffin. Thin sections were mounted on glass slides and dyed with hematoxylin/eosin. Digital images of tissue slices were captured using an Olympus BX60 microscope equipped with a Sony RT Slider Spot Camera (Camsen Group, Markham, Canada) at a magnification of 10x. Total cell number over the entire visual area was determined in seven to eight tissue samples for each depot and used to calculate average cell diameter.

Triglyceride-derived FA uptake
Rats were cannulated in the jugular vein 4 d before the end of the 3-wk protocol. On the last day, 6-h fasted rats were injected through the jugular catheter with 0.1 ml/kg 10% Intralipid containing 3H-9,10-labeled trioleoylglycerol (570 dpm/nmol FA; kindly provided by Drs. T. and G. Olivecrona, Umeå University, Sweden) diluted 1:8.5 with 20% Intralipid (160 mg/kg TAGs was injected) and prepared as described previously (24). Twenty minutes after injection, rats were killed by ketamine-xylazine injection. Radioactivity content of adipose tissues was quantified as described previously (24). Lipid uptake is expressed as percent injected dose.

Adipose tissue lipoprotein lipase (LPL) activity
Immediately upon tissue harvesting, samples (~50 mg) of adipose tissues were homogenized, processed, and frozen exactly as described (25). For determination of LPL activity, tissue homogenates were incubated at 28 C with a substrate mixture containing [carboxyl-14C]triolein, and 14C-nonesterified FAs released by LPL were separated and counted. LPL activity is expressed as nanokatals per milligram of total protein.

Adipose tissue carnitine palmitoyltransferase (CPT) 1 activity
Pieces (~40 mg) of thawed adipose tissues were homogenized in a glass-on-glass Duall homogenizer in 10 volumes of ice-cold extracting medium [0.1 M phosphate buffer, 2 mM EDTA (pH 7.2)]. The homogenate was transferred into 1.5 ml polypropylene microtubes and sonicated six times for 5 sec at 20 W, on ice, with pauses of 85 sec between pulses. The sonicated homogenate was used for determination of CPT-1 activity (Vmax) by spectrophotometry, as previously described (26). Enzyme activity is expressed in nanokatals of substrate per gram wet weight.

Adipose tissue RNA isolation and quantification of SCD1, FAS, DGAT1, ATGL, and PEPCK mRNA levels
Total RNA was prepared from MES, RET, and EPI samples using QIAzol and the RNeasy Lipid Tissue Kit (QIAGEN, Mississauga, Canada). For cDNA synthesis, Expand reverse transcriptase (Invitrogen, Burlington, Canada) was used following manufacturer’s instructions, and cDNA was diluted in DNase-free water (1:25) before quantification by real-time PCR. Primers were validated with a sample adipose tissue cDNA. mRNA transcript levels were measured using a Rotor Gene 3000 system (Montreal Biotech, Montreal, Canada). Chemical detection of the PCR products was achieved with SYBR Green Jumpstart Taq ReadyMix (Sigma, St. Louis, MO). The primers, designed using the Vector NTI program and synthesized by Invitrogen, are presented in Table 1Go. Levels of mRNA were determined using a standard curve generated with the plasmid corresponding to the target gene and are expressed as number of copies per reaction. To control for sample loading, tissue samples were run in duplicate. Between-duplicate variation never exceeded 10%.


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  		TABLE 1. Primers used for mRNA quantification by real-time quantitative PCR

 
Statistical analysis
Data are presented as means ± SE. The control and treated groups were compared using Student’s unpaired t test. Some variables were log transformed before analysis to ensure homogeneity of variance. Differences were considered statistically significant at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The 11ß-HSD1 inhibitor had no significant effect on either cumulative food intake or body weight gain (Table 2Go). Adrenal weight was increased 38% by treatment, an indication of long-term HPA axis activation due to lower central GC concentration. Terminal serum ACTH and corticosterone levels were however unchanged by treatment. The 11ß-HSD1 inhibitor decreased serum nonesterified FAs (–20%) and TAGs (–45%), without significantly altering glucose and insulin levels. Liver TAG concentration (–26%) and total content (–23%) were lowered by the compound.


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  		TABLE 2. Cumulative food intake, body weight gain, adrenal weight, fasting (6 h) serum levels of hormones and metabolites, and liver TAG content in rats treated or not with compound A for 3 wk

 
The MES depot of treated rats was slightly but significantly smaller (–18%) than those of controls, whereas no significant treatment effect was observed on RET and EPI weights (Fig. 1Go). In concomitance, smaller average adipocyte diameter was observed only in MES (–16%) in response to 11ß-HSD1 inhibition. No significant treatment effect was observed on either total protein or total DNA content in any of the intraabdominal depots (data not shown).


