Denovan P. Begg

Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance

In addition to its role in the storage of fat, adipose tissue acts as an endocrine organ, and it contains a functional renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE) plays a key role in the RAS by converting angiotensin I to the bioactive peptide angiotensin II (Ang II). In the present study, the effect of targeting the RAS in body energy homeostasis and glucose tolerance was determined in homozygous mice in which the gene for ACE had been deleted (ACE−/−) and compared with wild-type littermates. Compared with wild-type littermates, ACE−/− mice had lower body weight and a lower proportion of body fat, especially in the abdomen. ACE−/− mice had greater fed-state total energy expenditure (TEE) and resting energy expenditure (REE) than wild-type littermates. There were pronounced increases in gene expression of enzymes related to lipolysis and fatty acid oxidation (lipoprotein lipase, carnitine palmitoyl transferase, long-chain acetyl CoA dehydrogenase) in the liver of ACE−/− mice and also lower plasma leptin. In contrast, no differences were detected in daily food intake, activity, fed-state plasma lipids, or proportion of fat excreted in fecal matter. In conclusion, the reduction in ACE activity is associated with a decreased accumulation of body fat, especially in abdominal fat depots. The decreased body fat in ACE−/− mice is independent of food intake and appears to be due to a high energy expenditure related to increased metabolism of fatty acids in the liver, with the additional effect of increased glucose tolerance.

Green tea, black tea, and epigallocatechin modify body composition, improve glucose tolerance, and differentially alter metabolic gene expression in rats fed a high-fat diet

The mechanisms of how tea and epigallocatechin-3-gallate (EGCG) lower body fat are not completely understood. This study investigated long-term administration of green tea (GT), black tea (BT), or isolated EGCG (1 mg/kg per day) on body composition, glucose tolerance, and gene expression related to energy metabolism and lipid homeostasis; it was hypothesized that all treatments would improve the indicators of metabolic syndrome. Rats were fed a 15% fat diet for 6 months from 4 weeks of age and were supplied GT, BT, EGCG, or water. GT and BT reduced body fat, whereas GT and EGCG increased lean mass. At 16 weeks GT, BT, and EGCG improved glucose tolerance. In the liver, GT and BT increased the expression of genes involved in fatty acid synthesis (SREBP-1c, FAS, MCD, ACC) and oxidation (PPAR-alpha, CPT-1, ACO); however, EGCG had no effect. In perirenal fat, genes that mediate adipocyte differentiation were suppressed by GT (Pref-1, C/EBP-beta, and PPAR-gamma) and BT (C/EBP-beta), while decreasing LPL, HSL, and UCP-2 expression; EGCG increased expression of UCP-2 and PPAR-gamma genes. Liver triacylglycerol content was unchanged. The results suggest that GT and BT suppressed adipocyte differentiation and fatty acid uptake into adipose tissue, while increasing fat synthesis and oxidation by the liver, without inducing hepatic fat accumulation. In contrast, EGCG increased markers of thermogenesis and differentiation in adipose tissue, while having no effect on liver or muscle tissues at this dose. These results show novel and separate mechanisms by which tea and EGCG may improve glucose tolerance and support a role for these compounds in obesity prevention.

The endocrinology of food intake

Many questions must be considered with regard to consuming food, including when to eat, what to eat and how much to eat. Although eating is often thought to be a homeostatic behaviour, little evidence exists to suggest that eating is an automatic response to an acute shortage of energy. Instead, food intake can be considered as an integrated response over a prolonged period of time that maintains the levels of energy stored in adipocytes. When we eat is generally determined by habit, convenience or opportunity rather than need, and meals are preceded by a neurally-controlled coordinated secretion of numerous hormones that prime the digestive system for the anticipated caloric load. How much we eat is determined by satiation hormones that are secreted in response to ingested nutrients, and these signals are in turn modified by adiposity hormones that indicate the fat content of the body. In addition, many nonhomeostatic factors, including stress, learning, palatability and social influences, interact with other controllers of food intake. If a choice of food is available, what we eat is based on pleasure and past experience. This article reviews the hormones that mediate and influence these processes.

