David H. St-Pierre

Lack of interaction between peripheral injection of CCK and obestatin in the regulation of gastric satiety signaling in rodents.

Obestatin is a new peptide for which anorexigenic effects were recently reported in mice. We investigate whether peripheral injection of obestatin or co-injection with cholecystokinin (CCK) can modulate food intake, gastric motor function (intragastric pressure and emptying) and gastric vagal afferent activity in rodents. Obestatin (30, 100 and 300 microg/kg, i.p.) did not influence cumulative food intake for the 2h post-injection in rats or mice nor gastric emptying in rats. In rats, obestatin (300 microg/kg) did not modify CCK (1 microg/kg, i.p.)-induced significant decrease in food intake (36.6%) and gastric emptying (31.0%). Furthermore, while rats injected with CCK (0.3 microg/kg, i.v.) displayed gastric relaxation, no change in gastric intraluminal pressure was elicited by obestatin (300 microg/kg, i.v.) pre- or post-CCK administration. In in vitro rat gastric vagal afferent preparations, 20 units that had non-significant changes in basal activity after obestatin at 30 microg responded to CCK at 10 ng by a 182% increase. These data show that obestatin neither influences cumulative food intake, gastric motility or vagal afferent activity nor CCK-induced satiety signaling.

Lack of obestatin effects on food intake: should obestatin be renamed ghrelin-associated peptide (GAP)?

Obestatin is a newly identified ghrelin-associated peptide (GAP) that is derived from post-translational processing of the prepro-ghrelin gene. Obestatin has been reported initially to be the endogenous ligand for the orphan receptor G protein-coupled receptor 39 (GPR39), and to reduce refeeding- and ghrelin-stimulated food intake and gastric transit in fasted mice, and body weight gain upon chronic peripheral injection. However, recent reports indicate that obestatin is unlikely to be the endogenous ligand for GPR39 based on the lack of specific binding on GRP39 receptor expressing cells and the absence of signal transduction pathway activation. In addition, a number of studies provided convergent evidence that ghrelin injected intracerebroventricularly or peripherally did not influence food intake, body weight gain, gastric transit, gastrointestinal motility, and gastric vagal afferent activity, as well as pituitary hormone secretions, in rats or mice. Similarly, obestatin did not alter ghrelin-induced stimulation of food intake or gastric transit. Therefore, the present state-of-knowledge on obestatin and GPR39 is leaving many unanswered questions that deserve further consideration. Those relate not only to redefining the biological action of obestatin that should be renamed GAP, but also the identification of the native ligand for GPR39.

Metabolic effects of overnight continuous infusion of unacylated ghrelin in humans

OBJECTIVE To clarify the metabolic effects of an overnight i.v. infusion of unacylated ghrelin (UAG) in humans. UAG exerts relevant metabolic actions, likely mediated by a still unknown ghrelin receptor subtype, including effects on β-cell viability and function, insulin secretion and sensitivity, and glucose and lipid metabolism. DESIGN We studied the effects of a 16-h infusion (from 2100 to 1300  h) of UAG (1.0  μg/kg per h) or saline in eight normal subjects (age (mean±s.e.m.), 29.6±2.4 years; body mass index (BMI), 22.4±1.7  kg/m(2)), who were served, at 2100 and 0800  h respectively, with isocaloric balanced dinner and breakfast. Glucose, insulin, and free fatty acid (FFA) levels were measured every 20  min. RESULTS In comparison with saline, UAG induced significant (P<0.05) changes in glucose, insulin, and FFA profiles. UAG infusion decreased glucose area under the curve (AUC) values by 10% (UAG(0 - 960  min): 79.0±1.7×10(3)  mg/dl per min vs saline(0- 960  min): 87.5±3.8×10(3)  mg/dl per min) and the AUC at night by 14% (UAG(180)(-)(660  min): 28.4±0.5×10(3)  mg/dl per min vs saline(180 - 660  min): 33.2±1.1×10(3)  mg/dl per min). The overall insulin AUC was not significantly modified by UAG infusion; however, insulin AUC observed after meals was significantly increased under the exposure to UAG with respect to saline at either dinner or breakfast. The FFA AUC values were decreased by 52% under the exposure to UAG in comparison with saline (UAG(0 - 960  min): 0.3±0.02×10(3)  mEq/l per min vs saline(0 - 960  min): 0.6±0.05×10(3)  mEq/l per min). CONCLUSIONS Exposure to the i.v. administration of UAG improves glucose metabolism and inhibits lipolysis in healthy volunteers. Thus, in contrast to the diabetogenic action of AG, UAG displays hypoglycemic properties.

