Michel Grino

The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes.

Aims/hypothesisObesity is associated with adipose tissue inflammation. The CD40 molecule, TNF receptor superfamily member 5 (CD40)/CD40 ligand (CD40L) pathway plays a role in the onset and maintenance of the inflammatory reaction, but has not been studied in human adipose tissue. Our aim was to examine CD40 expression by human adipocytes and its participation in adipose tissue inflammation.MethodsCD40 expression was investigated in human whole adipose tissue and during adipocyte differentiation by real-time PCR, Western blot and immunohistochemistry. The CD40/CD40L pathway was studied using recombinant CD40L (rCD40L) in adipocyte culture and neutralising antibodies in lymphocyte/adipocyte co-culture.ResultsCD40 mRNA levels in subcutaneous adipose tissue were higher in the adipocyte than in the stromal–vascular fraction. CD40 expression was upregulated during adipocyte differentiation. Addition of rCD40L to adipocytes induced mitogen activated protein kinase (MAPK) activation, stimulated inflammatory adipocytokine production, and decreased insulin-induced glucose transport in parallel with a downregulation of IRS1 and GLUT4 (also known as SCL2A4). rCD40L decreased the expression of lipogenic genes and increased lipolysis. CD40 mRNA levels were significantly higher in subcutaneous adipose tissue than in visceral adipose tissue of obese patients and were positively correlated with BMI, and with IL6 and leptin mRNA levels. Lymphocyte/adipocyte co-culture led to an upregulation of proinflammatory adipocytokines and a downregulation of leptin and adiponectin. Physical separation of the two cell types attenuated these effects, suggesting the involvement of a cell–cell contact. Blocking the CD40/CD40L interaction with neutralising antibodies reduced IL-6 secretion from adipocytes.Conclusions/interpretationAdipocyte CD40 may contribute to obesity-related inflammation and insulin resistance. T lymphocytes regulate adipocytokine production through both the release of soluble factor(s) and heterotypic contact with adipocytes involving CD40.

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 (11β-hydroxysteroid dehydrogenase type 1 [11β-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 11β-HSD-1 gene expression. MAT tumor necrosis factor (TNF)-α, 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-α 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 11β-HSD-1 inhibitors.

Adrenomedullin, an autocrine/paracrine factor induced by androgen withdrawal, stimulates 'neuroendocrine phenotype' in LNCaP prostate tumor cells

Neuroendocrine (NE) differentiation in prostate cancer (CaP) has been reported to be an early marker associated with the development of androgen independence. The mechanisms by which CaP acquires NE properties are poorly understood. In this study, a putative role of adrenomedullin (AM) in the NE differentiation was investigated. The expression of AM and AM receptors (calcitonin receptor-like receptor (CRLR)/receptor activity modifying protein-2 and -3 (RAMP2 and RAMP3) was evaluated after experimental manipulation of androgen status. Levels of AM mRNA and immunoreactive AM (ir-AM) increased four- to sevenfold in androgen-sensitive LNCaP cells after androgen withdrawal in vitro and in LNCaP xenografts in animals after castration. Treatment of LNCaP cells with androgen analogue (dihydrotestosterone; 10−9 M) prevented the increase in AM mRNA and ir-AM levels. Interestingly, the expression of CRLR, RAMP2 and RAMP3 is not regulated by androgen status. We demonstrate that in the presence of serum, AM is able to induce an NE phenotype in LNCaP cells via CRLR/RAMP2 and RAMP3, which includes extension of neuritic processes and expression of the neuron-specific enolase (NSE), producing cGMP in a dose-dependent manner, which is mediated by a pertussis toxin-sensitive GTP-binding protein. 8-bromo-cGMP mimicked the effects of AM on cell differentiation. We demonstrate that AM induces a G-kinase Iα translocation to the nucleus. The protein kinase G inhibitor KT-5823 inhibited the neurite outgrowth induced by both AM and 8-bromo-cGMP. In noncastrated animals, administration of AM enhanced expression of NSE and chromogranin A in LNCaP xenografts with a significant increase of NSE levels in serum and no changes in tumor growth. In castrated animals, intraperitoneal injection of AM resulted in a 240±18% (P<0.001) increase in tumor volume 36 days after treatment, indicating that the nature of effect of AM in CaP depends on the presence or absence of endogenous androgen. Together, these results demonstrate that AM may function as a mediator of NE-like differentiation in culture as well as in vivo and indicate that its production may be important for tumor resurgence following androgen ablation.

