Potential Treatment For Obesity Research Articles

G(q/11)α and G(s)α mediate distinct physiological responses to central melanocortins.

Activation of brain melanocortin 4 receptors (MC4Rs) leads to reduced food intake, increased energy expenditure, increased insulin sensitivity, and reduced linear growth. MC4R effects on energy expenditure and glucose metabolism are primarily mediated by the G protein G(s)α in brain regions outside of the paraventricular nucleus of the hypothalamus (PVN). However, the G protein(s) that is involved in MC4R-mediated suppression of food intake and linear growth, which are believed to be regulated primarily though action in the PVN, is unknown. Here, we show that PVN-specific loss of G(q)α and G11α, which stimulate PLC, leads to severe hyperphagic obesity, increased linear growth, and inactivation of the hypothalamic-pituitary-adrenal axis, without affecting energy expenditure or glucose metabolism. Moreover, we demonstrate that the ability of an MC4R agonist delivered to PVN to inhibit food intake is lost in mice lacking G(q/11)α in the PVN but not in animals deficient for G(s)α. The blood pressure response to the same MC4R agonist was only lost in animals lacking G(s)α specifically in the PVN. Together, our results exemplify how different physiological effects of GPCRs may be mediated by different G proteins and identify a pathway for appetite regulation that could be selectively targeted by G(q/11)α-biased MC4R agonists as a potential treatment for obesity.

Obesity and Natural Products

Obesity in adults is characterized when the Body Mass Index (BMI) is greater than or equal to 30. It is estimated that 1.7 billion people in the world are overweight or obese, and more than one third of U.S. adults (35.7%) are obese. There are a variety of factors that play a role in obesity, such as behavior, environment, and genetic factors. Usual countermeasures include adequate physical activity, avoidance of calorie-dense foods, and use of certain drugs for promoting weight loss. Surgery is an extreme measure and anyone considering it must have failed consistently in losing weight through lifestyle changes and less invasive methods. The main drugs currently employed in obesity treatment present dangerous side effects, namely: elevation of blood pressure, insomnia, constipation, headaches, among others. For this reason, a wide variety of natural materials have been explored for their obesity treatment potential. Considering that natural anti-obesity products have different mechanisms, the recommended approach to research a more effective obesity treatment, reaching the associated synergistic effects, must involve the combination of natural products and/or products with multiple activities. This chapter describes several natural products with anti-obesity activity, and active components and mechanisms of action to combat obesity.

Discovery and optimization of adamantane carboxylic acid derivatives as potent diacylglycerol acyltransferase 1 inhibitors for the potential treatment of obesity and diabetes

We have developed a series of adamantane carboxylic acid derivatives exhibiting potent diacylglycerol acyltransferase 1 (DGAT1) inhibitory activities. Optimization of the series led to the discovery of E-adamantane carboxylic acid compound 43c, which showed excellent in vitro activity with an IC50 value of 5 nM against human and mouse DGAT1, also good druggability as well as microsomal stability and safety profiles such as hERG, CYP and cytotoxicity. Compound 43c significantly reduced plasma triglyceride levels in vivo (in rodents and zebrafish) and also showed bodyweight gain reduction and glucose area under curve (AUC) lowering efficacy in diet-induced obesity (DIO) mice. [Display omitted]

Medication Trials for Hyperphagia and Food-Related Behaviors in Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by the absence of paternally expressed, imprinted genes on chromosome 15q11-13. Individuals with PWS characteristically have poor feeding and lack of appetite in infancy, followed by the development of weight gain and then uncontrolled appetite and lack of satiety, sometime after the age of two. The overwhelming drive to eat is coupled with reduced energy expenditure and decreased caloric requirements, thus, individuals with PWS will become severely obese unless their food intake is strictly controlled. The mechanisms underlying hyperphagia in PWS remain incompletely understood, and to date no drugs have proven effective in controlling appetite. However, clinical trials have started for several medications, which may provide therapeutic options for those with PWS. These medication trials may also provide insight into potential treatments for obesity in the general population. Ideally, these treatments will help alleviate the complex metabolic issues that are part of this syndrome.

