André Boivin

Maximum tolerable dose of red pepper decreases fat intake independently of spicy sensation in the mouth

Dietary red pepper suppresses energy intake and modifies macronutrient intake. We have investigated whether a stimulus in the mouth and the sensation of spiciness are necessary for red pepper-induced changes in energy and macronutrient intake in human volunteers. In a preliminary test, sixteen Japanese male volunteers tasted samples of a soup with graded doses of red pepper in order to define a moderate and a maximum tolerable (strong) dose of red pepper. On the day of the experiment, a standardised breakfast was given to the volunteers. At lunchtime, the subjects ingested one of four experimental soups containing either a placebo, a moderate or a strong dose of red pepper plus placebo capsules, or a placebo soup plus capsules delivering a strong dose of red pepper. The rest of the meal was given ad libitum to all subjects. The amount of food, protein and carbohydrate ingested was similar for all conditions. Energy and fat intake were similar after the ingestion of the moderate soup compared with placebo. However, the strong soup significantly lowered fat intake compared with placebo (P=0.043), and ingestion of strong capsules also tended to suppress it (P=0.080). Moreover, energy intake after strong soup and capsules tended to be lower than placebo (P=0.089 and 0.076, respectively). The present results indicate that the maximum tolerable dose is necessary to have a suppressive effect of red pepper on fat intake. The main site of the action of red pepper is not in the mouth.

Dietary rat models in which the development of hypertriglyceridemia and that of insulin resistance are dissociated

The consequences of chronic ingestion of a high-carbohydrate (starch + glucose [HCHO]) and high-fat (lard + corn oil [HFAT]) diet on triglyceride metabolism and insulin sensitivity were evaluated in fasted and fed rats. Compared with their HFAT counterparts, animals fed the HCHO diet displayed fasting and postprandial hypertriglyceridemia that was apparent after 3 weeks of feeding and persisted after 6 weeks. It was determined that hypertriglyceridemia was due to oversecretion of triglycerides into the circulation. During fasting triglyceride accumulation in plasma after administration of Triton WR1339 was indeed twofold higher in HCHO than in HFAT rats, whereas the global capacity for intravascular triglyceride hydrolysis, as assessed by an intravenous fat tolerance test and measurement of postheparin plasma lipoprotein and hepatic lipase activities, was comparable in both dietary cohorts. The postprandial increase in triglycerides after a high-carbohydrate meal was larger in HCHO than in HFAT rats. A fasting intravenous glucose tolerance test (IVGTT) showed that HFAT animals displayed insulin resistance after 3 weeks of feeding, which worsened after 6 weeks of treatment. Thus, the HCHO diet elicited fasting and postprandial hypertriglyceridemia without impairment of insulin sensitivity as compared with the HFAT diet, whereas the latter brought about deterioration of the sensitivity of glucose metabolism to insulin without affecting triglyceridemia. From these studies and other animal models, it is suggested that rapid delivery of fatty acids to tissues from chylomicron-derived triglycerides leads to insulin insensitivity, while fatty acids may not be available to increase endogenous production of triglycerides because they are mainly oxidized. In contrast, dietary starch/glucose increases hepatic synthesis and secretion of triglycerides that result in hypertriglyceridemia, but the deleterious effects of glucose-fatty acid competition on insulin sensitivity are prevented because endogenously derived triglycerides are catabolized more slowly and glucose is available for oxidation. The present results support the concept that coexistence of hypertriglyceridemia and resistance of glucose metabolism to insulin may be frequent but not obligatory.

