Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity (original) (raw)
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Diabetes, Obesity and Metabolism, 2020
Aim: To compare the effects of cold exposure and the β3-adrenergic receptor agonist mirabegron on plasma lipids, energy expenditure and brown adipose tissue (BAT) activity in South Asians versus Europids. Materials and Methods: Ten lean Dutch South Asian (aged 18-30 years; body mass index [BMI] 18-25 kg/m 2) and 10 age-and BMI-matched Europid men participated in a randomized, double-blinded, cross-over study consisting of three interventions: short-term (~2 hours) cold exposure, mirabegron (200 mg one dose p.o.) and placebo. Before and after each intervention, we performed lipidomic analysis in serum, assessed resting energy expenditure (REE) and skin temperature, and measured BAT fat fraction by magnetic resonance imaging. Results: In both ethnicities, cold exposure increased the levels of several serum lipid species, whereas mirabegron only increased free fatty acids. Cold exposure increased lipid oxidation in both ethnicities, while mirabegron increased lipid oxidation in Europids only. Cold exposure and mirabegron enhanced supraclavicular skin
Obesity is increasing worldwide with increasing comorbidities, and need is to develop medical therapies with earlier efforts failing to give any effective long term therapy. Thus earlier we have tried to find various medical methods of treating obesity medically, and find any updates of medical treatment, reviewing, roles Qsymia (topiramate/phentermine), Contrave(naltrexone/bupropion), liraglutide for both obesity and diabetes mellitus (DM), role of thylakoids , Glucagon like peptide 1 (GLP1) and different glucagon combinations but other than or list at till now no drug is found to have long term maintenance effects other than bariatric surgery (BS) [1-7] which can't be used for all obese subjects in view of cost and comorbidities associated with morbid obesity like DM, hyperlipidemia etc. Here we have emphasized on how white adipose tissue (WAT)/ Brown adipose tissue (BAT) metabolism can be exploited using the β3 adrenergic receptor agonist Mirabegron that was initially ABSTRACT The incidence of obesity along with its comorbidities are increasing markedly so much so that the term diabesity got coined. Hence the need of trying to treat the two conditions together. We have been reviewing how to get a better antiobesity drug helping in medical treatment that is preferable over the more expensive bariatric surgery (BS). Here we have further extended our previous publications on utilizing BAT/WAT As targets for introducing antiobesity therpy. In view of brown adipose tissue (BAT) hardly present in adult human beings the importance of beiging was highlighted earlier. Hence the accidental discovery of Mirabegron that has been used in OAB for long was detected to be a special β3 adrenergic receptor agonist having actions besides bladder on Adipose tissue (AT) lipolysis and beiging of white adipose tissue (WAT) along with increasing uncoupling protein 1 (UCP1) induction in WAT helped in trying to use it as the treatment of patients having diabesity in preference to BS. The only problem is recent some doubts that have arisen regarding safety profile of Mirabegron with upper airway angioedema along with rise in BP and prolongation of QT c interval on ECG, newer compounds are being studied on the basis of Comparative molecular field analysis (CoMFA) and Comparative molecular similarity index analysis (CoMSIA) studies and formation of contour maps. On the basis of quantitative structure-activity relationship (QSAR) 41 Aryloxy Propanol-Amine Agonists in a serial basis, were evaluated and validated certain drugs having antiobesity andantidiabetic effects for further evaluation for developing newer β3 adrenergic receptor agonists to replace Mirabegron.
Diabetes, 2018
β3-adrenergic receptor (AR) agonists are approved to treat only overactive bladder. However, rodent studies suggest that these drugs could have other beneficial effects on human metabolism. We performed tissue receptor profiling and showed that the human β3-AR mRNA is also highly expressed in gallbladder and brown adipose tissue (BAT). We next studied the clinical implications of this distribution in twelve healthy men given one-time randomized doses of placebo; the approved dose of 50 mg; and 200 mg of the β3-AR agonist mirabegron. There was a more-than-dose proportional increase in BAT metabolic activity as measured by F-FDG PET/CT (medians 0.0 vs. 18.2 vs. 305.6 mL*SUVmean*g/mL). Only the 200 mg dose elevated both non-esterified fatty acids (+68%) and resting energy expenditure (+5.8%). Previously undescribed increases in gallbladder size (+35%) and reductions in conjugated bile acids were also discovered. Therefore, besides urinary bladder relaxation, the human β3-AR contributes...
Objective: Increasing efforts are being made towards pharmacologic activation of brown adipose tissue (BAT) in animals and humans for potential use in the treatment of obesity and diabetes. We and others have reported a number of animal studies using either experimental or therapeutic drugs. There are now efforts to translate these findings to human studies. The goal of this review is to evaluate the various drugs currently being used that have the potential for BAT activation. Methods: Drugs were classified into 4 classes based on their mechanism of action. Class 1 drugs include the use of 3 adrenoceptor agonists for BAT activation. Class 2 drugs include drugs that affect norepinephrine levels and activate BAT with the potential of reducing obesity. Class 3 includes acti-vators of peroxisome proliferator-activated receptor-in pursuit of lowering blood sugar, weight loss and diabetes and finally Class 4 includes natural products and other emerging drugs with limited information on BAT activation and their effects on diabetes and weight loss. Results: Class 1 drugs are high BAT activators followed by Class 2 and 3. Some of these drugs have now been extended to diabetes and obesity animal models and human BAT studies. Drugs in Class 3 are used clinically for Type 2 diabetes, but the extent of BAT involvement is unclear. Conclusion: Further studies on the efficacy of these drugs in diabetes and measuring their effects on BAT activation using noninvasive imaging will help in establishing a clinical role of BAT.
