Chooi Yeng Lee

The Effect of High-Fat Diet-Induced Pathophysiological Changes in the Gut on Obesity: What Should be the Ideal Treatment?

Obesity is a metabolic disorder and fundamental cause of other fatal diseases including atherosclerosis and cancer. One of the main factor that contributes to the development of obesity is high-fat (HF) consumption. Lipid ingestion will initiate from the gut feedback mechanisms to regulate glucose and lipid metabolisms. But these lipid-sensing pathways are impaired in HF-induced insulin resistance, resulting in hyperglycemia. Besides that, duodenal lipid activates mucosal mast cells, leading to the disruption of the intestinal tight junction. Lipopolysaccharide that is co-transited with dietary fat postprandially, promotes the release of cytokines and the development of metabolic syndrome. HF-diet also alters microbiota composition and enhances fat storage. Although gut is protected by immune system and contains high level of antioxidants, obesity developed presumably when this protective mechanism is compromised by the presence of excessive fat. Several therapeutic approaches targeting different pathways have been proposed. There may be no one single most effective treatment, but all aimed to prevent obesity. This review will elaborate on the physiological and molecular changes in the gut that lead to obesity, and will provide a summary of potential treatments to manage these pathophysiological changes.

Chronic restraint stress induces intestinal inflammation and alters the expression of hexose and lipid transporters

Psychosocial stress is reported to be one of the main causes of obesity. Based on observations in studies that relate stress and gut inflammation to obesity, the present study hypothesized that chronic stress, via inflammation, alters the expression of nutrient transporters and contributes to the development of metabolic syndrome. Rats were exposed to restraint stress for 4 h/day for 5 days/week for eight consecutive weeks. Different segments of rat intestine were then collected and analysed for signs of pathophysiological changes and the expression of Niemann‐Pick C1‐like‐1 (NPC1L1), sodium‐dependent glucose transporter‐1 (SLC5A1, previously known as SGLT1) and facilitative glucose transporter‐2 (SLC2A2, previously known as GLUT2). In a separate experiment, the total anti‐oxidant activity (TAA)–time profile of control isolated intestinal segments was measured. Stress decreased the expression of NPC1L1 in the ileum and upregulated SLC5A1 in both the jejunum and ileum and SLC2A2 in the duodenum. Inflammation and morphological changes were observed in the proximal region of the intestine of stressed animals. Compared with jejunal and ileal segments, the rate of increase in TAA was higher in the duodenum, indicating that the segment contained less anti‐oxidants; anti‐oxidants may function to protect the tissues. In conclusion, stress alters the expression of hexose and lipid transporters in the gut. The site‐specific increase in the expression of SLC5A1 and SLC2A2 may be correlated with pathological changes in the intestine. The ileum may be protected, in part, by gut anti‐oxidants. Collectively, the data suggest that apart from causing inflammation, chronic stress may promote sugar uptake and contribute to hyperglycaemia.

The Gut–Brain-Axis as a Target to Treat Stress-Induced Obesity

The emergence of obesity as a pandemic has led to increased efforts to determine the causes for this disorder and potential new treatments to prevent and/or treat those affected by it. The mechanisms underlying the ontogeny of obesity are complex. They involve an interaction between a genetic predisposition to this disorder and environmental conditions that catalyze the development of an obese phenotype (1). It has become evident that stress may be a strong environmental factor leading to metabolic changes that lead to obesity. Stress is a concept coined to describe the state that is generated when physiological or psychological wellbeing is challenged. It is associated with physiological and behavioral responses considered adaptive and conducive to reduce or to cope with the challenges posed by the stressor (2, 3). Continuous stressful events, however, result in pathological states including some of the same conditions associated with obesity (4, 5). In particular, continuous social stressors result in increased body weight and abdominal fat deposition, insulin resistance, and cardiovascular disease (2, 4). The underlying mechanisms and relevant potential treatments are less well documented. Nevertheless, there is increasing evidence to suggest that psychological stressors represent a homeostatic challenge, and as such have a strong impact on the brain systems associated with homeostatic control (3).

Phenylacetic acids were detected in the plasma and urine of rats administered with low-dose mulberry leaf extract

The use of a high quercetin dose to demonstrate its absorption and bioavailability does not reflect the real dietary situation because quercetin glycosides are usually present in small amounts in the human diet. This study aimed to demonstrate the absorption and bioavailability of quercetin in mulberry leaves that represents a more physiologic dietary situation. Mulberry leaf ethanol extract was prepared similar to tea infusion, which is the way the tea leaves are generally prepared for consumption. Accordingly, rats were fed by oral intubation the mulberry leaf ethanol extract (15 g%/rat per day) or pure rutin (135 microg/rat per day) for 2 weeks. The control group received a similar volume of the vehicle, 10% ethanol. There was a significant increase in total antioxidant activity (TAA) in the urine and feces of the antioxidants-fed rats. Phenylacetic acid, a microbial metabolite of quercetin, was detected in the urine of the test animals, and quercetin was present in the fecal samples. By using an in situ intestinal preparation, 3-hydroxyphenylacetic acid, another microbial metabolite of quercetin, was detected in the plasma when the duodenal segment was instilled with 2 mg of rutin. This microbial metabolite retained 50% of the TAA of quercetin. The results of this study indicate that in a more realistic dietary situation, an increase in TAA in the body after consumption of quercetin-containing foods is contributed mainly by the microbial metabolites.

