Non-overweight depressed patients who respond to antidepressant treatment have a higher risk of later metabolic syndrome: findings from the METADAP cohort.

BACKGROUND: Major depressive disorder (MDD) is a complex disorder with a significant public health burden. Depression remission is often associated with weight gain, a major risk factor for metabolic syndrome (MetS). The primary objective of our study was to assess prospectively the impact of response to antidepressant treatment on developing MetS in a sample of MDD patients with a current major depressive episode (MDE) and who are newly initiating their treatment. METHODS: In the 6-month prospective METADAP cohort, non-overweight patients, body mass index <25 kg/m2, with MDD and a current MDE were assessed for treatment response after 3 months of treatment, and incidence of MetS after 3 and 6 months of treatment. Outcome variables were MetS, number of MetS criteria, and each MetS criterion (high waist circumference, high blood pressure, high triglyceridemia, low high-density lipoprotein-cholesterolemia, and high fasting plasma glucose). RESULTS: In total, 98/169 patients (58%) responded to treatment after 3 months. A total of 2.7% (1/38) developed MetS out of which 12.7% (10/79) (p value < 0.001) had responded to treatment after 3 months. The fixed-effect regression models showed that those who responded to treatment after 3 months of follow-up had an 8.6 times higher odds of developing MetS (odds ratio = 8.58, 95% confidence interval 3.89-18.93, p value < 0.001). CONCLUSION: Compared to non-responders, non-overweight patients who responded to treatment after 3 months of antidepressant treatment had a significantly higher risk of developing MetS during the 6 months of treatment. Psychiatrists and nurses should closely monitor the metabolic profile of their patients, especially those who respond to treatment.

Nitric Oxide Synthase activity in major depressive episodes before and after antidepressant treatment: Results of a large case-control treatment study.

BACKGROUND: Nitric oxide synthase (NOS) activity, an enzyme potentially involved in the major depressive episodes (MDE), could be indirectly measured by the L-Citrulline/L-Arginine ratio (L-Cit/L-Arg). The aim of this study was: (1) to compare the NOS activity of patients with a MDE to that of healthy controls (HC); (2) to assess its change after antidepressant treatment. METHODS: A total of 460 patients with a current MDE in a context of major depressive disorder (MDD) were compared to 895 HC for NOS activity (L-Cit/L-Arg plasma ratio). L-Arg and L-Cit plasma levels were measured using a MS-based liquid chromatography method. Depressed patients were assessed at baseline, and after 3 and 6 months of antidepressant treatment for depression severity and clinical response. RESULTS: Depressed patients had a lower NOS activity than HC at baseline [0.31 ± 0.09 v. 0.38 ± 0.12; 95% confidence interval (CI) -0.084 to -0.062, p < 0.0001]. Lower NOS activity at baseline predicted a higher response rate [odds ratio (OR) = 29.20; 95% CI 1.58-536.37; p = 0.023]. NOS activity in depressed patients increased significantly up to 0.34 ± 0.08 after antidepressant treatment (Est = 0.0034; 95% CI 0.0002-0.0067; p = 0.03). CONCLUSIONS: Depressed patients have a decreased NOS activity that improves after antidepressant treatment and predicts drug response. NOS activity may be a promising biomarker for MDE in a context of MDD.

PPAR-γ Agonists for the Treatment of Major Depression: A Review.

Introduction: Selective agonists of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ) are used for the treatment of type 2 diabetes. We reviewed their efficacy and safety for the treatment of major depression and the association of their potential antidepressant effects with changes in biomarkers of metabolism and inflammation. Methods: From 8 studies, 4 open-label trials, and 4 randomized controlled trials (RCT) (3 vs. placebo and 1 vs. metformin), 448 patients with major depression were included, of which 209 patients received PPAR-γ agonists (pioglitazone or rosiglitazone) for 6-12 weeks, either alone or in add-on therapy to conventional treatments. Results: PPAR-γ agonists have antidepressant effects in the 4 open-label studies and in 3 out of 4 RCT. No major adverse event was reported. Improvement in depression scores was associated with improvement in 3 biomarkers of insulin resistance (homeostatic model assessment [HOMA-IR], oral glucose tolerance test, and fasting plasma glucose) and 1 biomarker of inflammation (interleukin-6) among 21 biomarkers studied. Conclusion: PPAR-γ agonists may have antidepressant properties, which need to be assessed in further studies of major depressive episodes.