Contribution of hyperinsulinemia to modulation of lipoprotein lipase activity on the obese Zucker rat

This study was designed to assess the contribution of hyperinsulinemia to the maintenance of high adipose and low muscle lipoprotein lipase (LPL) activity in the obese Zucker fa/fa rat. Insulinemia in obese Zucker rats was reduced for 4 days with a single injection of low-dose streptozotocin (STZ). Saline-injected intact obese (obese-INT) and STZ-injected obese (obese-STZ) rats were compared with a lean Fa/? reference group. LPL activity was assessed after a 12-hour fast, with or without a 1-hour refeeding period. Fasting serum insulin levels were 17-fold higher in obese-INT versus lean rats and were reduced to 60% of obese-INT levels in obese-STZ animals. In the postprandial state, serum insulin levels remained low in obese-STZ rats and were similar to the values in lean animals, whereas insulinemia increased in the obese-INT group to 18-fold the levels in lean rats. Serum glucose, nonesterified fatty acid (NEFA), and triglyceride levels, which were higher in obese-INT versus lean rats, were further increased in the obese-STZ group. Tissue weights of obese rats were unaffected by STZ treatment. Fasting LPL specific activity was higher in white adipose tissue ([WAT] +87%) and brown adipose tissue ([BAT] +167%) of obese-INT versus lean rats. Reducing the insulinemia in obese-STZ rats reduced fasting enzyme activity to the levels in lean animals in both WAT and BAT. Insulinemia and adipose LPL activity were positively correlated in the fasted state. Acute food intake increased WAT LPL activity in lean animals, but not in obese animals. Soleus LPL activity was lower in obese-INT compared with lean rats and was further decreased in obese-STZ animals. Heart LPL was decreased only in obese-STZ rats compared with the lean group. LPL in muscle tissue was not correlated with insulinemia, but an inverse relationship was found between serum NEFA levels and enzyme activity. It is concluded that in the obese Zucker rat, hyperinsulinemia is responsible for the maintenance of elevated basal LPL activity in adipose tissue independently of fat mass, whereas muscle enzyme activity appears to be more strongly and inversely related to the availability or tissue utilization of lipid substrates.

Gender difference of androgen actions on skeletal muscle transcriptome

Sarcopenia is related to metabolic syndrome in postmenopausal women. Hormone replacement therapies with androgens improve muscle functions by molecular mechanisms that are still unknown, at least partly because the skeletal muscle transcriptome has been less characterized in females. We performed the serial analysis of gene expression method in six experimental groups, intact (male and female), ovariectomy (OVX), OVX+dihydrotestosterone (DHT) injection 1, 3, or 24 h before kill in mice. The 438 transcript species differentially expressed between gender showed that females had higher expression levels of mRNA related to cytoskeleton/contractile apparatus and mitochondrial processes as well as protein, lipid, and amino acid metabolisms. In females, OVX and DHT modulated 109 and 128 transcript species respectively. OVX repressed transcripts of fast/glycolytic fiber, glycolysis, and glucose transport, whereas all these effects were reversed 3 h after the DHT injection. Moreover, DHT treatment induced transcripts which reduce intracellular Ca(2+) level at early time points. These results may suggest that DHT treatment in OVX mice increases muscle contractility by affecting fiber distribution and intracellular Ca(2+) concentration as well as improving glucose metabolism. On the other hand, transcripts of fast/oxidative fiber, oxidative phosphorylation, and ATP production were repressed 24 h after DHT administration. In our previous study using male mice, transcripts in oxidative phosphorylation and ATP production were induced 24 h after DHT injection (Yoshioka M, Boivin A, Ye P, Labrie F & St-Amand J 2006 Effects of dihydrotestosterone on skeletal muscle transcriptome in mice measured by serial analysis of gene expression. Journal of Molecular Endocrinology 36 247-259 ). These results demonstrate gender differences in DHT actions on skeletal muscle, and contribute to a precise understanding of the molecular mechanisms of androgen actions in the female skeletal muscle.

Atlas of dihydrotestosterone actions on the transcriptome of prostate in vivo.

Using serial analysis of gene expression (SAGE), we studied the transcriptomic changes in vivo by dihydrotestosterone (DHT) treatment in mice to better understand androgen effects in the prostate.