Obesity and Clinical Riskiness Relationship: Therapeutic Management by Dietary Antioxidant Supplementation--a Review.

Obesity is a global health problem affecting all age groups, leading to many complications such as type 2 diabetes, systemic hypertension, cardiovascular disease, dyslipidemia, atherosclerosis, and stroke. Physiologically, obesity arises from metabolic changes in the tissues and organs of the human body; these changes result in an imbalance between energy intake and energy expenditure, which in turn results in increased fat accumulation in adipose tissue. Such fat accumulation predisposes individuals to development of several health problems. Two different obesity treatment drugs are currently on the market; Orlistat, which reduces intestinal fat absorption via inhibiting pancreatic lipase, and Sibutramine, an anorectic or appetite suppressant. Both drugs have hazardous side effects, including increased blood pressure, dry mouth, constipation, headache, and insomnia. For this reason, a wide variety of natural materials have been explored for their obesity treatment potential. Therefore, the present review focuses on the safety and efficacy of some herbal medicines in the management of obesity through covering their beneficial effects and mechanism of action.

Rapamycin as a Potential Treatment for Obesity

Obesity has been a rising pandemic leading to increased cardiovascular disease, the leading cause of death in the world at present. There is a pressing need to improve the health outcomes of individuals suffering from obesity. Rapamycin treatment has reported to result in both positive and negative effects on metabolic syndrome. With an aim to maximize the beneficial aspects, we have investigated the potential therapeutic effects of a low and intermittent dose of rapamycin on diet-induced obesity in six-month-old male Sprague Dawley rats. Rats were fed either standard chow diet (Chow) or 60% high fat diet (HF) for 14 weeks then randomly placed in four groups with n=6 as follows: Chow+vehicle; Chow+Rapamycin (Rapa) (1mg/kg); HF+vehicle; HF+Rapa. Rapamycin or vehicle was administered by ip injection Monday, Wednesday, and Friday for 5 weeks. Rapamycin treatment significantly reduced body weight (14.43% in Chow vs. Chow+Rapa and 15.12% in HF vs. HF+Rapa) and kcal intake (21.03% in Chow vs. Chow+Rapa and 19.00% in HF vs. HF+Rapa). In the HF fed rats, this reduction in body weight coincided with a decrease in serum leptin levels (45.86%) and white adipose tissue weights (39.37%) measured at sacrifice. Rapamycin treatment also resulted in a decrease in fasting glucose levels in rats fed the HF diet. These results suggest rapamycin may be a potential pharmacological intervention for obese individuals.

Biological activity of alginate and its effect on pancreatic lipase inhibition as a potential treatment for obesity

Alginates are classed as a dietary fibre and have been shown to inhibit digestive enzymes in vitro, and therefore could be used as an obesity treatment. The current study aims to assess whether alginate in a bread vehicle maintains its inhibition properties despite cooking and digestion, and may therefore be used as a potential treatment for obesity. After 180 min in a model gut that replicates digestion in the mouth, stomach and small intestines alginate bread (AB), control bread (CB), CB with Manucol® DM alginate, free DM alginate and model gut solution were collected. DM, LFR 5/60 and SF200 were heated at 37 °C and 200 °C, with DM also heated at 50, 100 and 150 °C. Samples from the model gut and heated alginate were assessed for molecular size and inhibition properties using viscosity, gel filtration and a lipase turbidity assay. AB does not significantly increase viscosity in the model gut. Viscosity of alginate reduces beyond 100 °C, although alginate retains its inhibition properties up to 150 °C. Cooking into the bread does not reduce the molecular size of the alginate or affect its inhibition properties. These data demonstrate the robustness of alginates lipase inhibition despite the cooking process and digestion. Therefore adding alginate to a bread vehicle may have the potential in the treatment for obesity.

Characterising a novel regulator of dietary fat digestion as a potential obesity treatment; from microplate to synthetic gut system

Characterising a novel regulator of dietary fat digestion as a potential obesity treatment; from microplate to synthetic gut system

Daily cold exposure – A therapy to stimulate beige fat or a recipe for diabesity in mice?