Brown adipose tissue activity as a target for the treatment of obesity/insulin resistance
Frontiers in Physiology, 2015
Presence of brown adipose tissue (BAT), characterized by the expression of the thermogenic uncoupling protein 1 (UCP1), has recently been described in adult humans. UCP1 is expressed in classical brown adipocytes, as well as in "beige cells" in white adipose tissue (WAT). The thermogenic activity of BAT is mainly controlled by the sympathetic nervous system. Endocrine factors, such as fibroblast growth factor 21 (FGF21) and bone morphogenic protein factor-9 (BMP-9), predominantly produced in the liver, were shown to lead to activation of BAT thermogenesis, as well as to "browning" of WAT. This was also observed in response to irisin, a hormone secreted by skeletal muscles. Different approaches were used to delineate the impact of UCP1 on insulin sensitivity. When studied under thermoneutral conditions, UCP1 knockout mice exhibited markedly increased metabolic efficiency due to impaired thermogenesis. The impact of UCP1 deletion on insulin sensitivity in these mice was not reported. Conversely, several studies in both rodents and humans have shown that BAT activation (by cold exposure, β3-agonist treatment, transplantation and others) improves glucose tolerance and insulin sensitivity. Interestingly, similar results were obtained by adipose tissue-specific overexpression of PR-domain-containing 16 (PRDM16) or BMP4 in mice. The mediators of such beneficial effects seem to include FGF21, interleukin-6, BMP8B and prostaglandin D2 synthase. Interestingly, some of these molecules can be secreted by BAT itself, indicating the occurrence of autocrine effects. Stimulation of BAT activity and/or recruitment of UCP1-positive cells are therefore relevant targets for the treatment of obesity/type 2 diabetes in humans.
Human Brown Adipocyte Thermogenesis Is Driven by β2-AR Stimulation
Cell Metabolism, 2020
Highlights d A therapeutic dose (50 mg) of mirabegron does not stimulate human BAT thermogenesis d Human brown adipocytes lack b 3-AR and do not respond to mirabegron in vitro d Norepinephrine-induced respiration is driven by b 2-AR, which co-localizes with UCP1 d b 2-AR is the main target for pharmacological activation of human brown adipocytes
Thermogenesis and related metabolic targets in anti-diabetic therapy
Handbook of experimental pharmacology, 2011
Exercise, together with a low-energy diet, is the first-line treatment for type 2 diabetes type 2 diabetes . Exercise improves insulin sensitivity insulin sensitivity by increasing the number or function of muscle mitochondria mitochondria and the capacity for aerobic metabolism, all of which are low in many insulin-resistant subjects. Cannabinoid 1-receptor antagonists and β-adrenoceptor agonists improve insulin sensitivity in humans and promote fat oxidation in rodents independently of reduced food intake. Current drugs for the treatment of diabetes are not, however, noted for their ability to increase fat oxidation, although the thiazolidinediones increase the capacity for fat oxidation in skeletal muscle, whilst paradoxically increasing weight gain.There are a number of targets for anti-diabetic drugs that may improve insulin sensitivity insulin sensitivity by increasing the capacity for fat oxidation. Their mechanisms of action are linked, notably through AMP-activated protein ...
Chemico-Biological Interactions, 2010
Excess visceral adiposity may predispose to chronic diseases like hypertension and type 2 diabetes with a high risk for coronary artery disease. Adipose tissue secreted cytokines and oxidative stress play an important role in chronic disease progression. To combat adiposity, plant-derived triterpenes are currently receiving much attention as they possess antioxidant and anti-inflammatory properties and the ability to regulate glucose and lipid metabolism. In the search for potential antiobese compounds from natural sources, this study evaluated the effects of oleanolic acid (OA), a pentacyclic triterpene commonly present in fruits and vegetables, in glucose tolerance test and on high-fat diet (HFD)-induced obesity in mice. Adult male Swiss mice treated or not with OA (10 mg/kg) were fed a HFD during 15 weeks. Sibutramine (SIB) treated group (10 mg/kg) was included for comparison. Weekly body weights, food and water consumption were measured, and at the end of study period, the levels of blood glucose and lipids, plasma hormone levels of insulin, ghrelin and leptin, and the visceral abdominal fat content were analysed. Mice treated with OA and fed a HFD showed significantly (p < 0.05) improved glucose tolerance, decreased body weights, visceral adiposity, blood glucose, plasma lipids relative to their respective controls fed no OA. Additionally, OA treatment, while significantly elevating the plasma hormone level of leptin, decreased the level of ghrelin. However, it caused a greater decrease in plasma amylase activity than lipase. Sibutramine-treated group also manifested similar effects like OA except for blood glucose level that was not different from HFD control. These findings suggest that OA ameliorates visceral adiposity and improves glucose tolerance in mice and thus has an antiobese potential through modulation of carbohydrate and fat metabolism.
Effect of mitratapide on body composition, body measurements and glucose tolerance in obese Beagles
Veterinary Research Communications, 2009
The objective of this study was to confirm that weight loss after treatment with mitratapide (Yarvitan®) is loss of adipose tissue. Obese dogs were treated with the recommended treatment schedule of mitratapide. Dual-energy X-ray absorptiometry (DEXA) was done before and after the treatment schedule. Body weight, feed consumption and pelvic circumference were recorded and a glucose tolerance test was performed. Dualenergy X-ray absorptiometry measurements showed an impressive loss of fat tissue, corresponding to a mean loss of approximately 41.6% of the body fat mass recorded before treatment. After treatment with mitratapide, the mean body fat percentage had returned within the normal range. At the end of the study, the dogs had lost on average 14.2% of their body weight and 15.2% of their pelvic circumference compared to baseline. The results also suggest that losing weight with mitratapide might help to reverse insulin resistance.