Crosstalk between intestinal microbiota, adipose tissue and skeletal muscle as an early event in systemic low-grade inflammation and the development of obesity and diabetes

Obesity is associated with a systemic chronic low‐grade inflammation that contributes to the development of metabolic disorders such as cardiovascular diseases and type 2 diabetes. However, the etiology of this obesity‐related pro‐inflammatory process remains unclear. Most studies have focused on adipose tissue dysfunctions and/or insulin resistance in skeletal muscle cells as well as changes in adipokine profile and macrophage recruitment as potential sources of inflammation. However, low‐grade systemic inflammation probably involves a complex network of signals interconnecting several organs. Recent evidences have suggested that disturbances in the composition of the gut microbial flora and alterations in levels of gut peptides following the ingestion of a high‐fat diet may be a cause of low‐grade systemic inflammation that may even precede and predispose to obesity, metabolic disorders or type 2 diabetes. This hypothesis is appealing because the gastrointestinal system is first exposed to nutrients and may thereby represent the first link in the chain of events leading to the development of obesity‐associated systemic inflammation. Therefore, the present review will summarize the latest advances interconnecting intestinal mucosal bacteria‐mediated inflammation, adipose tissue and skeletal muscle in a coordinated circuitry favouring the onset of a high‐fat diet‐related systemic low‐grade inflammation preceding obesity and predisposing to metabolic disorders and/or type 2 diabetes. A particular emphasis will be given to high‐fat diet‐induced alterations of gut homeostasis as an early initiator event of mucosal inflammation and adverse consequences contributing to the promotion of extended systemic inflammation, especially in adipose and muscular tissues. Copyright

Brain activation following peripheral administration of the GLP-1 receptor agonist exendin-4

The aim of our study was to investigate the anorectic and brain stimulatory effects of various doses of exendin-4 (Ex-4) and to investigate the role of the vagus nerve in Ex-4-induced brain activation. A dose-related increase in c-fos mRNA expression was observed following Ex-4 administration (0.155-15.5 μg/kg). Doses of Ex-4 that caused anorexia without aversive effects (0.155, 0.775 μg/kg) induced c-fos expression in the hypothalamic arcuate and paraventricular (PVH; parvocellular) nuclei as well as in the limbic and brainstem structures. Doses of Ex-4 that caused aversion (1.55, 15.5 μg/kg) stimulated the same regions (in a more intense way) and additionally activated the magnocellular hypothalamic structures (supraoptic nucleus and PVH magnocellular). The brain c-fos pattern induced by Ex-4 showed both similarities and differences with that induced by refeeding. Subdiaphragmatic vagotomy significantly blunted the stimulation of c-fos mRNA expression induced by Ex-4 in the nodose ganglion, the medial part of nucleus of the solitary tract, and the parvocellular division of the PVH. Pretreatment with Ex-9-39 (330 μg/kg ip) impaired the neuronal activation evoked by Ex-4 in all brain regions and in the nodose ganglion. Effects of Ex-4 on hypothalamic-pituitary-adrenal axis activity were not altered by vagotomy. Results of this study demonstrate and relate the anorectic and brain stimulatory effects of aversive and nonaversive doses of Ex-4 and indicate that the activation of specific central regions induced by the peripheral administration of Ex-4 is, at least in part, dependent on the integrity of the vagus nerve.