Expression of the semicarbazide-sensitive amine oxidase in articular cartilage: its role in terminal differentiation of chondrocytes in rat and human.

OBJECTIVE: Semicarbazide-sensitive amine oxidase (SSAO) catalyzes the oxidation of primary amines into ammonia and reactive species (hydrogen peroxide, aldehydes). It is highly expressed in mammalian tissues, especially in vascular smooth muscle cells and adipocytes, where it plays a role in cell differentiation and glucose transport. The study aims at characterizing the expression and the activity of SSAO in rat and human articular cartilage of the knee, and to investigate its potential role in chondrocyte terminal differentiation. DESIGN: SSAO expression was examined by immunohistochemistry and western blot. Enzyme activity was measured using radiolabeled benzylamine as a substrate. Primary cell cultures of rat chondrocytes were treated for 21 days by a specific SSAO inhibitor, LJP 1586. Terminal chondrocyte differentiation markers were quantified by RT-qPCR. The basal and IL1ß-stimulated glucose transport was monitored by the entrance of (3)[H]2-deoxyglucose in chondrocytes. RESULTS: SSAO was expressed in chondrocytes of rat and human articular cartilage. SSAO expression was significantly enhanced during the hypertrophic differentiation of chondrocytes characterized by an increase in MMP13 and in alkaline phosphatase (ALP) expressions. SSAO inhibition delayed the late stage of chondrocyte differentiation without cell survival alteration and diminished the basal and IL1ß-stimulated glucose transport. Interestingly, SSAO activity was strongly increased in human osteoarthritic cartilage. CONCLUSIONS: SSAO was expressed as an active form in rat and human cartilage. The results suggest the involvement of SSAO in rat chondrocyte terminal differentiation via a modulation of the glucose transport. In man, the increased SSAO activity detected in osteoarthritic patients may trigger hypertrophy and cartilage degeneration.

Characterization of diabetic osteoarthritic cartilage and role of high glucose environment on chondrocyte activation: toward pathophysiological delineation of diabetes mellitus-related osteoarthritis.

OBJECTIVE: To examine the relationship between osteoarthritis (OA) and type 2 diabetes mellitus (DM). METHODS: OA cartilage from DM and non-DM patients undergoing knee replacement were stimulated by IL-1ß for 24 h and release of interleukin-6 (IL-6) and prostaglandin E2 (PGE2) was measured. Primary cultured murine chondrocytes were stimulated for 24 and 72 h with or without IL-1ß (5 ng/mL) under normal-glucose (5.5 mM) or high-glucose (25 mM) conditions. The expression and release of pro-inflammatory mediators (IL-6, cyclooxygenase 2 [COX2]/PGE2) were analyzed by quantitative RT-PCR and ELISA/EIA. Glucose uptake was assessed with ((14)C)-2-deoxyglucose. Reactive oxygen species (ROS) and nitric oxide (NO) production were measured. To analyze the mechanism of IL-1ß-induced inflammation, cells were pretreated or treated with inhibitors of glucose transport (cytochalasin B), the polyol pathway (epalrestat), mitochondrial oxidative stress (MitoTEMPO) or nitric oxide synthase (l-NAME). RESULTS: With IL-1ß stimulation, IL-6 and PGE2 release was greater in human DM than non-DM OA cartilage (2.7- and 3-fold, respectively) (P < 0.05). In vitro, with IL-1ß stimulation, IL-6 and COX2 mRNA expression, IL-6 and PGE2 release, and ROS and NO production were greater under high-than normal-glucose conditions in cultured chondrocytes. IL-1ß-increased IL-6 release was reduced with cytochalasin B, epalrestat, L-NAME or MitoTEMPO treatment (-45%, -62%, -38% and -40%, respectively). CONCLUSION: OA cartilages from DM patients showed increased responsiveness to IL-1ß-induced inflammation. Accordingly, high glucose enhanced IL-1ß-induced inflammation in cultured chondrocytes via oxidative stress and the polyol pathway. High glucose and diabetes may thus participate in the increased inflammation in OA.

Thiazolidinediones partially reverse the metabolic disturbances observed in Bscl2/seipin-deficient mice.