Since the discovery that cold exposure stimulates browning of human white fat, clinical trials have been investigating cold exposure as a potential treatment for obesity. However, cold exposure is a form of stress and might be expected to have some adverse consequences. We thus investigated the effects of chronic daily cold exposure (standing in iced water for 1 hour/day for 6 weeks) on food intake, body weight and serum glucose in male C57/Bl6 mice fed either normal chow or a high fat diet (HFD), and potential neuronal pathways for any effects. Chronic daily cold exposure increased energy intake, body weight and serum glucose levels compared to control values, significantly so in mice on the HFD. One hour after the final cold exposure in mice on the HFD, c-fos immunoreactivity was significantly increased in the medial amygdala compared to control mice on the HFD, indicating neuronal activation in this brain region. Notably, 60% of these c-fos-immunopositive neurons also expressed the anorexigenic peptide neuropeptide Y (NPY), and NPY mRNA and peptide levels were significantly increased in the medial amygdala of cold-exposed versus control mice. Interestingly, cold exposure also led to a significant decrease in ventromedial hypothalamic (VMH) mRNA levels of the anorexigenic brain-derived neurotrophic factor (BDNF), and an increase in mRNA for growth hormone releasing hormone (GHRH), which stimulates circulating glucose levels. Taken together, we thus hypothesize that NPYergic neurons in the amygdala are activated by chronic cold exposure combined with a high fat diet, leading via direct or indirect neuronal pathways to decreased BDNF and increased GHRH mRNA expression in the VMH, in turn contributing to positive energy balance and deregulated glucose homeostasis. Further work is required to test this hypothesis, but such potential adverse effects should be taken into consideration whenmanipulating temperature to stimulate the browning of white fat.

Endocannabinoids and energy homeostasis: an update.

The endocannabinoid system (ECS) is a widespread intercellular signaling system that plays a critical role in energy homeostasis, meant as the precise matching of caloric intake with energy expenditure which normally keeps body weight stable over time. Complex interactions between environmental and neurohormonal systems directly contribute to the balance of energy homeostasis. This review highlights established and more recent data on the brain circuits in which the ECS plays an important regulatory role, with focus on the hypothalamus, a region where numerous interacting systems regulating feeding, satiety, stress, and other motivational states coexist. Although not meant as an exhaustive review of the field, this article will discuss how endocannabinoid tone, in addition to reinforcing reward circuitries and modulating food intake and the salience of food, controls lipid and glucose metabolism in several peripheral organs, particularly the liver and adipose tissue. Direct actions in the skeletal muscle and pancreas are also emerging and are briefly discussed. This review provides new perspectives into endocannabinoid control of the neurochemical causes and consequences of energy homeostasis imbalance, a knowledge that might lead to new potential treatments for obesity and related morbidities.

The effects of co-administration of probiotics with herbal medicine on obesity, metabolic endotoxemia and dysbiosis: A randomized double-blind controlled clinical trial

Probiotics help maintain balance in composition of the gut microbiota, and have been considered as a potential treatment for obesity. This study was conducted in order to assess the effects of probiotics when combined with herbal medicine in treatment of obesity. Probiotics were tested for the ability to modulate gut microbiota, gut permeability, and endotoxin level, which may have correlation with factors involved in obesity. A randomized, double-blind, placebo controlled study was conducted, in which patients with higher BMI (>25kg/m(2)) and waist circumference (>85cm) were enrolled and randomly assigned to receive Bofutsushosan with either probiotics or placebo capsules for a period of eight weeks. Assessment of body composition parameters, metabolic biomarkers, endotoxin level, gut permeability, and fecal bacteria in stool was performed at baseline and at week 8. The study was registered at the Clinical Research Information Service, approved by the Korea National Institute of Health (KCT0000386). Although both groups showed a significant reduction in weight and waist circumference (p=0.000), no significant differences in body composition and metabolic markers were observed. In correlation analysis, change in body composition showed positive correlation with endotoxin level (r=0.441, p<0.05 for BW; and r=0.350, p<0.05 for fat mass) and the population of gut Lactobacillus plantarum (r=0.425, p<0.05 for BW; and r=0.407, p<0.05 for BMI). The Gram negative bacterial population in gut also exhibited positive correlation with changes in body composition (WC) and total cholesterol level (r=0.359, and 0.393, for the former and later parameters, respectively, p<0.05 for both). While, the profile of gut Bifidobacterium breve population showed negative correlation with endotoxin level (r=-0.350, p<0.05). Correlations between gut microbiota and change in body composition indicate that probiotics may influence energy metabolism in obesity. Correlation between endotoxin level and weight reduction indicates that probiotics may play an important role in prevention of endotoxin production, which can lead to gut microbiota dysbiosis associated with obesity.

