Postnatal diet-induced obesity in rats upregulates systemic and adipose tissue glucocorticoid metabolism during development and in adulthood: its relationship with the metabolic syndrome.

In humans, a hyperactivity of glucocorticoid metabolism was postulated to be involved in the intrauterine programming of the metabolic syndrome in adulthood. We studied in rats the effects of overfeeding, obtained by reducing the size of the litter in the immediate postnatal period, a time crucial for neuroendocrine maturation such as late gestation in humans. Overfeeding induced early-onset obesity and accelerated the maturation of the hypothalamo-pituitary-adrenal (HPA) axis together with an upregulation of adipose tissue glucocorticoid receptor (GR) mRNA. In adulthood, neonatally overfed rats presented with moderate increases in basal and stress-induced corticosterone secretion and striking changes in visceral adipose tissue glucocorticoid signaling, that is, enhanced GR and 11beta-hydroxysteroid dehydrogenase type 1 mRNA levels. The above-mentioned alterations in the endocrine status of overfed rats were accompanied by a moderate overweight status and significant metabolic disturbances comparable to those described in the metabolic syndrome. Our data demonstrate for the first time that postnatal overfeeding accelerates the maturation of the HPA axis and leads to permanent upregulation of the HPA axis and increased adipose tissue glucocorticoid sensitivity. Thus, the experimental paradigm of postnatal overfeeding is a powerful tool to understand the pathophysiology of glucocorticoid-induced programming of metabolic axes.

[Obesity: where are we now?]. / Obésité: où en sommes-nous?

Overweight and obesity correspond to excess fat, defined and assessed in clinical practice by the body mass index (BMI: ratio of weight in kilograms to height in meters squared). Obesity has numerous negative health consequences: metabolic, cardiovascular, and mechanical complications, predisposition to some cancers, and psychosocial repercussions. In France in 2003, 30% of adults were overweight and 11% obese. The increase in fat reserves that characterizes obesity results from an energy imbalance, which in turn arises from complex interactions. This explains the clinical and biological heterogeneity of human obesity. Control of this epidemic in the years to come probably depends more on the implementation of activities coordinated by various social actors than on the development of a specific drug.

[Glucocorticoids, 11 beta-hydroxysteroid dehydrogenase type 1, and visceral obesity]. / Glucocorticoïdes, 11 beta-hydroxystéroïde déshydrogénase de type 1 et obésité viscérale.

Glucocorticoids are implicated as a pathophysiological mediator of obesity and its accompanying metabolic and cardiovascular complications. Obese patients exhibit normal circulating cortisol levels, related to increased glucocorticoid production and degradation. However, it has been demonstrated that local production of active cortisol from inactive cortisone driven by 11 beta-hydroxysteroid dehydrogenase type 1 is exaggerated in adipose tissue of obese subjects. Such local hypercortisolism may be responsible for increased adipocyte differentiation and enhanced secretion of free fatty acids and other substances involved in the metabolic and cardiovascular complications observed in obesity.

[Corticotherapy withdrawal in older people]. / Arrêt de la corticothérapie chez la personne âgée.

Synthetic glucocorticoids treatment for their antiinflammatory and immunosuppressive activities for more than 3 weeks decreases corticotropic axis and induces a risk of adrenal insufficiency upon treatment withdrawal. Dose, duration and unknown individual factors play a role in the occurrence of adrenal insufficiency. Serum cortisol at 7-8 am, possibly completed by an 1-24 ACTH stimulation test makes the diagnosis. A scheme for care of patients is included with a progressive decrease of synthetic glucocorticoids dose, a replacement of this medication with physiological doses of hydrocortisone (in case of adrenal insufficiency) and a follow-up of endogenous secretion for detection of adrenal function recovery.

Effects of bariatric surgery on cardiac ectopic fat: lesser decrease in epicardial fat compared to visceral fat loss and no change in myocardial triglyceride content.