AIMS/HYPOTHESIS: Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterised by near absence of adipose tissue and severe insulin resistance. We aimed to determine how seipin deficiency alters glucose and lipid homeostasis and whether thiazolidinediones can rescue the phenotype. METHODS: Bscl2 (-/-) mice were generated and phenotyped. Mouse embryonic fibroblasts (MEFs) were used as a model of adipocyte differentiation. RESULTS: As observed in humans, Bscl2 (-/-) mice displayed an early depletion of adipose tissue, with insulin resistance and severe hepatic steatosis. However, Bscl2 (-/-) mice exhibited an unexpected hypotriglyceridaemia due to increased clearance of triacylglycerol-rich lipoproteins (TRL) and uptake of fatty acids by the liver, with reduced basal energy expenditure. In vitro experiments with MEFs demonstrated that seipin deficiency led to impaired late adipocyte differentiation and increased basal lipolysis. Thiazolidinediones were able to rescue the adipogenesis impairment but not the alteration in lipolysis in Bscl2 (-/-) MEFs. In vivo treatment of Bscl2 (-/-) mice with pioglitazone for 9 weeks increased residual inguinal and mesenteric fat pads as well as plasma leptin and adiponectin concentrations. Pioglitazone treatment increased energy expenditure and improved insulin resistance, hypotriglyceridaemia and liver steatosis in these mice. CONCLUSIONS/INTERPRETATION: Seipin plays a key role in the differentiation and storage capacity of adipocytes, and affects glucose and lipid homeostasis. The hypotriglyceridaemia observed in Bscl2 (-/-) mice is linked to increased uptake of TRL by the liver, offering a new model of liver steatosis. The demonstration that the metabolic complications associated with BSCL can be partially rescued with pioglitazone treatment opens an interesting therapeutic perspective for BSCL patients.

Dunnigan lipodystrophy syndrome: French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins).

Dunnigan syndrome, or Familial Partial Lipodystrophy type 2 (FPLD2; ORPHA 2348), is a rare autosomal dominant disorder due to pathogenic variants of the LMNA gene. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins), is to provide health professionals with a guide to optimal management and care of patients with FPLD2, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Diseases of Insulin Secretion and Insulin Sensitivity (PRISIS), is available on the French Health Authority website (in French). Dunnigan syndrome is characterized by a partial atrophy of the subcutaneous adipose tissue and by an insulin resistance syndrome, associated with a risk of metabolic, cardiovascular and muscular complications. Its prevalence, assessed at 1/100.000 in Europe, is probably considerably underestimated. Thorough clinical examination is key to diagnosis. Biochemical testing frequently shows hyperinsulinemia, abnormal glucose tolerance and hypertriglyceridemia. Elevated hepatic transaminases (hepatic steatosis) and creatine phosphokinase, and hyperandrogenism in women, are common. Molecular analysis of the LMNA gene confirms diagnosis and allows for family investigations. Regular screening and multidisciplinary monitoring of the associated complications are necessary. Diabetes frequently develops from puberty onwards. Hypertriglyceridemia may lead to acute pancreatitis. Early atherosclerosis and cardiomyopathy should be monitored. In women, polycystic ovary syndrome is common. Overall, the management of patients with Dunnigan syndrome requires the collaboration of several health care providers. The attending physician, in conjunction with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are described to provide such a support.

[Drawing up guidelines for the attendance of physical health of patients with severe mental illness]. / Elaboration de recommandations pour le suivi somatique des patients atteints de pathologie mentale sévère.