Hypothesis: An amino acid sequence in lipoprotein lipase codes for its degradation by Ca2+-dependent proteases

Lipoprotein lipase (E.C. 3.1. 1.34; LPL) is a glycosylated homodimer bound to the intraluminal surface of capillaries in most extrahepatic tissues and is responsible for the hydrolysis of circulating triacylglycerols into fatty acids and monoacylglycerol. Its activity is particularly high in adipose tissue and muscle, corresponding to their use of triacylglycerolderived fatty acids for storage and/or oxidation. The regulation of LPL is tissue-specific. The enzyme activity is high in adipose tissue in the postprandial state and low during fasting, whereas the converse occurs in muscle (1). The degradation of LPL could be a key regulatory mechanism of the level of tissue LPL activity. Four pathways of LPL degradation have been suggested: (i) newly synthetized LPL is degraded in the lysosome before its secretion; (ii) the secreted enzyme can be re-internalized by parenchymal cells to enter the lysosomes and be degraded; (iii) the endothelium-bound enzyme can be detached and can reach the liver through the circulation; and (iv) the degradation of LPL can occur in the endoplasmic reticulum (2). Little is known, however, about the possible molecular mechanisms involved in these processes. It has been found that LPL contains a sequence rich in the amino acids proline (P), glutamate (E), serine (S) and threonine (T), which is known to modulate protein degradation (3). The PEST-rich sequence of LPL spans 23 to 52 amino acids depending on the species and contains as much as 50% of PEST residues, which is about twice their frequency in the whole protein. In addition, the basic residues arginine, lysine and histidine are absent in the PEST-rich region but more frequent in the flanking regions than in the whole LPL sequence (4,5) (Fig. 1). Thus LPL meets the criterion of a protein characterized as having a PEST sequence. A PEST-rich sequence is a typical feature of rapidly degraded proteins (3), so it is not surprising that LPL contains one, since this enzyme has a half-life in various cell lines of about one hour (2). A PEST sequence is present in some proteins that are not rapidly degraded, but it has been suggested that, in these few cases, it is absent from the surface of the protein when it assumes its normal tertiary structure (3). The tertiary structure of LPL is not known, but it is frequently compared with human pancreatic

Identification of the principal transcriptional regulators for low-fat and high-fat meal responsive genes in small intestine

BackgroundHigh-fat (HF) diet is a well-known cause of obesity. To identify principle transcriptional regulators that could be therapeutic targets of obesity, we investigated transcriptomic modulation in the duodenal mucosa following low-fat (LF) and HF meal ingestion.MethodsWhereas one group of mice was sacrificed after fasting, the others were fed ad libitum with LF or HF meal, and sacrificed 30xa0min, 1xa0h and 3xa0h after the beginning of the meal. A transcriptome analysis of the duodenal mucosa of the 7 groups was conducted using both microarray and serial analysis of gene expression (SAGE) method followed by an Ingenuity Pathways Analysis (IPA).ResultsSAGE and microarray showed that the modulation of a total of 896 transcripts in the duodenal mucosa after LF and/or HF meal, compared to the fasting condition. The IPA identified lipid metabolism, molecular transport, and small molecule biochemistry as top three molecular and cellular functions for the HF-responsive, HF-specific, HF-delay, and LF-HF different genes. Moreover, the top transcriptional regulator for the HF-responsive and HF-specific genes was peroxisome proliferator-activated receptor alpha (PPARα). On the other hand, the LF-responsive and LF-specific genes were related to carbohydrate metabolism, cellular function and maintenance, and cell death/cellular growth and proliferation, and the top transcriptional regulators were forkhead box protein O1 (FOXO1) and cAMP response element binding protein 1 (CREB1), respectively.ConclusionsThese results will help to understand the molecular mechanisms of intestinal response after LF and HF ingestions, and contribute to identify therapeutic targets for obesity and obesity-related diseases.