Lifestyle behaviours and components of energy balance as independent predictors of ghrelin and adiponectin in young non-obese women

AIM Dysregulation of the normal levels of ghrelin, leptin and adiponectin in young non-obese subjects could promote food intake, diabetes and cardiovascular disease in later stages of life. Little information is available on how plasmatic concentrations of these hormones may be influenced by eating habits and/or components of energy balance in a young population, which if known, could facilitate their voluntary regulation. METHODS In this cross-sectional study we examined the predictors of fasting plasma ghrelin, adiponectin and leptin in a population of well-characterized young non-obese women (N = 63). Energy intake was assessed by 24-hour dietary recall, resting metabolic rate (RMR) by indirect calorimetry, physical activity energy expenditure (PAEE) by tri-axial accelerometer, physical fitness by VO(2 peak), and eating behaviors by self administrated questionnaire. RESULTS Lower RMR and higher HDL-cholesterol were independent predictors of higher plasma ghrelin explaining 17.6% of its variation even after correcting for BMI. Higher total or central fat mass was the only predictor of higher plasma leptin, and no other variable added any power to the prediction equation. Finally, higher energy intake and waist circumference and lower PAEE predicted lower plasma adiponectin in young non-obese women, explaining 43% of the variation in its concentrations even after correcting for total or central fat mass. CONCLUSION Components of the energy balance (ie: energy intake and/or expenditure) influence adiponectin and ghrelin circulating levels. That is, higher energy intake and lower physical activity independently predict lower adiponectin concentrations, whereas lower resting metabolic rate independently predicts higher ghrelin levels in young non-obese women. Prospective studies are needed to examine whether circulating concentrations of ghrelin and adiponectin can be voluntarily regulated by lifestyle interventions.

Relationship between insulin sensitivity and the triglyceride-HDL-C ratio in overweight and obese postmenopausal women : a MONET study.

The objective of this cross-sectional study was to examine the relationship between the triglyceride-HDL-cholesterol ratio (TG:HDL-C) and insulin sensitivity in overweight and obese sedentary postmenopausal women. The study population consisted of 131 non-diabetic overweight and obese sedentary postmenopausal women (age; 57.7+/-5.0 y; body mass index (BMI), 32.2+/-4.3 kg/m2). Subjects were characterized by dividing the entire cohort into tertiles based on the TG:HDL-C (T1<0.86 vs. T2=0.86 to 1.35 vs. T3>1.35, respectively). We measured (i) insulin sensitivity (using the hyperinsulinenic-euglycemic clamp and homeostasis model assessment (HOMA)), (ii) body composition (using dual-energy X-ray absorptiometry), (iii) visceral fat (using computed tomography), (iv) plasma lipids, C-reactive protein, 2 h glucose concentration during an oral glucose tolerance test (2 h glucose), as well as fasting glucose and insulin, (v) peak oxygen consumption, and (vi) lower-body muscle strength (using weight training equipment). Significant correlations were observed between the TG:HDL-C and the hyperinsulinemic-euglycemic clamp (r=-0.45; p<0.0001), as well as with HOMA (r=0.42; p<0.0001). Moreover, the TG:HDL-C significantly correlated with lean body mass, visceral fat, 2 h glucose, C-reactive protein, and muscle strength. Stepwise regression analysis showed that the TG:HDL-C explained 16.4% of the variation in glucose disposal in our cohort, which accounted for the greatest source of unique variance. Other independent predictors of glucose disposal were 2 h glucose (10.1%), C-reactive protein (CRP; 7.6%), and peak oxygen consumption (5.8%), collectively (including the TG:HDL-C) explaining 39.9% of the unique variance. In addition, the TG:HDL-C was the second predictor for HOMA, accounting for 11.7% of the variation. High levels of insulin sensitivity were associated with low levels of the TG:HDL-C. In addition, the TG:HDL-C was a predictor for glucose disposal rates and HOMA values in our cohort of overweight and obese postmenopausal women.