OBJECTIVES: This study investigated the effect of bariatric surgery (BS)-induced weight loss on cardiac ectopic fat using 3T magnetic resonance imaging in morbid obesity. BACKGROUND: Heart disease is one of the leading causes of mortality and morbidity in obese patients. Deposition of cardiac ectopic fat has been related to increased heart risk. Whether sustained weight loss can modulate epicardial fat or myocardial fat is unknown. METHODS: Twenty-three morbidly obese patients underwent 1H-magnetic resonance spectroscopy to determine myocardial triglyceride content (MTGC), magnetic resonance imaging to assess epicardial fat volume (EFV), cardiac function, and computed tomography visceral abdominal fat (VAF) measurements at baseline and 6 months after BS. RESULTS: The BS reduced body mass index significantly, from 43.1±4.5 kg/m2 to 32.3±4.0 kg/m2, subcutaneous fat from 649±162 cm2 to 442±127 cm2, VAF from 190±83 cm2 to 107±44 cm2, and EFV from 137±37 ml to 98±25 ml (all p<0.0001). There was no significant change in MTGC: 1.03±0.2% versus 1.1±0.2% (p=0.85). A significant reduction in left ventricular mass (118±24 g vs. 101±18 g) and cardiac output (7.1±1.6 l/min vs. 5.4±1.0 l/min) was observed and was statistically associated with weight loss (p<0.05). The loss in EFV was limited (-27±11%) compared to VAF diminution (-40±19%). The EFV variation was not correlated with percentage of body mass index or VAF loss (p=0.007). The ratio of %EFV to %VAF loss decreased with sleep apnea syndrome (1.34±0.3 vs. 0.52±0.08, p<0.05). CONCLUSIONS: Six-month BS modulates differently cardiac ectopic fat deposition, with a significant decrease in epicardial fat and no change in myocardial fat. Epicardial fat volume loss was limited in patients with sleep apnea. (Impact of Bariatric Surgery on Epicardial Adipose Tissue and on Myocardial Function; NCT01284816).

[What can we do with genetic screening of obesity in clinical practice?]. / Que faire de la génétique de l'obésité en pratique clinique?

The discovery of genetic abnormalities in obesity improves the knowledge on the physiology of energetic homeostasis, and demonstrates that it is a fully recognized disease and not only a behavioral problem. In cases of early obesity and very severe degree, with severely abnormal dietary behavior, endocrine abnormalities, and a ground of parental consanguinity, monogenic obesity or a syndromic obesity (in the case of a rare genetic disease) must be suspected. In that case, a genetic screening is necessary because it helps the global care of the patient and sometimes an effective specific therapeutics can be proposed. Except in the previous cases, oligogenic obesity (mutation of an important gene) or polygenic obesity (association of polymorphisms on various genes) are suspected. The genetic abnormalities express themselves only in association with deleterious environment. In these situations, it is not at the moment recommended to make a systematic screening in clinical practice.

Postnatal programming of glucocorticoid metabolism in rats modulates high-fat diet-induced regulation of visceral adipose tissue glucocorticoid exposure and sensitivity and adiponectin and proinflammatory adipokines gene expression in adulthood.

OBJECTIVE: Alterations of the perinatal environment, which lead to increased prevalence of the metabolic syndrome in adulthood, program an upregulation of systemic and/or adipose tissue glucocorticoid metabolism (11 beta-hydroxysteroid dehydrogenase type 1 [11 beta-HSD-1]-induced corticosterone reactivation). We hypothesized that postnatal programming could modulate high-fat diet-induced adipose tissue dysregulation in adulthood. RESEARCH DESIGN AND METHODS: We compared the effects of chronic (since weaning) high- or low-fat diet in postnatally normofed (control) or overfed (programmed) rats. RESULTS: Postnatal programming accentuated high-fat diet-induced overweight, insulin resistance, glucose intolerance, and decrease in circulating and epididymal adipose tissue adiponectin. Neither manipulation altered liver function. Postnatal programming or high-fat diet increased systemic corticosterone production, which was not further modified when both manipulations were associated. Postnatal programming suppressed high-fat diet-induced decrease in mesenteric adipose tissue (MAT) glucocorticoid sensitivity and triggered high-fat diet-induced increase in MAT glucocorticoid exposure, subsequent to enhanced MAT 11 beta-HSD-1 gene expression. MAT tumor necrosis factor (TNF)-alpha, TNF-receptor 1, interleukin (IL)-6, resistin, and plasminogen activator inhibitor-1 mRNAs were not changed by high-fat feeding in control rats and showed a large increase in programmed animals, with this effect further enhanced by high-fat diet for TNF-alpha and IL-6. CONCLUSIONS: Our data show for the first time that postnatal manipulation programs high-fat diet-induced upregulation of MAT glucocorticoid exposure, sensitivity, and inflammatory status and therefore reveal the pivotal role of the environment during the perinatal period on the development of diet-induced adipose tissue dysregulation in adulthood. They also urge the need for clinical trials with specific 11 beta-HSD-1 inhibitors.

Renin receptor expression in human adipose tissue.