Regulation of gastric emptying rate and its role in nutrient-induced GLP-1 secretion in rats after vertical sleeve gastrectomy

Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) are effective weight loss surgeries that also improve glucose metabolism. Rapid, early rises of circulating insulin and glucagon-like peptide-1 (GLP-1) concentrations following food ingestion are characteristic of these procedures. The purpose of the current study was to test the hypothesis that postprandial hormone release is due to increased nutrient emptying from the stomach. Radioscintigraphy and chemical and radiolabeled tracers were used to examine gastric emptying in rat models of VSG and RYGB surgery. Intraduodenal nutrient infusions were used to assess intestinal GLP-1 secretion and nutrient sensitivity in VSG rats compared with shams. Five minutes after a nutrient gavage, the stomachs of RYGB and VSG rats were completely emptied, whereas only 6.1% of the nutrient mixture had emptied from sham animals. Gastric pressure was increased in VSG animals, and rats with this procedure did not inhibit gastric emptying normally in response to increasing caloric loads of dextrose or corn oil, and they did not respond to neural or endocrine effectors of gastric motility. Finally, direct infusion of liquid nutrients into the duodenum caused significantly greater GLP-1 release in VSG compared with shams, indicating that increases in GLP-1 secretion after VSG are the result of both greater gastric emptying rates and altered responses at the level of the intestine. These findings demonstrate greatly accelerated gastric emptying in rat models of RYGB and VSG. In VSG this is likely due to increased gastric pressure and reduced responses to inhibitory feedback from the intestine.

Angiotensin converting enzyme inhibition lowers body weight and improves glucose tolerance in C57BL/6J mice maintained on a high fat diet

The renin-angiotensin system (RAS) is functional within adipose tissue and angiotensin II, the active component of RAS, has been implicated in adipose tissue hypertrophy and insulin resistance. In this study, captopril, an angiotensin converting enzyme (ACE) inhibitor that prevents angiotensin II formation, was used to study the development of diet-induced obesity and insulin resistance in obesity prone C57BL/6J mice. The mice were fed a high fat diet (w/w 21% fat) and allowed access to either water or water with captopril added (0.2 mg/ml). Body weight was recorded weekly and water and food intake daily. Glucose tolerance was determined after 11-12 weeks. On completion of the study (after 16 weeks of treatment), the mice were killed and kidney, liver, epididymal fat and extensor digitorum longus muscle (EDL) were weighed. Blood samples were collected and plasma analysed for metabolites and hormones. Captopril treatment decreased body weight in the first 2 weeks of treatment. Food intake of captopril-treated mice was similar to control mice prior to weight loss and was decreased after weight loss. Glucose tolerance was improved in captopril-treated mice. Captopril-treated mice had less epididymal fat than control mice. Relative to body weight, captopril-treated mice had increased EDL weight. Relative to control mice, mice administered captopril had a higher plasma concentration of adiponectin and lower concentrations of leptin and non-esterified fatty acids (NEFA). The results indicate that captopril both induced weight loss and improved insulin sensitivity. Thus, captopril may eventually be used for the treatment of obesity and Type 2 diabetes.

Short-term docosapentaenoic acid (22:5n-3) supplementation increases tissue docosapentaenoic acid, DHA and EPA concentrations in rats.

The metabolic fate of dietary n-3 docosapentaenoic acid (DPA) in mammals is currently unknown. The aim of the present study was to determine the extent of conversion of dietary DPA to DHA and EPA in rats. Four groups of male weanling Sprague–Dawley rats (aged 5 weeks) were given 50 mg of DPA, EPA, DHA or oleic acid, daily for 7 d by gavage. At the end of the treatment period, the tissues were analysed for concentrations of long-chain PUFA. DPA supplementation led to significant increases in DPA concentration in all tissues, with largest increase being in adipose (5-fold) and smallest increase being in brain (1·1-fold). DPA supplementation significantly increased the concentration of DHA in liver and the concentration of EPA in liver, heart and skeletal muscle, presumably by the process of retroconversion. EPA supplementation significantly increased the concentration of EPA and DPA in liver, heart and skeletal muscle and the DHA concentration in liver. DHA supplementation elevated the DHA levels in all tissues and EPA levels in the liver. Adipose was the main tissue site for accumulation of DPA, EPA and DHA. These data suggest that dietary DPA can be converted to DHA in the liver, in a short-term study, and that in addition it is partly retroconverted to EPA in liver, adipose, heart and skeletal muscle. Future studies should examine the physiological effect of DPA in tissues such as liver and heart.

The heritability of melatonin secretion and sensitivity to bright nocturnal light in twins

The super-sensitivity of the neurohormone melatonin to light in patients with bipolar disorder provides evidence of the circadian nature of the disorder. This response has been proposed as an endophenotype for identifying people at risk of the disorder and guiding investigations of molecular genetic targets. However, before this response is used as an endophenotypic marker, the heritable nature of melatonin sensitivity in the normal population must be established. The aim of this study was to investigate the heritability of nocturnal melatonin secretion and sensitivity to light in monozygotic and dizygotic twins with no psychiatric history. This study investigated overall melatonin levels (between 2000 and 2400 h) and suppression by 500 lx of light (between 2400 and 0100 h) in 20 pairs of twins (nine monozygotic, 11 dizygotic). The results indicate that melatonin secretion is highly heritable with secretion in one twin being a significant predictor of secretion in their twin in both monozygotic and dizygotic pairs. In relation to light sensitivity, genetic loading appears to play a significant role with the greatest concordance between monozygotic twins, followed by dizygotic twins and finally low concordance in unrelated individuals. This provides additional support for the usefulness of melatonin sensitivity to light as a potential endophenotypic marker of bipolar affective disorder.