INTRODUCTION: Having a mental illness has been and remains even now, a strong barrier to effective medical care. Most mental illness, such as schizophrenia, bipolar disorder, and depression are associated with undue medical morbidity and mortality. It represents a major health problem, with a 15 to 30 year shorter lifetime compared with the general population. METHODS: Based these facts, a workshop was convened by a panel of specialists: psychiatrists, endocrinologists, cardiologists, internists, and pharmacologists from some French hospitals to review the information relating to the comorbidity and mortality among the patients with severe mental illness, the risks with antipsychotic treatment for the development of metabolic disorders and finally cardiovascular disease. The French experts strongly agreed on these points: that the patients with severe mental illness have a higher rate of preventable risk factors such as smoking, addiction, poor diet, lack of exercise; the recognition and management of morbidity are made more difficult by barriers related to patients, the illness, the attitudes of medical practitioners, and the structure of healthcare delivery services; and improved detection and treatment of comorbidity medical illness in people with severe mental illness will have significant benefits for their psychosocial functioning and overall quality of life. GUIDELINES FOR INITIATING ANTIPSYCHOTIC THERAPY: Based on these elements, the French experts propose guidelines for practising psychiatrists when initiating and maintaining therapy with antipsychotic compounds. The aim of the guidelines is practical and concerns the detection of medical illness at the first episode of mental illness, management of comorbidity with other specialists, family practitioner and follow-up with some key points. The guidelines are divided into two major parts. The first part provides: a review of mortality and comorbidity of patients with severe mental illness: the increased morbidity and mortality are primarily due to premature cardiovascular disease (myocardial infarction, stroke...).The cardiovascular events are strongly linked to non modifiable risk factors such as age, gender, personal and/or family history, but also to crucial modifiable risk factors, such as overweight and obesity, dyslipidemia, diabetes, hypertension and smoking. Although these classical risk factors exist in the general population, epidemiological studies suggest that patients with severe mental illness have an increased prevalence of these risk factors. The causes of increased metabolic and cardiovascular risk in this population are strongly related to poverty and limited access to medical care, but also to the use of psychotropic medication. A review of major published consensus guidelines for metabolic monitoring of patients treated with antipsychotic medication that have recommended stringent monitoring of metabolic status and cardiovascular risk factors in psychiatric patients receiving antipsychotic drugs. There have been six attempts, all published between 2004 and 2005: Mount Sinai, Australia, ADA-APA, Belgium, United Kingdom, Canada. Each guideline had specific, somewhat discordant, recommendations about which patients and drugs should be monitored. However, there was agreement on the importance of baseline monitoring and follow-up for the first three to four months of treatment, with subsequent ongoing reevaluation. There was agreement on the utility of the following tests and measures: weight and height, waist circumference, blood pressure, fasting plasma glucose, fasting lipid profile. In the second part, the French experts propose guidelines for practising psychiatrists when initiating and maintaining therapy with antipsychotic drugs: the first goal is identification of risk factors for development of metabolic and cardiovascular disorders: non modifiable risk factors: these include: increasing age, gender (increased rates of obesity, diabetes and metabolic syndrome are observed in female patients treated with antipsychotic drugs), personal and family history of obesity, diabetes, heart disease, ethnicity as we know that there are increased rates of diabetes, metabolic syndrome and coronary heart disease in patients of non European ethnicity, especially among South Asian, Hispanic, and Native American people. Modifiable risk factors: these include: obesity, visceral obesity, smoking, physical inactivity, and bad diet habits. Then the expert's panel focussed on all the components of the initial visit such as: family and medical history; baseline weight and BMI should be measured for all patients. Body mass index can be calculated by dividing weight (in kilograms) by height (in meters) squared; visceral obesity measured by waist circumference; blood pressure; fasting plasma glucose; fasting lipid profiles. These are the basic measures and laboratory examinations to do when initiating an antipsychotic treatment. ECG: several of the antipsychotic medications, typical and atypical, have been shown to prolong the QTc interval on the ECG. Prolongation of the QTc interval is of potential concern since the patient may be at risk for wave burst arrhythmia, a potentially serious ventricular arrhythmia. A QTc interval greater than 500 ms places the patient at a significantly increased risk for serious arrhythmia. QTc prolongation has been reported with varying incidence and degrees of severity. The atypical antipsychotics can also cause other cardiovascular adverse effects with, for example, orthostatic hypotension. Risk factors for cardiovascular adverse effects with antipsychotics include: known cardiovascular disease, electrolyte disorders, such as hypokaliemia, hypomagnesaemia, genetic characteristics, increasing age, female gender, autonomic dysfunction, high doses of antipsychotics, the use of interacting drugs, and psychiatric illness itself. In any patient with pre-existing cardiac disease, a pre-treatment ECG with routine follow-up is recommended. CONCLUDING REMARKS: Patients on antipsychotic drugs should undergo regular testing of blood sugar, lipid profile, as well as body weight, waist circumference and blood pressure, with recommended time intervals between measures. Clinicians should track the effects of treatment on physical and biological parameters, and should facilitate access to appropriate medical care. In order to prevent or limit possible side effects, information must be given to the patient and his family on the cardiovascular and metabolic risks. The cost-effectiveness of implementing these recommendations is considerable: the costs of laboratory tests and additional equipment costs (such as scales, tape measures, and blood pressure devices) are modest. The issue of responsibility for monitoring for metabolic abnormalities is much debated. However, with the prescription of antipsychotic drugs comes the responsibility for monitoring potential drug-induced metabolic abnormalities. The onset of metabolic disorders will imply specific treatments. A coordinated action of psychiatrists, general practitioners, endocrinologists, cardiologists, nurses, dieticians, and of the family is certainly a key determinant to ensure the optimal care of these patients.