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.

Inflammatory Phenotyping Identifies CD11d as a Gene Markedly Induced in White Adipose Tissue in Obese Rodents and Women

In severe obesity, white adipose tissue (WAT) inflammation and macrophage infiltration are thought to contribute to WAT and whole-body insulin resistance. Specific players involved in triggering and maintaining inflammation (i.e. those regulating adipokine release and WAT macrophage recruitment, retention, or function) remain to be fully elaborated, and the degree to which moderate obesity promotes WAT inflammation remains to be clarified further. Therefore, we characterized adiposity and metabolic phenotypes in adult male C57BL/6J mice fed differing levels of dietary fat (10, 45, and 60% of energy) for 12 wk, concurrent with determinations of WAT inflammation markers and mRNA expression of leukocyte-derived integrins (CD11b, CD11c, CD11d) involved in macrophage extravasation and tissue macrophage homing/retention. As expected, a lard-based, very high-fat diet (60% energy) significantly increased adiposity and glucose intolerance compared with 10% fat-fed controls, coincident with higher retroperitoneal (RP) WAT transcript levels for proinflammatory factors and macrophage markers, including TNFα and CD68 mRNA, which were ~3- and ~15-fold of control levels, respectively (P < 0.001). Mice fed the 45% fat diet had more moderate obesity, less glucose intolerance, and lower WAT macrophage/inflammatory marker mRNA abundances compared with 60% fat-fed mice; TNFα and CD68 mRNA levels were ~2- and ~5-fold of control levels (P < 0.01). Relative WAT expression of CD11d was massively induced by obesity to an extent greater than any other inflammatory marker (to >300-fold of controls in the 45 and 60% fat groups) (P < 0.0001) and this induction was WAT specific. Because we found that CD11d expression also increased in RP-WAT of Zucker obese rats and in the subcutaneous WAT of obese adult women, this appears to be a common feature of obesity. Observed correlations of WAT macrophage transcript marker abundances with body weight in lean to modestly obese mice raises an interesting possibility that the activities of at least some WAT macrophages are closely linked to the normal adipose remodeling that is a requisite for changes in WAT energy storage capacity.

Diet Modulates Endogenous Thrombin Generation, A Biological Estimate of Thrombosis Risk, Independently of the Metabolic Status

Objective—High endogenous thrombin potential (ETP) is associated with venous and arterial thrombosis. Better knowledge of environmental influences on ETP may help to prevent thrombosis. Methods and Results—Weaning rats exhibited high ETP values that decreased in low-fat diet and remained elevated on high-fat diet. In adult rats, high-fat diet–induced ETP increase was independent of coagulation factors, obesity, and insulin resistance and negatively associated with polyunsaturated fatty acid levels. Switching from high-fat diet to low-fat diet reversed the procoagulant phenotype with a slower kinetic than the normalization of hyperinsulinemia. In humans, ETP was independent of body weight whereas it was negatively associated with nutritional markers such as the percentage of energy provided by proteins, the protein:fat ratio, circulating phenolic compounds, and omega-3 polyunsaturated fatty acid. A recommended 3-month healthy diet with reduced energy density, including lipids, decreased ETP (−21%; P<0.0001). Changes in ETP were not associated with body weight, insulin sensitivity, or coagulation factor variations, but correlated negatively with plasma docosahexaenoic acid, a nutritional status sensitive fatty acid, and compounds reflecting vegetable intake. Conclusion—Diet plays a pivotal role in regulating ETP, independently of obesity and insulin resistance. Global nutritional recommendations could be useful in primary prevention of venous thrombosis.