Morbid Obesity Resulting from Inactivation of the Ciliary Protein CEP19 in Humans and Mice

Obesity is a major public health concern, and complementary research strategies have been directed toward the identification of the underlying causative gene mutations that affect the normal pathways and networks that regulate energy balance. Here, we describe an autosomal-recessive morbid-obesity syndrome and identify the disease-causing gene defect. The average body mass index of affected family members was 48.7 (range = 36.7-61.0), and all had features of the metabolic syndrome. Homozygosity mapping localized the disease locus to a region in 3q29; we designated this region the morbid obesity 1 (MO1) locus. Sequence analysis identified a homozygous nonsense mutation in CEP19, the gene encoding the ciliary protein CEP19, in all affected family members. CEP19 is highly conserved in vertebrates and invertebrates, is expressed in multiple tissues, and localizes to the centrosome and primary cilia. Homozygous Cep19-knockout mice were morbidly obese, hyperphagic, glucose intolerant, and insulin resistant. Thus, loss of the ciliary protein CEP19 in humans and mice causes morbid obesity and defines a target for investigating the molecular pathogenesis of this disease and potential treatments for obesity and malnutrition.

Can neuropeptides treat obesity? A review of neuropeptides and their potential role in the treatment of obesity

Obesity is a major worldwide public health issue. The physiological systems that regulate body weight are thus of great interest as targets for anti-obesity agents. Peptidergic systems are critical to the regulation of energy homeostasis by key regions in the hypothalamus and brainstem. A number of neuropeptide systems have therefore been investigated as potential treatments for obesity. Blocking orexigenic peptide signals such as neuropeptide Y, melanin-concentrating hormone, orexins, relaxin-3 and galanin-like peptide or stimulating anorectic signalling pathways used by peptides such as the melanocortins, ciliary neurotrophic factor and brain-derived neurotrophic factor, are approaches that have shown some promise, but which have also highlighted possible concerns. Manipulation of central peptidergic systems poses a number of therapeutic problems, including brain access and side effects. Given that the homeostatic defence of body weight may limit the effectiveness of any single-target therapy developed, a combination therapy approach may offer the best hope for the effective prevention and treatment of obesity. This article is part of a themed section on Neuropeptides. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.170.issue-7.

ANTI-OBESE THERAPEUTICS FROM MEDICINAL PLANTS-A REVIEW

Obesity is a global health problem. It is also known to be a risk factor for the development of metabolic disorders such as type 2 diabetes, systemic hypertension, cardiovascular disease, dyslipidemia, and atherosclerosis. Two different obesity-treatment drugs are currently on the market: Orlistat, which reduces intestinal fat absorption via inhibiting pancreatic lipase; and Sibutramine, an anorectic or appetite suppressant. Both drugs have hazardous side-effects, including increased blood pressure, dry mouth, constipation, headache, and insomnia. For this reason, a wide variety of natural materials have been explored for their obesity treatment potential. These are mainly complex products having several components with different chemical and pharmacological features. This presented review focused on literature covering natural products with anti-obesity activity, including experimental methodologies, active components, and mechanisms of action against obesity.