Adipose tissue synthesizes all components of the renin-angiotensin system. The renin receptor (RenR) is able, on renin binding, to increase its efficiency to generate angiotensin I from angiotensinogen. We demonstrate that RenR is specifically synthesized in the stromal portion of human adipose tissue in both isolated interadipocyte stromal cells and in stromal areas. RenR is expressed at the periphery of cells, strongly suggesting a membranal localization. RenR protein expression in primary cultures of human stromal cells decreased significantly during differentiation, whereas RenR mRNA levels did not change, demonstrating that RenR was expressed in both preadipocyte and nonpreadipocyte cells, and was regulated at a posttranscriptional level. Double-labeling immunohistochemistry of human adipose tissue sections revealed that RenR was colocalized with renin, whereas incubation of 3T3-L1, a preadipocyte cell line, with renin stimulated the phosphorylation state of the intracellular signaling pathway ERK 1/2, and short exposure of human adipose stromal cells in primary culture to renin was followed by a long-lasting dose-dependent increase of angiotensin I generation, indicating that adipose RenR is functional. We show, using a large set of human adipose tissue biopsies, that RenR expression was increased in visceral compared with subcutaneous adipose tissue of lean and obese patients. Taken together with our finding that RenR was colocalized with plasminogen activator inhibitor type 1, the main inhibitor of the fibrinolytic system in visceral adipose tissue, the above-mentioned data suggest that RenR plays a role in obesity-induced visceral adipose tissue accumulation and its accompanying cardiovascular complications.

Perinatal programming of central obesity and the metabolic syndrome: role of glucocorticoids.

Intrauterine growth retardation (IUGR) is associated with increased prevalence, at the adult age, of central obesity, the metabolic syndrome, and its complications (type 2 diabetes and coronary heart disease). Programming of the corticotropic function is one of the mechanisms underlying the above-mentioned phenomenon. An increased passage of active glucocorticoids from the mother to the fetus can act, at the central nervous system level, to program an enhanced response to stress and, at the peripheral level, in adipose tissue to induce an increased local glucocorticoid exposure and sensitivity. In addition to an improvement of the health of pregnant women, early diagnosis of metabolic and hormonal disturbances is important in children with IUGR, in order to prevent a compensatory catch-up growth and its subsequent obesity, and to set up a therapeutic intervention against the deleterious consequences of hypercorticism.

11beta-hydroxysteroid dehydrogenase type 1 mRNA is increased in both visceral and subcutaneous adipose tissue of obese patients.

OBJECTIVE: Data from rodents provide evidence for a causal role of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) in the development of obesity and its complications. In humans, 11beta-HSD-1 is increased in subcutaneous adipose tissue (SAT) of obese patients, and higher adipose 11beta-HSD-1 was associated with features of the metabolic syndrome. To date, there is no evidence for an increased expression of 11beta-HSD-1 in human visceral adipose tissue (VAT), although VAT is the major predictor for insulin resistance and the metabolic syndrome. RESEARCH METHODS AND PROCEDURES: 11beta-HSD-1 and hexose-6-phosphate dehydrogenase (the enzyme responsible for the synthesis of nicotinamide adenine dinucleotide phosphate, the cofactor required for 11beta-HSD-1 oxoreductase activity) mRNA levels were measured using real-time quantitative reverse transcriptase-polymerase chain reaction in abdominal SAT and VAT biopsies obtained from 10 normal-weight and 12 obese women. Adiponectin mRNA was used as an internal control. RESULTS: 11beta-HSD-1 mRNA concentrations were significantly increased in both SAT and VAT of obese patients (720% and 450% of controls, respectively; p < 0.05) and correlated with hexose-6-phosphate dehydrogenase mRNA levels. The level of VAT 11beta-HSD-1 mRNA correlated with anthropometric parameters: BMI (r = 0.41, p = 0.05), waist circumference (r = 0.44, p = 0.04), abdominal sagittal diameter (r = 0.51, p = 0.02), and percentage fat (r = 0.51, p = 0.02). DISCUSSION: Our results demonstrate for the first time that 11beta-HSD-1 mRNA expression is increased in VAT from obese patients. They strengthen the importance of 11beta-HSD-1 in human obesity and its associated complications and suggest the need of clinical studies with specific 11beta-HSD-1 inhibitors.

Insulin resistance induced by hydrocortisone is increased in patients with abdominal obesity.