Adipokines: the missing link between insulin resistance and obesity.

White adipose tissue was believed to be just an energy-storage organ, but it is now recognized to be an active participant in energy homoeostasis and physiological functions such as immunity and inflammation. Macrophages are components of adipose tissue and actively participate in its activities. Adipose tissue is known to express and secrete a variety of products known as 'adipokines', including leptin, adiponectin, resistin and visfatin, as well as cytokines and chemokines such as tumor necrosis factor-alpha, interleukin-6 and monocyte chemoattractant protein-1. The release of adipokines by either adipocytes or adipose tissue-infiltrated macrophages leads to a chronic subinflammatory state that could play a central role in the development of insulin resistance and type 2 diabetes, and the increased risk of cardiovascular disease associated with obesity.

Potential role of progestogens in the control of adipose tissue and salt sensitivity via interaction with the mineralocorticoid receptor.

Beside their role in the control of water and electrolyte homeostasis, recent data clearly indicate that aldosterone and the mineralocorticoid receptor (MR) are involved in adipocyte biology. It has been recently shown that aldosterone promotes white and brown adipocyte differentiation in vitro through specific activation of the MR. In addition, a non-epithelial pro-inflammatory role for MR activation has been recently inferred from studies on mineralocorticoid/salt administration in experimental animal models and from clinical studies. The mineralocorticoid system could hence represent a potential target for new therapeutic strategies in obesity and the metabolic syndrome. Progesterone has high affinity for the MR and is a natural antagonist of aldosterone. Differently from classic synthetic progestins, which are devoid of antimineralocorticoid properties, progesterone and new progestogens show remarkable antimineralocorticoid effects. Here, we discuss the potential role of the antimineralocorticoid properties of progestogens in the control of body weight, adipose tissue proliferation and salt sensitivity; their therapeutic use in postmenopausal women, as well as in women affected by polycystic ovary syndrome, may open new and unexpected possibilities in the treatment of related metabolic disorders.

Antenatal antipsychotic exposure induces multigenerational and gender-specific programming of adiposity and glucose tolerance in adult mouse offspring.

Second-generation antipsychotics (SGAs) are well known for their metabolic side effects in humans, including obesity and diabetes. These compounds are maintained during pregnancy to prevent the relapse of psychoses, but they readily diffuse across the placenta to the fetus, as documented with the widely-prescribed drug olanzapine (OLZ). However, observational studies have provided conflicting results on the potential impact of SGAs on fetal growth and body weight, and their effects on metabolic regulation in the offspring. For this reason, our study has tested whether antenatal exposure of CD1 mice to OLZ influenced metabolic outcomes in the offspring of the first (F1) and second (F2) generations. In F1 mice, OLZ antenatal treatment caused a decrease in neonatal body weight in both genders, an effect that persisted throughout life only in male animals. Interestingly, F1 female mice also displayed altered glucose homoeostasis. F2 mice, generated by mating normal males with F1 female mice exposed to OLZ during antenatal life, exhibited higher neonatal body weights which persisted only in F2 female animals. This was associated with expansion of fat mass and a concordant pattern of adipose tissue gene expression. Moreover, male and female F2 mice were glucose-intolerant. Thus, our study has demonstrated that antenatal OLZ exposure induces multigenerational and gender-specific programming of glucose tolerance in the offspring mice as adults, and points to the need for careful monitoring of children exposed to SGAs during pregnancy.

Id3 prevents differentiation of preadipose cells.

We have studied the expression of the Id1, Id2, and Id3 genes during adipose differentiation of 3T3-F442A cells. All three Id mRNAs are present in preadipose cells, but the mRNA for Id3 is the most abundant. All three Id mRNAs sharply decline in the course of adipose differentiation, and their virtual disappearance precedes differentiation. The decrease in Id2 and Id3 is associated with adipose differentiation rather than with growth arrest since it is not observed in 3T3-C2 cells, a fibroblast line with a very low susceptibility to adipose conversion. The decline in Id2 and Id3 mRNAs is associated with a reduced transcription rate of the two genes. Id1 mRNA is reduced in amount during adipose conversion of 3T3-F442A cells, but the decrease is also observed in resting 3T3-C2 cells and is associated with very little decrease in transcription of the gene. Addition of fresh serum reactivates Id3 gene expression in quiescent 3T3-C2 cells but not in adipose 3T3-F442A cells. Stably transformed preadipose cells expressing an Id3 cDNA under the control of a viral promoter are virtually unable to differentiate. We postulate that the Id3 protein is a negative regulator of fat cell formation and presumably acts by preventing an as yet unidentified basic helix-loop-helix protein from activating the program of differentiation.