Figure 1
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  		FIG. 1. Adipocyte morphology, depot weight, and average cell diameter in the MES, RET, and EPI (magnification, x10) of rats treated or not with compound A for 3 wk. Each column represents the mean ± SE of five animals or seven to eight determinations for cell diameter. *, P < 0.05 vs. control.

 
To assess which aspects of adipose lipid metabolism were affected by 11ß-HSD1 inhibition, we next assessed TG-derived FA uptake and one of its major determinant, LPL activity, as well as the mRNA levels of genes favoring FA commitment to storage (FAS, SCD1, DGAT1) and those of lipolysis (ATGL) and FA reesterification (PEPCK), which together partly determine lipid release/recycling, and the activity of CPT1, the rate-limiting enzyme of FA transport into the mitochondrion and subsequent oxidation. TG-derived FA uptake was not significantly modified by 11ß-HSD1 inhibition in any of the intraabdominal adipose depots, nor was the activity of LPL (Table 3Go). As depicted in Fig. 2Go, MES depot mRNA levels for genes related to FA desaturation (SCD1, Fig. 2AGo), synthesis (FAS, Fig. 2BGo), and esterification to TAGs (DGAT1, Fig. 2CGo) were robustly decreased (–50 to –80%) by chronic 11ß-HSD1 inhibition, as were those of ATGL (–70%, Fig. 2DGo) and PEPCK (–65%, Fig. 2EGo). CPT1 activity was increased 30% in rats treated with the 11ß-HSD1 inhibitor (Fig. 2FGo).


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  		TABLE 3. Intraabdominal adipose depot TAG-derived FA uptake and LPL activity in rats treated or not with compound A for 3 wk

 

Figure 2
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  		FIG. 2. mRNA levels of SCD1 (A), FAS (B), DGAT1 (C), ATGL (D), PEPCK (E), and activity of CPT1 (F) in the MES of rats treated (black columns) or not (white columns) with compound A for 3 wk. Each column represents the mean ± SE of five animals. *, P < 0.05 vs. control.

 
The 11ß-HSD1 inhibitor had no effect on gene expression in the RET depot (data not shown). Treatment effects on mRNA levels of the above genes in the EPI depot are illustrated in Fig. 3Go. In sharp contrast with the MES depot, the mRNA levels of the lipid synthesis genes SCD1 (Fig. 3AGo), FAS (Fig. 3BGo), and DGAT1 (Fig. 3CGo) were increased by 11ß-HSD1 inhibition (40% to 6.5-fold), as were those of ATGL (37%, Fig. 3DGo) and PEPCK (39%, Fig. 3EGo). CPT1 activity was slightly (–14%) but significantly decreased in EPI of rats treated with the inhibitor (Fig. 3FGo).


Figure 3
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  		FIG. 3. mRNA levels of SCD1 (A), FAS (B), DGAT1 (C), ATGL (D), PEPCK (E), and activity of CPT1 (F) in the EPI of rats treated (black columns) or not (white columns) with compound A for 3 wk. Each column represents the mean ± SE of five animals. *, P < 0.05 vs. control.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study aimed to assess the effects of pharmacological inhibition of 11ß-HSD1 on intraabdominal adipose depot distribution and function as well as some components of the metabolic profile of rats fed an obesogenic diet. Inhibition of 11ß-HSD1, at a dose that did not affect food intake, specifically reduced MES weight and cell size and exerted intraabdominal depot-specific actions on the expression or activity of enzymes of lipid storage, cycling, and oxidation. Such changes would tend to reduce fat storage in the portally drained MES and favor storage in the metabolically safer EPI depot. Inhibition of 11ß-HSD1 also reduced circulating lipids and hepatic steatosis, thereby dampening diet-induced deterioration of the global metabolic profile.

Long-term activation of the HPA axis, a well-recognized effect of 11ß-HSD1 inhibition (13, 27), did occur even at the low dose of compound A used here as witnessed by the increase in adrenal weight. Importantly, however, ingestive behavior was not affected by low-dose 11ß-HSD1 inhibition. An increase in systemic GC levels at the nadir of the circadian rhythm has been reported in 11ß-HSD1 knockout mice (13); however, terminal levels of ACTH and corticosterone were unchanged in the present study. The metabolic improvements achieved with 11ß-HSD1 inhibition clearly establish that any upward change in systemic GC is overridden by local inhibition of GC activation.