A Role for Phosphodiesterase 3B in Acquisition of Brown Fat Characteristics by White Adipose Tissue in Male Mice

Obesity is linked to various diseases, including insulin resistance, diabetes, and cardiovascular disorders. The idea of inducing white adipose tissue (WAT) to assume characteristics of brown adipose tissue (BAT), and thus gearing it to fat burning instead of storage, is receiving serious consideration as potential treatment for obesity and related disorders. Phosphodiesterase 3B (PDE3B) links insulin- and cAMP-signaling networks in tissues associated with energy metabolism, including WAT. We used C57BL/6 PDE3B knockout (KO) mice to elucidate mechanisms involved in the formation of BAT in epididymal WAT (EWAT) depots. Examination of gene expression profiles in PDE3B KO EWAT revealed increased expression of several genes that block white and promote brown adipogenesis, such as C-terminal binding protein, bone morphogenetic protein 7, and PR domain containing 16, but a clear BAT-like phenotype was not completely induced. However, acute treatment of PDE3B KO mice with the β3-adrenergic agonist, CL316243, markedly increased the expression of cyclooxygenase-2, which catalyzes prostaglandin synthesis and is thought to be important in the formation of BAT in WAT and the elongation of very long-chain fatty acids 3, which is linked to BAT recruitment upon cold exposure, causing a clear shift toward fat burning and the induction of BAT in KO EWAT. These data provide insight into the mechanisms of BAT formation in mouse EWAT, suggesting that, in a C57BL/6 background, an increase in cAMP, caused by ablation of PDE3B and administration of CL316243, may promote differentiation of prostaglandin-responsive progenitor cells in the EWAT stromal vascular fraction into functional brown adipocytes.

Glucagon and GLP-1 inhibit food intake and increase c-fos expression in similar appetite regulating centres in the brainstem and amygdala

Glucagon and glucagon-like peptide-1 (GLP-1) are evolutionarily related anorectic hormones. Glucagon also increases energy expenditure. The combination of glucagon and GLP-1 could cause weight loss through a simultaneous reduction in food intake and increased energy expenditure. However, the effect of combined administration of glucagon and GLP-1 on food intake and neuronal activation has not previously been studied. Furthermore, the effect of glucagon on neuronal activation in appetite regulating centres has not been assessed. Characterisation of the effects of glucagon when administered singly and in combination with GLP-1 on neuronal activation will be important for determining the mechanism of action of related potential antiobesity therapies. To investigate the effects of peripherally administered GLP-1 and glucagon on food intake, neuronal activation and blood glucose in mice when administered individually and in combination. Food intake, blood glucose and c-fos expression in the hypothalamus, amygdala and brainstem were measured in response to GLP-1 and glucagon, alone and in combination. Peripherally administered GLP-1 and glucagon decreased food intake and increased c-fos expression in the brainstem and amygdala. Doses of GLP-1 and glucagon that individually did not significantly affect feeding, in combination were anorectic and stimulated neuronal activation in the area postrema (AP) and central nucleus of the amygdala. Combined administration of GLP-1 and glucagon prevented the acute hyperglycemic effect of glucagon alone. Anorectic doses of glucagon and GLP-1 induced similar patterns of c-fos expression. Combined administration of low dose GLP-1 and glucagon inhibited food intake and induced c-fos expression in the AP and amygdala. The combination of both hormones may offer the opportunity to utilise the beneficial effects of reduced food intake and increased energy expenditure, and may therefore be a potential treatment for obesity.

Proxyfan acts as a neutral antagonist of histamine H3 receptors in the feeding‐related hypothalamic ventromedial nucleus