Glucocorticoids hypersensitivity may be involved in the development of abdominal obesity and insulin resistance. Eight normal weight and eight obese women received on two occasions a 3-h intravenous infusion of saline or hydrocortisone (HC) (1.5 microg x kg(-1) x min(-1)). Plasma cortisol, insulin, and glucose levels were measured every 30 min from time(-30) (min) (time(-30)) to time(240). Free fatty acids, adiponectin, and plasminogen activator inhibitor-1 (PAI-1) levels were measured at time(-30), time(180), and time(240). At time(240), subjects underwent an insulin tolerance test to obtain an index of insulin sensitivity (K(ITT)). Mean(30-240) cortisol level was similar in control and obese women after saline (74 +/- 16 vs. 75 +/- 20 microg/l) and HC (235 +/- 17 vs. 245 +/- 47 microg/l). The effect of HC on mean(180-240) insulin, mean(180-240) insulin resistance obtained by homeostasis model assessment (HOMA-IR), and K(ITT) was significant in obese (11.4 +/- 2.0 vs. 8.2 +/- 1.3 mU/l, P < 0.05; 2.37 +/- 0.5 vs. 1.64 +/- 0.3, P < 0.05; 2.81 +/- 0.9 vs. 3.32 +/- 1.02%/min, P < 0.05) but not in control women (3.9 +/- 0.6 vs. 2.8 +/- 0.5 mU/l; 0.78 +/- 0.1 vs. 0.49 +/- 0.1; 4.36 +/- 1.1 vs. 4.37 +/- 1.2%/min). In the whole population, the quantity of visceral fat, estimated by computerized tomography scan, was correlated with the increment of plasma insulin and HOMA-IR during HC infusion [Delta mean(30-240) insulin (r = 0.61, P < 0.05), Delta mean(30-240) HOMA-IR (r = 0.66, P < 0.01)]. The increase of PAI-1 between time(180) and time(240) after HC was higher in obese women (+25%) than in controls (+12%) (P < 0.05), whereas no differential effect between groups was observed for free fatty acids or adiponectin. A moderate hypercortisolism, equivalent to that induced by a mild stress, has more pronounced consequences on insulin sensitivity in abdominally obese women than in controls. These deleterious effects are correlated with the amount of visceral fat.

Cluster analysis: an alternative method for covariate selection in population pharmacokinetic modeling.

To be analyzed, the heterogeneity characterizing biological data calls for using appropriate models involving numerous variables. A high variable number could become problematic when one needs to determine a priori the most significant variable combination in order to reduce the inter-individual variability (IIV). Alternatively to multiple introductions of single variables, we propose a single introduction of a multivariate variable. We present cluster analysis as a stratification strategy that combines the initial single covariates to build a multivariate categorical covariate. It is an exploratory multivariate analysis that outlines homogeneous categories of individuals (clusters) according to similarities from the set of covariates. It includes many clustering techniques combining a distance measure and a linkage algorithm, and leading to various stratification patterns. The cluster analysis approach is illustrated by a case study on cortisol kinetics in 82 patients after intravenous bolus administration of synacthen (synthetic corticotropin). Using NONMEM, a basic infusion model was initially achieved for cortisol, and then a classical covariate selection was applied to improve IIV. The best fit was between the elimination rate constant k and the body mass index (BMI), which improved IIV of k. An alternative method is presented consisting in the population into homogeneous and non-overlapping groups by applying a cluster analysis. Such categorization (or clustering) was carried out using Euclidean distance and complete-linkage algorithm. This algorithm gave five dissimilar clusters that differed by increasing BMI, obesity duration, and waist-hip ratio. The dispersion of k according to the five clusters showed three distinctvariation ranges a priori, which corresponded a posteriori(after NONMEM modeling) to three sub-populations of k. After grouping the clusters that had similar variation ranges of k, we obtained three final clusters representing non-obese, intermediate, and extreme obese sub-populations. The pharmacokinetic model based on three clusters was better than the basic model, similar to the classical covariate model, but had a stronger interpretability: It showed that the stimulation and elimination of cortisol were higher in the extreme obese followed by intermediate then non-obese subjects.

Expression of the mRNAs coding for the glucocorticoid receptor isoforms in obesity.

OBJECTIVE: Glucocorticoids may be a pathophysiological mediator for the development of visceral obesity. In obese patients, adipose tissue reactivation of cortisone to cortisol is enhanced. In addition, changes in glucocorticoid receptor (GR) could also be important, either at the central nervous system level, by modulating the negative glucocorticoid feedback, or at a peripheral level, by regulating adipose tissue activity. RESEARCH METHODS AND PROCEDURES: Using quantitative reverse transcriptase-polymerase chain reaction, we studied the expression of the GR mRNA isoforms (active, GRalpha; inactive, GRbeta) in circulating mononuclear leukocytes (in which GR shares the same regulation with central nervous system GR) obtained from normal weight women (n = 65) and patients with gluteofemoral (n = 26) or visceral (n = 39) obesity. Using in situ hybridization, we measured GRalpha mRNA levels in adipose tissue from control (n = 10) or obese (n = 15) patients. RESULTS: The mean alpha/beta ratio was decreased in mononuclear leukocytes from obese patients (2.6, 9.2, and 32.1, respectively). GRalpha mRNA levels were significantly decreased in subcutaneous abdominal adipose tissue obtained from obese patients compared with nonobese ones, suggesting the existence of a downregulation of GR gene expression. This phenomenon was not found in visceral adipose tissue. DISCUSSION: This suggests that, in obese patients, the relative insensitivity to the negative glucocorticoid feedback is, at least in part, subsequent to a dysregulation of the GRalpha/GRbeta ratio and that visceral, but not subcutaneous, adipose tissue retains a full capacity to respond to increased local generation of cortisol.