In vitro relationship of CD4 cells from type I diabetic patients and xenogeneic beta-cell membranes.

In a rosette assay, 63 patients with recent-onset type I (insulin-dependent) diabetes mellitus had a higher (P less than .001) number of lymphocytes adhering to rat insulinoma RINm5F cells (diabetic rosettes) than 153 healthy control (background rosettes) or 20 nondiabetic subjects with other organ-specific autoimmune diseases. Furthermore, lymphocytes from diabetic patients displayed a highly correlated (r = .97, P less than .001) binding on two different xenogeneic beta-cell lines (RIN and hamster insulinoma HIT cells). This phenomenon was not found on a panel of seven non-beta-cell lines (e.g., exocrine pancreatic cells, endocrine cells). By increasing lymphocyte-to-RIN ratios (0.25:1 to 30:1), the supernumerary RIN-adherent lymphocytes from diabetic patients, expressed as the percentage of lymphocytes involved conjugates, were only detectable at lower ratios (0.25:1 to 4:1), and their binding efficiency was two times higher than that of control lymphocytes. This efficiency fell at higher ratios (greater than 4:1) to the level of background rosettes that remained constant through the ratio scale. This specific RIN-rosette formation was abrogated when lymphocytes from diabetic patients were preabsorbed on beta-cells (either HIT or RIN) but not on non-beta-cells, whereas preabsorption of control lymphocytes did not modify the number of background rosettes. In addition, diabetic rosettes, but not background rosettes, were inhibited by competition with RIN membrane extracts but not by non-beta-cell extracts. Moreover, diabetic rosettes were inhibited during blocking experiments with anti-CD3 monoclonal antibody (MoAb) but not with unrelated MoAbs.(ABSTRACT TRUNCATED AT 250 WORDS)

Dexamethasone-dependent expression of beta 1-24 corticotropin stimulated adenylate cyclase during adipose conversion of 3T3-F442A cells.

When 3T3-F442A preadipocytes were grown in culture media supplemented with corticosteroid poor fetal calf serum and insulin they differentiated into adipocytes. Glycerophosphate dehydrogenase, a marker of terminal differentiation, developed a 600-fold increase of activity whereas the adenylate cyclase system remained unresponsive to the synthetic ACTH(1-24) analog. In contrast, 3T3-F442A adipocytes, differentiated in the presence of dexamethasone, exhibited an adenylate cyclase activity which was stimulated 4-fold by ACTH(1-24). The stimulation of the adenylate cyclase activity by GTP gamma S remained unchanged (about 20-25-fold) suggesting that the G regulatory coupling protein was not functionally modified by dexamethasone. Binding studies with 125I-ACTH revealed that specific cellular binding could be evidenced in dexamethasone-treated cells while control adipocytes did not exhibit any specific binding of 125I-ACTH. These findings lend support to the hypothesis that the setting off of this ACTH responsiveness in 3T3-F442A cells is regulated by dexamethasone after cells are committed to adipose differentiation.

The human beta 3-adrenergic receptor: relationship with atypical receptors.

Atypical beta-adrenergic receptors (beta AR), different from beta 1 and beta 2ARs, have been suggested to modulate energy expenditure. We have characterized a gene coding for a third human beta AR, beta 3AR, whose sequence is 402 amino acids long and is 50.7% and 45.5% homologous to that of the human beta 1 and beta 2AR, respectively. The KD of [125I]-iodocyanopindolol for beta 3AR is 10-fold higher than for beta 1 or beta 2AR. The receptor has an apparent molecular weight of 65,000. Agonists for the beta 3AR induce cyclic AMP accumulation. Among 11 beta antagonists tested, only ICI118551 and CGP20712A, previously classified as, respectively, beta 1 and beta 2 selective, inhibit this effect. The beta 1 and beta 2 antagonists pindolol, oxprenolol, and CGP12177 are agonists of the beta 3AR. The potency order of beta agonists at beta 3 sites correlates with that for stimulation of lipolysis in rat fat tissues. Moreover, because beta 3AR mRNA was detected in rodent adipose tissues, liver, and muscle, we propose that the beta 3AR participates to the control by catecholamines of energy expenditure.