Centrally acting histamine H(3) receptor ligands are proposed as potential treatments for obesity, although the value of inverse agonists at these receptors is still debated. Functional inhibition of H(3) autoreceptors activates neurones in a hypothalamic 'satiety' centre. The H(3) receptor antagonist, proxyfan was used as a tool to assess the action of histaminergic compounds in this model. We compared the actions of histamine on feeding with those of an H(3) receptor agonist (imetit) and inverse agonist (thioperamide) in rats and mice. Sites of action were identified by immunohistochemistry and the hypothalamic ventromedial nucleus (VMN) was investigated using electrophysiological techniques. Central histamine or thioperamide decreased fast-induced feeding, whereas imetit increased feeding. Systemic thioperamide entered the brain to activate hypothalamic feeding centres and to reduce feeding without causing any adverse behaviours. Thioperamide activated neurones in the VMN through an action on histamine autoreceptors, whilst imetit had the opposite effect. Proxyfan administered alone did not affect either feeding or electrical activity. However, it blocked the actions of both thioperamide and imetit, acting as a neutral antagonist in this system. The H(3) receptor inverse agonist, thioperamide, potently reduced appetite without adverse behavioural effects. This action was blocked by proxyfan, acting as a neutral antagonist in this model and, therefore, this compound is useful in determining the selectivity of H(3) receptor-directed drugs. A major action of thioperamide is through presynaptic autoreceptors, inducing stimulation by endogenous histamine of postsynaptic H(1 ) receptors on anorectic hypothalamic neurones.

Peptide Therapeutics: it‘s All in the Delivery

Recent work has demonstrated that the route of administration affects the pharmacokinetics and biological activity of peptides. For example, the physiological profile of insulin consists of basal and prandial components with a small-scale oscillatory element. Insulin is used more efficiently when the pharmacokinetic profile mimics features of physiological release. Noninvasive administration of insulin by oral, transdermal, nasal and pulmonary routes resembles the relatively sharp peak and short duration of exposure of prandial release. The route of administration per se, can affect the response by avoiding first-pass metabolism or perhaps altering the timing in which the peptide reaches different sets of receptors. GLP-I delivered by injection and inhalation produces different side effect profiles. Nonclinical studies on two potential treatments for obesity, oxyntomodulin and PYY 3-36, are also presented to illustrate the relationship between exposure and effect as functions of route of administration.

Development of functional food products in relation to obesity

The development of new eating habits, as well as actual trends in production and consumption, has a health, environmental and social impact. The entire world is fighting diseases characteristic of the modern age such as obesity, osteoporosis, cancer, diabetes, allergies, and dental problems. With a global increase in the prevalence of obesity, both nutrition and exercise play key roles in its prevention and treatment. Natural product (nutraceutical) interventions are currently being investigated on a large-scale basis as potential treatments for obesity and weight management. With advancing nutritional sciences, several nutrients such as; low-glycemic-index carbohydrates, 5-hydroxytryptophan, green tea extract, and chromium have been shown to promote weight loss. The first two nutrients decrease appetite, green tea increases the 24 hr energy expenditure, and chromium promotes the composition of the weight lost to be fat rather than lean tissue. These have been assembled, in efficacious doses, into a new functional food product and described in this review. Each component has already been shown to promote weight loss independently in clinical trials.Key words: obesity, weight loss, functional foods

Nonhuman primates and other animal models in diabetes research.

Animal models are important for determining the pathogenesis of and potential treatments for obesity and diabetes. Nonhuman primates (NHPs) are particularly useful for studying these disorders. As in humans, type 2 diabetes mellitus is the most common form of diabetes in NHPs and occurs more often in older obese animals, with a metabolic progression from insulin resistance (IR) and impaired glucose tolerance to overt diabetes. Histopathologic changes in pancreatic islets are also similar to those seen in humans with diabetes. Initially, there is islet hyperplasia with abundant insulin production to compensate for IR, followed by insufficient insulin production with replacement of islets with islet-associated amyloid. Diabetic NHPs also have adverse changes in plasma lipid and lipoprotein concentrations, biomarkers of obesity, inflammation, and oxidative stress, and protein glycation that contribute to the numerous complications of the disease. Furthermore, sex hormones, pregnancy, and environmental factors (e.g., diet and stress) affect IR and can also contribute to diabetes progression in NHPs. Additionally, due to their similar clinical and pathologic characteristics, NHPs have been used in many pharmacological studies to assess new therapeutic agents. For these reasons, NHPs are particularly valuable animal models of obesity and diabetes for studying disease pathogenesis, risk factors, comorbidities, and therapeutic interventions.