Pharmacological inhibition of 11ß-HSD1 substantially lowered plasma nonesterified FA and TAG levels, confirming previous reports (14, 20), as well as hepatic steatosis. GCs favor hepatic lipogenesis (28, 29) and VLDL secretion (30, 31), and overexpression of 11ß-HSD1 in the liver or adipose tissue of mice leads to hepatic steatosis (32, 33). Inhibition of liver 11ß-HSD1 undoubtedly contributed to the reduction in plasma and liver TAG levels; however, it is likely that adipose remodeling also contributed to such improvement, both because of lowered splanchnic GC production and reduced delivery of lipogenic precursors (FAs) to the liver (34). The present study extends previous findings by demonstrating that improvement in liver and plasma lipids by 11ß-HSD1 inhibition does occur even in the absence of a reduction in food intake. Finally, although fasting indices of insulin sensitivity were not affected by 11ß-HSD1 inhibition in the present study, improvement in insulin sensitivity has been reported in more severe models of obesity and type 2 diabetes (17, 18, 20), although the effect could not be dissociated from the concomitant reduction in food intake and body weight gain (19). Our preliminary data (Berthiaume, M., and Y. Deshaies, unpublished observations) obtained in postprandial conditions indicate that compound A used here does improve insulin sensitivity independently of changes in energy balance.

The depot specificity of action of pharmacological 11ß-HSD1 inhibition on fat mass agrees remarkably well with the fat distribution phenotype of both the adipose-specific 11ß-HSD1-overexpressing mouse [larger MES and unchanged EPI mass relative to wild-type (10)] and the obesity-sensitive C57BL/6J-11ß-HSD1–/– mouse [smaller MES and unchanged EPI mass on high-fat diet relative to wild-type (15)], despite differences in whole-body energetics among studies. Therefore, both lifelong gene invalidation in mice and short-term pharmacological inhibition of 11ß-HSD1 in rats impact depot-specific fat accretion similarly. The present study further demonstrates that such depot specificity of action occurs in the absence of any confounding effect of changes in food intake and therefore likely reflects direct effects of 11ß-HSD1 inhibition on adipocyte metabolism.

The reduction in MES weight was due to decreased cell size, with no change in total protein or DNA content. To gain insight into the mechanisms of the depot specificity of action of 11ß-HSD1 inhibition, activity or gene expression of major proteins of lipid metabolism were assessed. Uptake of lipids from the circulation is one pathway liable to impact fat accretion, and it is modulated by GC. Indeed, although with limited effect alone, GC amplify insulin action on LPL (35, 36), a key modulator of TAG-derived FA uptake by adipose tissue (37). Inhibition of 11ß-HSD1 exerted no effect on FA uptake or LPL activity in any of the depots, suggesting that in the present conditions, modulation of lipid metabolism involved intracellular processes rather than lipid uptake.

To address the impact of 11ß-HSD1 inhibition on intracellular lipid metabolism, we next focused on a set of enzymes that play major roles in the balance between lipid accumulation and disposal. The enzyme SCD1 converts saturated FAs, which are positive modulators of CPT-1-mediated FA transport to mitochondrial oxidation, into monounsaturated FAs, the preferred substrates for TAG synthesis. Mice lacking SCD1 display reduced adiposity and a gene expression pattern that may limit lipid synthesis and favor oxidation (38). In the present study, SCD-1 mRNA levels in the MES depot were robustly decreased by 11ß-HSD1 inhibition, in concomitance with higher CPT-1 activity, suggestive of increased FA oxidation. Also, in concordance with the notion of preferential routing of FAs toward oxidation rather than storage, 11ß-HSD1 inhibition reduced in the MES depot the expression of FAS, a GC-inducible gene (39) that is key to de novo FA synthesis, as well as that of DGAT1, which catalyzes a rate-limiting step in TAG synthesis (40). Therefore, the reduction in MES lipid content induced by 11ß-HSD1 inhibition appears to involve a coordinated alteration of enzymes involved in both arms of the adipocyte lipid balance. Finally, the inhibitor decreased in the MES depot the mRNA levels of ATGL, a newly described enzyme that plays an important role in basal lipolytic rates (41, 42, 43), as well as those of PEPCK, a GC target that favors FA reesterification (44), suggesting an overall reduction in FA movement between storage and metabolically available pools.