Association of insulin sensitivity and muscle strength in overweight and obese sedentary postmenopausal women

The objective of this study was to examine the relationship between insulin sensitivity and lower body muscle strength in overweight and obese sedentary postmenopausal women. The design of the study was cross-sectional. The study population consisted of 82 non-diabetic overweight and obese sedentary postmenopausal women (age: 58.2 +/- 5.1 y; body mass index (BMI): 32.4 +/- 4.6 kg.m-2). Subjects were classified by dividing the entire cohort into quartiles based on relative insulin sensitivity expressed per kilograms of lean body mass (LBM) (Q1, < 10.3, vs. Q2, 10.3-12.4, vs. Q3, 12.5-14.0, vs. Q4, >14.0 mg.min-1.kg LBM-1). We measured insulin sensitivity (using the hyperinsulinemic-euglycemic clamp technique), body composition (using dual-energy X-ray absorptiometry), visceral fat and muscle attenuation (using computed tomography), and a lower-body muscle strength index expressed as weight lifted in kilograms per kilogram of LBM (kg.kg LBM-1) (using weight-training equipment). A positive and significant relationship was observed between insulin sensitivity and the muscle strength index (r = 0.37; p < 0.001). Moreover, a moderate but significant correlation was observed between the muscle strength index and muscle attenuation (r = 0.22; p < 0.05). Finally, the muscle strength index was significantly higher in the Q4 group compared with the Q2 and Q1 groups, respectively (3.78 +/- 1.13 vs. 2.99 +/- 0.77 and 2.93 +/- 0.91 kg.kg LBM-1; p < 0.05). Insulin sensitivity is positively associated with lower-body muscle strength in overweight and obese sedentary postmenopausal women.

Surrogate indexes vs. euglycaemic-hyperinsulinemic clamp as an indicator of insulin resistance and cardiovascular risk factors in overweight and obese postmenopausal women

BACKGROUND There is considerable interest in validating the most convenient method to estimate insulin sensitivity in clinical research protocols that could best indicate cardiovascular risk factors. To address this issue we examined the interrelationships of several cardiovascular risk factors with surrogate indexes such as fasting insulin, the homeostasis model assessment (HOMA), the quantitative insulin sensitivity check index (QUICKI) and the revised QUICKI vs the euglycaemic-hyperinsulinemic (EH) clamp in a non-diabetic overweight or obese postmenopausal female population. DESIGN Cross-sectional study involving 88 obese postmenopausal women (age: 57.5+/-5.0 yrs; body mass index: 32.52+/-4.4 kg/m2; percent body fat: 46.35+/-4.9%). METHODS Insulin sensitivity was determined by the EH clamp technique as well as by surrogate indexes such as fasting insulin, HOMA, log HOMA, QUICKI and revised QUICKI. Body composition and body fat distribution were measured using dual energy x-ray absorptiometry and computed tomography, respectively. RESULTS Correlations between insulin resistance indexes (fasting insulin, revised QUICKI, QUICKI, log HOMA, HOMA) vs glucose disposal were similar (range of rs=0.40 to 0.49), suggesting that no index was superior to another with respect to its relationship with the EH clamp. Correlations between the insulin resistance indexes with plasma lipids were comparable among all indexes, however, systolic blood pressure, visceral fat and C-reactive protein were moderately superior with index vs the EH clamp. CONCLUSION Surrogate measures of insulin resistance, in particular fasting insulin, are simple tools appropriate for epidemiological studies that can be used as substitutes for the EH clamp to estimate glucose disposal and cardiovascular risk factors in overweight and obese postmenopausal women.

Degradation in insulin sensitivity with increasing severity of the metabolic syndrome in obese postmenopausal women

Aim:  We investigated the relationship between insulin sensitivity and the graded increase in the number of features of the metabolic syndrome in a cross‐sectional sample of obese postmenopausal women. We hypothesized that insulin sensitivity would deteriorate with an increased number of metabolic syndrome phenotypes.