Expression and nutritional regulation of the (pro)renin receptor in rat visceral adipose tissue

Background: Early life nutritional environment plays an important role in the development of visceral adipose tissue and interacts with nutritional regulations in adulthood, leading to metabolic dysregulations. Aim: We hypothesized that the renin-angiotensin system may play a role in the programming-induced development of visceral adipose tissue. Material and methods: We studied, using a model of programming of overweight and glucose intolerance, obtained by post-natal overfeeding with consecutive high-fat diet, the status of plasma renin activity and mesenteric adipose renin-angiotensin system, including the recently identified (pro)renin receptor, in adult rats. Results: Post-natal overfeeding or high-fat feeding lead to overweight with increased visceral fat mass and adipocytes surface. When both paradigms were associated, adipocytes surface showed a disproportionate increase. A strong immunoreactivity for (pro)renin receptor was found in stromal cells. Plasma renin activity increased in programmed animals whereas (pro)renin receptor expressing cells density was stimulated by high-fat diet. There was a positive, linear relationship between plasma renin activity and (pro)renin receptor expressing cells density and adipocytes surface. Conclusions: Our experiments demonstrate that association of post-natal overfeeding and high-fat diet increased plasma renin activity and adipose (pro)renin receptor expression. Such phenomenon could explain, at least in part, the associated disproportionate adipocyte hypertrophy and its accompanying increased glucose intolerance.

Surgical Management of Primary Hyperparathyroidism in Older Adults

To compare the feasibility, safety, and outcome of parathyroidectomy in the management of primary hyperparathyroidism (PHPT) in individuals aged 75 and older with that of those younger than 50.

Assessment of glycemic control in nursing home residents with diabetes

ObjectiveTo describe glycemic control in nursing home residents with diabetes and to evaluate the relevance of HbA1c in the detection of hypoglycemia risk.Design and methodsDiabetes treatment, geriatric assessment, blood capillary glucose (n= 24,682), and HbA1c were collected from medical charts of 236 southern France nursing home residents during a 4-month period. Glycemic control was divided into four categories: tight, fair, and moderate or severe chronic hyperglycemia using the High Blood Glucose Index or the analysis of blood glucose frequency distribution. Hypoglycemia episodes were identified by medical or biological records.ResultsGlucose control was tight in 59.3 % and fair in 19.1 % of the residents. Chronic exposure to hyperglycemia was observed in 21.6 % of the residents (severe in 9.7 % and moderate in 11.9 %). Hypoglycemia was noticed in 42/236 (17.8%), in all categories of glycemic control. Relative hypoglycemia risk was significantly (P = 0.0095) higher in residents with moderate chronic hyperglycemia compared with those with tight control. The majority of residents with hypoglycemia (39/42) or chronic hyperglycemia (45/51) were insulin-treated. The relative risk of hypoglycemia was not significantly associated with HbA1c values.ConclusionHypoglycemia risk in nursing home residents is observed in all categories of glycemic control. In tight control, the potency of antidiabetic treatment should be reduced. In chronic hyperglycemia, diet and treatment should be reevaluated in order to reduce glucose variability. HbA1c is not sufficient for hypoglycemia risk detection; capillary blood glucose monitoring is warranted for nursing homes residents with diabetes.

Ontogeny of the Hypothalamo-Pituitary-Adrenal Axis

In adult mammals, glucocorticoids play an important role in maintaining homeostasis under basal conditions and during exposure to stress. In developing rats, during the first 10 d after birth, basal circulating corticosterone levels are reduced and the adrenal response to stress is blunted. These low-circulating glucocorticoid levels are believed to be essential for normal brain and behavioral development. Rats treated with glucocorticoids during the first week of life have permanently reduced brain weight, neuronal, glial, and myelin alterations, as well as behavioral changes.