In sharp contrast with its effect in the MES depot, 11ß-HSD1 inhibition brought about in the EPI depot a coordinated increase in the expression of genes related to lipid synthesis (FAS, SCD1, DGAT1) or lipolysis/reesterification (ATGL, PEPCK) and a decrease in CPT1 activity, suggestive of a shift of metabolism toward lipid storage. Fat accumulation was not detected in the EPI depot, in the face of a small but significant decrease in weight of the MES depot, likely because in the absence of change in food intake, modulation of fat mass by 11ß-HSD1 is subtle. It should be noted that the reciprocity of effects of 11ß-HSD1 inhibition on gene expression in the MES and EPI depots was confirmed in a separate, identical study (Berthiaume, M., and Y. Deshaies, unpublished data). The tissue specificity of action of GC has long been recognized, the reciprocal modulation of PEPCK expression in the liver and kidney vs. adipose tissue being one germane example (45). The present study extends this notion by unveiling the previously unrecognized ability of GC attenuation (through 11ß-HSD1 inhibition) to alter the adipose gene expression program in opposite directions in different intraabdominal depots. Such depot specificity of action is reminiscent of that elicited by PPAR{gamma} agonists (46). Taken together, the above findings suggest that 11ß-HSD1 inhibition may counter MES fat accumulation through decreased lipid accumulation and increased energy dissipation and favor lipid storage in the less lipolytic, caval-drained, metabolically more protective (34, 47) EPI depot.

The mechanisms by which 11ß-HSD1 inhibition and consequent GC attenuation alters the gene expression program favoring a reduction in fat deposition in MES and possibly fat accretion in EPI are unknown. Among those adipose genes studied here, only GC response element-containing FAS and PEPCK are established direct targets of GC. Inhibition of 11ß-HSD1 and GC signaling may either impact the expression of each gene individually or may do so indirectly by altering one or several master modulators. For example, invalidation of the SCD1 gene, the expression of which was strongly decreased in MES by 11ß-HSD1 inhibition, reduces expression of several lipogenic genes and increases that of lipid oxidative genes (48), much akin to the pattern observed here in the MES depot. The near-perfect qualitative and quantitative reciprocity of the effects of 11ß-HSD1 inhibition on gene expression patterns in MES and EPI observed here strongly suggests mediation through a master modulator, and further studies are clearly warranted to investigate this possibility.

Although the marked adipose depot specificity of action of 11ß-HSD1 inhibition cannot readily be explained, several mechanisms can be considered. For instance, the PEPCK gene, which is reciprocally regulated by GC in liver and adipose, possesses a composite GC response element that binds the GR, which in turn can either repress or activate the gene (45). Beyond tissue-specific differences in GR density and amplitude of action (12), the transcriptional activity of GR depends on coactivators (45, 49), and subtle changes in their expression levels have been proposed to substantially alter the response to GC (50) and to mediate their tissue specificity of action (49). Whether variations in GR coactivator profiles contribute to the depot-specific regulation of adipose lipid metabolism by steroids remains to be established.

In summary, specific 11ß-HSD1 inhibition in the absence of change in food intake or body weight gain induced depot-specific remodeling of intraabdominal adipose depots with reduced fat accretion, decreased lipogenic gene expression, and increased oxidative enzyme activity in the metabolically disadvantageous MES. Opposite changes that may tend to favor long-term fat retention were observed in the metabolically safer EPI. Such adipose remodeling was associated with favorable changes in plasma lipids and reduced steatosis. Although proper caution should be exerted regarding drugs that target multiple organs including the brain, the present study demonstrates that specific 11ß-HSD1 inhibition, at a level that does not affect the central regulation of energy balance, is proving able to prevent some of the metabolic complications of diet-induced obesity.


   Acknowledgments
 
We acknowledge the technical assistance of Josée St-Onge and the contribution of the following personnel from Merck Research Laboratories (Rahway, NJ): Amanda Makarewicz for the preparation of compound A and Kathy Lyons, Liming Yang, Joseph Metzger, and Hratch Zokian for the background work in support of the studies presented herein.


   Footnotes
 
This work was supported by a grant from the Canadian Institutes of Health Research (to Y.D.). M.B. was the recipient of a Ph.D. Studentship award from Canadian Institutes of Health Research-Laval University.

R.T. is employed by Merck & Co., Inc., the maker of compound A, and is an inventor on Patent US20050070720A1. All other authors have nothing to disclose.

First Published Online February 1, 2007

Abbreviations: CPT, Carnitine palmitoyltransferase; EPI, epididymal adipose depot; FA, fatty acid; GC, glucocorticoid; GR, GC receptor; HPA, hypothalamic-pituitary-adrenal; 11ß-HSD1, 11ß-hydroxysteroid dehydrogenase type 1; LPL, lipoprotein lipase; MES, mesenteric adipose depot; RET, retroperitoneal adipose depot; TAG, triacylglycerol.

Received August 31, 2006.

Accepted for publication January 24, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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