Roux-en-Y Gastric Bypass Surgery But Not Vertical Sleeve Gastrectomy Decreases Bone Mass in Male Rats

The most effective treatment for obesity is bariatric surgery. However, there is increasing concern that bariatric surgery can cause nutrient deficiencies that translate into metabolic bone disease. Whether this is true for all surgery types is not yet clear. We therefore investigated the effects of 2 commonly applied bariatric surgeries (Roux-en-Y gastric bypass [RYGB] and vertical sleeve gastrectomy) on energy and bone metabolism in rats 60 days after surgery. Both surgeries resulted in similar reductions of body weight, body fat, and food intake. Glucose tolerance was improved to a similar extent after both surgeries and was accompanied by increased postprandial secretion of glucose-dependent insulinotropic peptide. Using microcomputed tomography, we found that, relative to sham-operated rats, bone volume was significantly reduced after RYGB but not vertical sleeve gastrectomy. RYGB rats also had markedly reduced lipid absorption from the intestine and significantly lower serum 25-hydroxyvitamin D and calcium levels. Importantly, dietary supplementation with calcium and vitamin D could not fully rescue the reduced bone volume after RYGB surgery. Both surgeries resulted in a significant increase in stomach pH, which may have worsened the malabsorption in RYGB rats. Our findings suggest that bone loss in RYGB rats is not exclusively driven by calcium and vitamin D malabsorption but also by additional factors that may not be rescuable by dietary supplementation. These data point toward important similarities and differences between bariatric procedures that should be considered in clinical settings as guidance for which procedure will be best for specific patient populations.

Angiotensin-converting enzyme inhibition reverses diet-induced obesity, insulin resistance and inflammation in C57BL/6J mice

Aim:Angiotensin-converting enzyme (ACE) inhibition can reduce the body weight of mice maintained on a high-fat diet. The current study examined the effect of the ACE inhibitor, captopril (CAP), on the reversal of diet-induced obesity (DIO), insulin resistance and inflammation in mice.Materials and methods:DIO was produced in C57BL/6J male mice (n=30) by maintaining animals on a high-fat diet (w/w 21% fat) for 12 weeks. During the subsequent 12-week treatment period, the animals were allowed access to the high-fat diet and either water containing CAP (0.05 mg ml−1) or plain tap water (CON, control).Results:From the first week of treatment, food intake and body weight decreased in CAP-treated mice compared with CON mice. Both peripheral insulin sensitivity and hepatic insulin sensitivity were improved in CAP-treated mice compared with CON mice. CAP-treated mice had decreased absolute and relative liver and epididymal fat weights compared with CON mice. CAP-treated mice had higher plasma adiponectin and lower plasma leptin levels than CON mice. Relative to CON mice, CAP-treated mice had reduced adipose and skeletal muscle monocyte chemoattractant protein 1 (MCP-1), adipose interleukin-6 (IL-6), toll-like receptor 4 (TLR4) and uncoupling protein 2 (UCP2) mRNA expressions. Furthermore, CAP-treated mice had increased peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), long chain acyl-CoA dehydrogenase (LCAD), hormone sensitive lipase (HSL) and decreased lipoprotein lipase (LPL) mRNA expressions in the liver.Conclusion:The results of the current study indicate that in mice with DIO, CAP treatment reduced food intake and body weight, improved insulin sensitivity and decreased the mRNA expression of markers of inflammation. Thus, CAP may be a viable treatment for obesity, insulin resistance and inflammation.

Angiotensin converting enzyme inhibition from birth reduces body weight and body fat in Sprague-Dawley rats.

In vitro studies have demonstrated that angiotensin II (ANG II) induces adipocyte hyperplasia and hypertrophy. The aim of the present study was to determine the effect of angiotensin-converting enzyme inhibition on body weight, adiposity and blood pressure in Sprague-Dawley rats. From birth half of the animals (n=15) were given water to drink, while the remainder were administered perindopril in their drinking water (2 mg/kg/day). Food intake, water intake and body weight were measured weekly. Blood pressure was measured by tail cuff plethysmography at 11-weeks. Body fat content and distribution were assessed using dual energy X-ray absorptiometry and Magnetic Resonance Imaging at 12 weeks. Animals administered with perindopril had a body fat proportion that was half that of controls. This was consistent with, but disproportionately greater than the observed differences in food intake and body weight. Perindopril treatment completely removed hypertension. We conclude that the chronic inhibition of ANG II synthesis from birth specifically reduces the development of adiposity in the rat.