The antiglucocorticoid RU38486 is a potent accelerator of adipose conversion of 3T3-F442A cells.

We examined the effects of RU38486, a potent glucocorticoid and progestin antagonist, upon several aspects of 3T3-F442A adipocyte differentiation. RU38486 accelerated the onset of differentiation, as monitored by cell morphological changes, accumulation of lipid droplets and widespread increases in the rate of expression of several enzyme adipose markers and specific mRNAs. RU38486, at a maximal concentration of 1 microM, dramatically hastened the emergence of both fatty-acid synthetase (FAS) and glycerol-3-phosphate dehydrogenase (G3PDH) enzyme activities (550% and 450% above control values 4 days after confluence, respectively). RU38486 induction of G3PDH-specific activity ran parallel to an increase in G3PDH mRNA content (2.4-fold the control content 4 days after confluence). Moreover, RU38486-treated cells exhibited enhancement of adenylate cyclase sensitivity to both isoproterenol and ACTH (160% and 350% above control activities 8 days after confluence, respectively). While the level of expression of lipogenic markers reached similar values at the mature stage, RU38486 enabled cells to acquire hypersensitivity in terms of ACTH-stimulated adenylate cyclase activity. Similarly, adipsin gene expression was highly potentiated by the drug at day 15 post-confluence (5-fold the control value). RU38486 responsiveness observed in differentiating 3T3-F442A cells is dependent upon their prior developmental activation; none of the studied markers could be induced by the drug in the undifferentiating 3T3-C2 cell subclone. Finally, this antiglucocorticoid appears to be a useful tool for studies on adipose conversion in vitro; it could permit a re-evaluation of the role of glucocorticoids in the understanding of adipocyte development.

Developmental expression and functional activity of beta 1- and beta 3-adrenoceptors in murine 3T3-F442A differentiating adipocytes.

Beta 1- and beta 3-adrenoceptor mRNA and protein expression, and contribution of each subtype to the catecholamine-sensitive adenylyl cyclase system were studied during the adipose conversion of the murine 3T3-F442A cell line. Northern and reverse transcriptase-polymerase chain reaction analyses indicated that emergence of beta 3-adrenoceptor transcripts was concomittant with that of the gene encoding adipsin, a very late marker of adipose differentiation. Conversely, the induction of the beta 1-adrenoceptor mRNA occurred early after cell commitment towards adipose conversion. Changes in beta-subtype gene expression were accompanied by parallel modifications in receptor expression and function. 125I-cyanopindolol saturation and competition binding experiments showed a 3-fold increase in beta 1-adrenoceptor density in day 3 post-confluent cells. The beta 3-subtype population became detectable later and represented approximately 95% of total beta-adrenoceptors in day 8 and day 12 post-confluent cells. Adenylyl cyclase activity in response to the beta 3-adrenoceptor-selective agonists CGP12177 (4-(3-t-butylamino-2-hydroxypropoxy)-benzimidazol-2-one), ICI201651 ([(R)-4-(2 hydroxy-3-phenoxypropylamino-ethoxy)-N-(2- methoxyethyl)phenoxy-acetamide]) and cyanopindolol was virtually absent in young adipocytes, but dramatically increased in mature cells. The respective contributions of the beta 1- and the beta 3-subtypes to the production of cAMP were resolved by an Eadie-Hofstee computer analysis of isoproterenol and norepinephrine concentration-response curve of adenylyl cyclase activity. Agonist response curves in the presence of beta 1- and beta 2-adrenoceptor antagonist indicated that the beta 1-subtype accounted for the totality of beta-adrenoceptor-mediated adenylyl cyclase activation in young adipocytes. In mature adipose cells approximately 90% of this response was due to an activation of the beta 3-adrenoceptor. In addition, approximately 84% of the maximal norepinephrine-stimulated lipolysis was mediated by the beta 3-adrenoceptor in fully differentiated adipocytes. The differentiation-dependent expression of beta-subtypes in adipocytes is a biphasic process involving an initial and moderate induction of beta 1-adrenoceptors followed by the emergence of a prominent beta 3-adrenoceptor population. Compared analysis of both receptor occupancy and cAMP production shows that the beta 3-subtype is more efficiently coupled to the adenylyl cyclase system than the beta 1-adrenoceptor. Thus in mature adipose cells this receptor subtype represents the core of cAMP-dependent regulation of the lipolytic, antilipogenic and thermogenic effects of catecholamines.

Carbamazepine directly inhibits adipocyte differentiation through activation of the ERK 1/2 pathway.

BACKGROUND AND PURPOSE: Carbamazepine (CBZ), known for its anti-epileptic, analgesic and mood-stabilizing properties, is also known to induce weight gain but the pathophysiology of this adverse effect is still largely unknown. We tested the hypothesis that CBZ could have a direct effect on adipocyte development and metabolism. EXPERIMENTAL RESEARCH: We studied the effects of CBZ on morphological biochemical and molecular markers of adipogenesis, using several pre-adipocyte murine cell lines (3T3-L1, 3T3-F442A and T37i cells) and primary cultures of human pre-adipocytes. To delineate the mechanisms underlying the effect of CBZ, clonal expansion of pre-adipocytes, pro-adipogenic transcription factors, glucose uptake and lipolysis were also examined. KEY RESULTS: CBZ strongly inhibited pre-adipocyte differentiation and triglyceride accumulation in a time- and dose-dependent manner in all models. Pleiotropic mechanisms were at the basis of the inhibitory effects of CBZ on adipogenesis and cell lipid accumulation. They included suppression of both clonal expansion and major adipogenic transcription factors such as PPAR-γ and CCAAT/enhancer binding protein-α, activation of basal lipolysis and decrease in insulin-stimulated glucose transport. CONCLUSIONS AND IMPLICATIONS: The effect of CBZ on adipogenesis involves activation of the ERK1/2 pathway. Our results show that CBZ acts directly on pre-adipocytes and adipocytes to alter adipose tissue development and metabolism.

[New pathophysiological mechanisms of metabolic syndrome: implication of orphan nuclear receptors?]. / Nouveaux mécanismes physiopathologiques du Syndrome Métabolique: implication des récepteurs nucléaires orphelins?

This review focuses on a number of new data on biology and pathophysiology of the metabolic syndrome (MetS) and the involvement of nuclear receptors that have been presented during the last Endocrine Society meeting, held in Houston in June 2012. Several studies have reported beneficial effects of various orphan nuclear receptors, including SHP (Small Heterodimeric Partner, NR0B2) and LXR (Liver X Receptor, NR1H3 and NR1H2), on various components of MetS. By using an inactivation model of SHP, David Moore has shown that SHP exerts "antidiabetic" effects but associated with hepatic steatosis development. He also showed that DLPC (dilauroyl phosphatidylcholine), an unconventional phospholipid, exhibited anti-diabetic properties through its binding to LRH-1 (Liver Receptor Homolog-1, NR5A2), a molecular partner of SHP. Interestingly, Carolyn Cummins investigated LXR α and ß isoforms knock-out mice and provided experimental evidence for the detailed mechanisms involved in the deleterious metabolic effects of glucocorticoids, pointing out to the functional interaction between LXRß, and the glucocorticoid receptor. These new and original studies open new therapeutic opportunities for the management of metabolic disorders in humans by selective modulators of these receptors.

Diabetes and inflammation: fundamental aspects and clinical implications.

AIM: The aim of this paper is to provide the fundamental background of the inflammation theory associated with type 2 diabetes, to discuss the clinical consequences of low-grade inflammation, particularly in terms of cardiovascular risk, and to infer some clinical therapeutic strategies deriving from drugs that already exist or are in development. METHODS: This non-exhaustive work is the result of a Pubmed(®) research, based on requests including the following keywords: diabetes, inflammation, innate immunity, obesity, reticulum endoplasmic stress, cytokines, endothelial dysfunction. RESULTS: Obesity and type 2 diabetes are linked with a low-grade inflammation state that reflects the activation of innate immunity where metabolic, environmental and genetic factors are implicated. The role of endoplasmic reticulum stress and unfold protein response is underlined. Inflammation markers are predictive for the risk to develop diabetes, and are associated with an increased cardiovascular risk. While lifestyle modifications are followed by an improvement in inflammation markers, treatments inferred from the inflammation theory are of great interest, although quite moderate effects on glycaemic control have been observed with some of them. CONCLUSION: The development of molecules targeting different inflammatory mechanisms could lead in diabetic patients to improvement of both glycaemia and cardiovascular prognosis.