Glucagon-Like Peptide-1 Formulation – the Present and Future Development in Diabetes Treatment

Type 2 diabetes mellitus is a chronic metabolic disorder that has become the fourth leading cause of death in the developed countries. The disorder is characterized by pancreatic β-cells dysfunction, which causes hyperglycaemia leading to several other complications. Treatment by far, which focuses on insulin administration and glycaemic control, has not been satisfactory. Glucagon-like peptide-1 (GLP1) is an endogenous peptide that stimulates post-prandial insulin secretion. Despite being able to mimic the effect of insulin, GLP1 has not been the target drug in diabetes treatment due to the peptides metabolic instability. After a decade-long effort to improve the pharmacokinetics of GLP1, a number of GLP1 analogues are currently available on the market. The current Minireview does not discuss these drugs but presents strategies that were undertaken to address the weaknesses of the native GLP1, particularly drug delivery techniques used in developing GLP1 nanoparticles and modified GLP1 molecule. The article highlights how each of the selected preparations has improved the efficacy of GLP1, and more importantly, through an overview of these studies, it will provide an insight into strategies that may be adopted in the future in the development of a more effective oral GLP1 formulation.

Modulating Specific Central and Peripheral Pathways to Effectively Treat Obesity

Dysregulation of the homeostatic control of appetite and hepatic glucose production, and the imbalance of the interrelation between the gut microbiota and the innate immune system, are currently believed to be the main causes of obesity. Most of these mechanisms function by interacting with one another, rendering high levels of complexity in continual maintainance of a stable body weight. Understand the molecule that acts specifically or having a regulatory role in each of the pathway, is therefore crucial in effective management of obesity development. A number of function-specific mechanisms and pathways of the hypothalamus and the gut have been identified as potential therapeutic targets. The arcuate nucleus (ARC) of the hypothalamus is particularly important in the integration of central and peripheral signals that regulate appetite. The ARC houses two neuronal circuits, ie. the appetite- and the satiety-stimulating circuits, which signal using specific neurotransmitters to modulate feeding behavior and energy expenditure. Gut hormones have long been recognised as the primary peripheral signals that determine the release of specific central neuropeptides [1]. Most recently, favourable outcome from bariatric surgeries has led to a rejuvenated interest in the gut and the gut-brain neuronal axis. Bariatric surgeries performed on obese, non-diabetic patients caused a reduction in acyl-ghrelin, and significant increase in anorexigenic peptides such as peptide YY 3-36 (PYY 3-36 ) and glucagonlike peptide (GLP)-1 [2]. Because bariatric surgery is currently the only clinically used obesity treatment that has resulted in significant long-term weight loss, these hormones may be critical in the regulation of body weight. However, ghrelin receptor is widely expressed in the central nervous system, and exerts different effects in different areas of the brain. Infusion of ghrelin receptor antagonist into the cerebral ventricles decreases caloric intake and weight gain [3], but chronic antagonism of ghrelin receptor in the paraventricular nucleus (PVN) increases the animal’s preference for high fat-diet (HFD) and their body weight gain [4]. Therefore, unless the inhibitor of ghrelin receptor can be designed to reach brain regions other than the PVN, its use may be of limited beneficial effects. GLP-1 is effective in reducing appetite and body weight [5], but has unwanted side effect, ie. it may cause hypoglycaemia in non-diabetic subjects [6]. Compare with ghrelin and GLP-1, PYY 3-36 may be a more promising target. Daily, intermittent intravenous infusion of PYY 3-36 has been reported to cause a sustained reduction in daily food intake and body weight [7]. Since PYY 3-36 has higher affinity to the ARC Y 2 than other Y receptors, peripheral administration of suitable dose of PYY 3-36 to specifically target Y 2 receptor may be effective in long-term body weight control.

Quercetin/adenosine combination may induce insulin resistance in high fat diet-fed mice

SUMMARY Quercetin and adenosine are natural antioxidants separately claimed to improve metabolic syndrome parameters. The effect of this combination (QA) was examined in high fat diet-fed mice. Results showed that growth and blood parameters, as observed for quercetin-treated mice, were not significantly different from the control. Adenosine alone caused hyperglycemia and reduced plasma adiponectin. QA feeding led to increased adiposity and circulatory insulin, and concomitantly down-regulated liver eNOS and LFABP expressions. This showed that interaction occurred between quercetin and adenosine, and combined ingestion may lead to insulin resistance, while adenosine does not prevent the development of metabolic syndrome.: