Anti-obesity Treatment Research Articles

In silico and in vitro analysis of PPAR – α / γ dual agonists: Comparative evaluation of potential phytochemicals with anti-obesity drug orlistat

Obesity is an abnormal fat accumulation disorder in the metabolic syndrome constellation, and a risk factor for diabetes, cardiovascular disorders, non-alcoholic fatty liver disease (NAFLD), and cancer. Nuclear receptors (Peroxisome proliferator-activated receptor, PPAR) are implicated in metabolic syndrome and NAFLD, and have potential for therapeutic targeting. Nuclear receptors are ligand-dependent transcription factors that have diverse roles in metabolism, including regulating genes involved in lipid and glucose metabolism, modulating inflammatory genes, and are crucial for maintaining metabolic flexibility. PPAR activates adipose triglyceride lipase, which then releases fatty acids as ligands for PPAR, indicating the interdependency of nuclear receptors and lipases. Here, molecular docking was performed with selected phytochemical ligands that can bind with PPAR-α/γ (PDB ID: 2ZNN and 2ATH, respectively) using Glide module of Schrodinger software followed by molecular dynamics simulation study using Desmond module, and ADMET analysis. Interestingly, orlistat which is a well-known lipase and fatty acid synthase inhibitor also demonstrated favorable binding affinity with both PPAR-α/γ (−10.96 kcal/mol against PPARα and −10.26 kcal/mol against PPARγ). The highest docking scores were however shown by the flavonoids - rutin (−14.88 kcal/mol against PPARα and −13.64 kcal/mol against PPARγ), and its aglycone, quercetin (−10.08 kcal/mol in PPARα and −9.89 kcal/mol in PPARγ). The other phytochemicals (genistein, esculin, daidzin, naringenin, daidzein, dihydroxy coumarin, hydroquinone) showed lower binding affinity as dual agonists. The anti-obesity effects were experimentally validated in cultured adipocytes, which revealed better lipid inhibition by rutin and quercetin than orlistat (quercetin > rutin > orlistat) pointing to their strong potential in anti-obesity treatment.

A Review on Rhubarb-Derived Substances as Modulators of Cardiovascular Risk Factors-A Special Emphasis on Anti-Obesity Action.

The currently available anti-obesity therapies encounter many associated risks and side effects often causing the ineffectiveness of treatment. Therefore, various plant-derived substances have been extensively studied as a promising support or even an alternative for existing anti-obesity therapies. This review is dealing with the anti-obesity potential of edible and ethnomedicinal rhubarb species and emerging possible role of the rhubarb-derived extracts or individual compounds in the prevention of obesity and perspectives for their use in an anti-obesity treatment. A special emphasis is put on the most popular edible specimens, i.e., Rheum rhabarbarum L. (garden rhubarb) and Rheum rhaponticum L. (rhapontic rhubarb, Siberian rhubarb); however, the anti-obesity potential of other rhubarb species (e.g., R. officinale, R. palmatum, and R. emodi) is presented as well. The significance of rhubarb-derived extracts and low-molecular specialized rhubarb metabolites of diversified chemical background, e.g., anthraquinones and stilbenes, as potential modulators of human metabolism is highlighted, including the context of cardiovascular disease prevention. The available reports present multiple encouraging rhubarb properties starting from the anti-lipidemic action of rhubarb fibre or its use as purgative medicines, through various actions of rhubarb-derived extracts and their individual compounds: inhibition of enzymes of cholesterol and lipid metabolism, targeting of key molecular regulators of adipogenesis, regulators of cell energy metabolism, the ability to inhibit pro-inflammatory signalling pathways and to regulate glucose and lipid homeostasis contributing to overall in vivo and clinical anti-obesity effects.

Growth differentiation factor 15 (GDF15) and semaglutide inhibit food intake and body weight through largely distinct, additive mechanisms.

To evaluate whether the potent hypophagic and weight-suppressive effects of growth differentiation factor-15 (GDF15) and semaglutide combined would be a more efficacious antiobesity treatment than either treatment alone by examining whether the neural and behavioural mechanisms contributing to their anorectic effects were common or disparate. Three mechanisms were investigated to determine how GDF15 and semaglutide induce anorexia: the potentiation of the intake suppression by gastrointestinal satiation signals; the reduction in motivation to feed; and the induction of visceral malaise. We then compared the effects of short-term, combined GDF15 and semaglutide treatment on weight loss to the individual treatments. Rat pharmaco-behavioural experiments assessed whether GDF15 or semaglutide added to the satiating effects of orally gavaged food and exogenous cholecystokinin (CCK). A progressive ratio operant paradigm was used to examine whether GDF15 or semaglutide reduced feeding motivation. Pica behaviour (ie, kaolin intake) and conditioned affective food aversion testing were used to evaluate visceral malaise. Additionally, fibre photometry studies were conducted in agouti-related protein (AgRP)-Cre mice to examine whether GDF15 or semaglutide, alone or in combination with CCK, modulate calcium signalling in hypothalamic AgRP neurons. Semaglutide reduced food intake by amplifying the feeding-inhibitory effect of CCK or ingested food, inhibited the activity of AgRP neurons when combined with CCK, reduced feeding motivation and induced malaise. GDF15 induced visceral malaise but, strikingly, did not affect feeding motivation, the satiating effect of ingested food or CCK signal processing. Combined GDF15 and semaglutide treatment produced greater food intake and body weight suppression than did either treatment alone, without enhancing malaise. GDF15 and semaglutide reduce food intake and body weight through largely distinct processes that produce greater weight loss and feeding suppression when combined.

Prevalence of Antiobesity Treatment and Weight-Inducing Antihyperglycemic Agents Among Patients With Type 2 Diabetes in the United States

Nearly 90% of individuals with type 2 diabetes mellitus (T2DM) are either overweight or obese, placing them at high risk of microvascular and macrovascular complications. The main objective of this study was to assess the use of antiobesity medications and antihyperglycemic agents that produce weight gain among patients with T2DM who qualify for National Institutes of Health guideline-recommended pharmacologic weight loss therapy. This study used the 2005-2006 through 2015-2016 biannual cycles of the National Health and Nutrition Examination Survey and included adults aged ≥20 years who reported a diagnosis of T2DM and who qualified for antiobesity treatment (defined as a body mass index ≥27 kg/m2) at the time of physical examination. Antiobesity medication use was defined as use of orlistat, phentermine, diethylpropion, lorcaserin, phentermine/topiramate, bupropion/naltrexone, or liraglutide. Use of weight-inducing antihyperglycemic agents was defined as use of sulfonylureas, thiazolidinediones, or insulin (any type), either alone or in combination with any other antihyperglycemic agent regardless of effect on weight. Among adults with T2DM who qualified for antiobesity treatment (N=2910), only 40 participants (2.2%; 95% CI, 1.5-3.3) were on pharmacologic antiobesity treatment within 30 days of survey interview. The only antiobesity medications identified were liraglutide (n=34 [1.9%]), phentermine (n=4 [0.2%]), orlistat (n=1 [0.1%]), and phentermine/topiramate (n=1 [0.0%]). Among those who were on antihyperglycemic treatment (n=2401), 1661 (66%; 95% CI, 63.1-68.8) were on weight-inducing antihyperglycemic agents; however, a downward trend in the use of these agents over time was observed (from 78.4% in 2005-2006 to 53.3% in 2015-2016; P < 0.0005). This is the first national epidemiologic study evaluating the use of antiobesity medications and weight-inducing antihyperglycemic agents among patients with T2DM who qualify for weight loss therapy. This study documents that patients are not on guideline-directed weight loss therapy. Furthermore, weight loss goals are likely compromised by 66% of individuals being on weight-inducing antihyperglycemic therapy. Use of antiobesity medications could play a significant role in promoting weight loss and potentially lead to a healthier lifestyle, which could reduce microvascular and macrovascular complications. Stronger recommendations in using guideline-directed therapy in obesity complicated by T2DM are necessary.

Puerarin Attenuates Obesity-Induced Inflammation and Dyslipidemia by Regulating Macrophages and TNF-Alpha in Obese Mice.

Obesity causes low-grade inflammation that results in dyslipidemia and insulin resistance. We evaluated the effect of puerarin on obesity and metabolic complications both in silico and in vivo and investigated the underlying immunological mechanisms. Twenty C57BL/6 mice were divided into four groups: normal chow, control (HFD), HFD + puerarin (PUE) 200 mg/kg, and HFD + atorvastatin (ATO) 10 mg/kg groups. We examined bodyweight, oral glucose tolerance test, serum insulin, oral fat tolerance test, serum lipids, and adipocyte size. We also analyzed the percentage of total, M1, and M2 adipose tissue macrophages (ATMs) and the expression of F4/80, tumor necrosis factor-α (TNF-α), C-C motif chemokine ligand 2 (CCL2), CCL4, CCL5, and C-X-C motif chemokine receptor 4. In silico, we identified the treatment-targeted genes of puerarin and simulated molecular docking with puerarin and TNF, M1, and M2 macrophages based on functionally enriched pathways. Puerarin did not significantly change bodyweight but significantly improved fat pad weight, adipocyte size, fat area in the liver, free fatty acids, triglycerides, total cholesterol, and HDL-cholesterol in vivo. In addition, puerarin significantly decreased the ATM population and TNF-α expression. Therefore, puerarin is a potential anti-obesity treatment based on its anti-inflammatory effects in adipose tissue.

Cardio-psycho-metabolic outcomes of bariatric surgery: design and baseline of the WAS trial.

Obesity is a rapidly emerging health problem and an established risk factor for cardiovascular diseases. Bariatric surgery profoundly reduces body weight and mitigates sequelae of obesity. The open, randomized controlled Würzburg Adipositas Studie (WAS) trial compares the effects of Roux-en-Y gastric bypass (RYGB) vs psychotherapy-supported lifestyle modification in morbidly obese patients. The co-primary endpoint addresses 1-year changes in cardiovascular function (peak VO2 during cardiopulmonary exercise testing) and the quality of life (QoL) (Short-Form-36 physical functioning scale). Prior to randomization, all included patients underwent a multimodal anti-obesity treatment for 6–12 months. Thereafter, the patients were randomized and followed through month 12 to collect the primary endpoints. Afterwards, patients in the lifestyle group could opt for surgery, and final visit was scheduled for all patients 24 months after randomization. Sample size calculation suggested to enroll 90 patients in order to arrive at minimally 22 patients per group evaluable for the primary endpoint. Secondary objectives were to quantify changes in body weight, left ventricular hypertrophy, systolic and diastolic function (by echocardiography and cardiac MRI), functional brain MRI, psychometric scales, and endothelial and metabolic function. WAS enrolled 93 patients (72 women, median age 38 years, BMI 47.5 kg/m2) exhibiting a relevantly compromised exercise capacity (median peakVO2 18.3 mL/min/kg) and the QoL (median physical functioning scale 50). WAS is the first randomized controlled trial focusing on the effects of RYGB on cardiovascular function beyond hypertension. In addition, it will provide a wealth of high-quality data on the cerebral, psychiatric, hepatic, and metabolic function in obese patients after RYGB.

Gut Microbiota and Mycobiota Evolution Is Linked to Memory Improvement after Bariatric Surgery in Obese Patients: A Pilot Study.

Patients with obesity are known to exhibit gut microbiota dysbiosis and memory deficits. Bariatric surgery (BS) is currently the most efficient anti-obesity treatment and may improve both gut dysbiosis and cognition. However, no study has investigated association between changes of gut microbiota and cognitive function after BS. We prospectively evaluated 13 obese patients on anthropometric data, memory functions, and gut microbiota-mycobiota before and six months after BS. The Rey Auditory Verbal Learning Test (AVLT) and the symbol span (SS) of the Weschler Memory Scale were used to assess verbal and working memory, respectively. Fecal microbiota and mycobiota were longitudinally analyzed by 16S and ITS2 rRNA sequencing respectively. AVLT and SS scores were significantly improved after BS (AVLT scores: 9.7 ± 1.7 vs. 11.2 ± 1.9, p = 0.02, and SS scores: 9.7 ± 23.0 vs. 11.6 ± 2.9, p = 0.05). An increase in bacterial alpha-diversity, and Ruminococcaceae, Prevotella, Agaricus, Rhodotorula, Dipodascus, Malassezia, and Mucor were significantly associated with AVLT score improvement after BS, while an increase in Prevotella and a decrease in Clostridium, Akkermansia, Dipodascus and Candida were linked to SS scores improvement. We identified several changes in the microbial communities that differ according to the improvement of either the verbal or working memories, suggesting a complex gut-brain-axis that evolves after BS.

The Beneficial Effects of Essential Oils in Anti-Obesity Treatment.

Obesity is a complex disease caused by an excessive amount of body fat. Obesity is a medical problem and represents an important risk factor for the development of serious diseases such as insulin resistance, type 2 diabetes, cardiovascular disease, and some types of cancer. Not to be overlooked are the psychological issues that, in obese subjects, turn into very serious pathologies, such as depression, phobias, anxiety, and lack of self-esteem. In addition to modifying one’s lifestyle, the reduction of body mass can be promoted by different natural compounds such as essential oils (EOs). EOs are mixtures of aromatic substances produced by many plants, particularly in medicinal and aromatic ones. They are odorous and volatile and contain a mixture of terpenes, alcohols, aldehydes, ketones, and esters. Thanks to the characteristics of the various chemical components present in them, EOs are used in the food, cosmetic, and pharmaceutical fields. Indeed, it has been shown that EOs possess great antibiotic, anti-inflammatory, and antitumor powers. Emerging results also demonstrate the anti-obesity effects of EOs. We have examined the main data obtained in experimental studies and, in this review, we summarize the effect of EOs in obesity and obesity-related metabolic diseases.

Empagliflozin Induces White Adipocyte Browning and Modulates Mitochondrial Dynamics in KK Cg-Ay/J Mice and Mouse Adipocytes.

Background: White adipose tissue (WAT) browning is a promising target for obesity prevention and treatment. Empagliflozin has emerged as an agent with weight-loss potential in clinical and in vivo studies, but the mechanisms underlying its effect are not fully understood. Here, we investigated whether empagliflozin could induce WAT browning and mitochondrial alterations in KK Cg-Ay/J (KKAy) mice, and explored the mechanisms of its effects.Methods: Eight-week-old male KKAy mice were administered empagliflozin or saline for 8 weeks and compared with control C57BL/6J mice. Mature 3T3-L1 adipocytes were treated in the presence or absence of empagliflozin. Mitochondrial biosynthesis, dynamics, and function were evaluated by gene expression analyses, fluorescence microscopy, and enzymatic assays. The roles of adenosine monophosphate–activated protein kinase (AMPK) and peroxisome proliferator–activated receptor-γ coactivator-1-alpha (PGC-1α) were determined through AICAR (5-Aminoimidazole-4-carboxamide1-β-D-ribofuranoside)/Compound C and RNA interference, respectively.Results: Empagliflozin substantially reduced the bodyweight of KKAy mice. Mice treated with empagliflozin exhibited elevated cold-induced thermogenesis and higher expression levels of uncoupling protein 1 (UCP1) and other brown adipose tissue signature proteins in epididymal and perirenal WAT, which was an indication of browning in these WAT depots. At the same time, empagliflozin enhanced fusion protein mitofusin 2 (MFN2) expression, while decreasing the levels of the fission marker phosphorylated dynamin-related protein 1 (Ser616) [p-DRP1 (Ser616)] in epididymal and perirenal WAT. Empagliflozin also increased mitochondrial biogenesis and fusion, improved mitochondrial integrity and function, and promoted browning of 3T3-L1 adipocytes. Further, we found that AMPK signaling activity played an indispensable role in empagliflozin-induced browning and mitochondrial biogenesis, and that PGC-1α was required for empagliflozin-induced fusion. Whether empagliflozin activates AMPK by inhibition of SGLT2 or by independent mechanisms remains to be tested.Conclusion: Our results suggest that empagliflozin is a promising anti-obesity treatment, which can immediately induce WAT browning mitochondrial biogenesis, and regulate mitochondrial dynamics.

Oxytocin as an Anti-obesity Treatment.

Obesity is a growing health concern, as it increases risk for heart disease, hypertension, type 2 diabetes, cancer, COVID-19 related hospitalizations and mortality. However, current weight loss therapies are often associated with psychiatric or cardiovascular side effects or poor tolerability that limit their long-term use. The hypothalamic neuropeptide, oxytocin (OT), mediates a wide range of physiologic actions, which include reproductive behavior, formation of prosocial behaviors and control of body weight. We and others have shown that OT circumvents leptin resistance and elicits weight loss in diet-induced obese rodents and non-human primates by reducing both food intake and increasing energy expenditure (EE). Chronic intranasal OT also elicits promising effects on weight loss in obese humans. This review evaluates the potential use of OT as a therapeutic strategy to treat obesity in rodents, non-human primates, and humans, and identifies potential mechanisms that mediate this effect.

Hypothesizing Nutrigenomic-Based Precision Anti-Obesity Treatment and Prophylaxis: Should We Be Targeting Sarcopenia Induced Brain Dysfunction?

Background: The United States Centers for Disease Control and Prevention (CDC) estimates a total obesity rate of 30% for 12 states and a 20% obesity rate nationwide. The obesity epidemic continues to increase in spite of preventative measures undertaken worldwide. Pharmacological treatments promise to reduce total fat mass. However, medications may have significant side effects and can be potentially fatal. Data Retrieval: This brief review, based on a PUBMED search of the key terms “Obesity” and” Sarcopenia,” will present evidence to corroborate the existence of Reward Deficiency Syndrome (RDS) in obesity and the involvement of catecholaminergic pathways in substance seeking behavior, particularly as it relates to carbohydrates cravings. Expert Opinion: The genetic basis and future genetic testing of children for risk of aberrant generalized craving behavior are considered a prevention method. Here we present evidence supporting the use of precursor amino acid therapy and modulation of enkephalinase, MOA, and COMT inhibition in key brain regions. Such treatments manifest in improved levels of dopamine/norepinephrine, GABA, serotonin, and enkephalins. We also present evidence substantiating insulin sensitivity enhancement via Chromium salts, which affect dopamine neuronal synthesis regulation. We believe our unique combination of natural ingredients will influence many pathways leading to the promotion of well-being and normal healthy metabolic functioning. Sarcopenia has been shown to reduce angiogenesis and possible cerebral blood flow. Exercise seems to provide a significant benefit to overcome this obesity-promoting loss of muscle density. Conclusion: Utilization of proposed nutrigenomic formulae based on coupling genetic obesity risk testing promotes generalized anti-craving of carbohydrates and can inhibit carbohydrate bingeing, inducing significant healthy fat loss and relapse prevention.

Dynamic regional alterations in mouse brain neuronal activity following short-term changes in energy balance.

Knowledge of the functional contribution to energy homeostatic control by different brain areas is limited. This study employed a systematic approach to identify brain regions specifically influenced by a positive energy balance. The c-fos expression was mapped throughout the mouse brain after varying durations (24 hours to up to 14 days) of high-fat diet (HFD) exposure or after reversal from a 7-day HFD to a chow diet. In parallel, the metabolic and behavioral impacts of these treatments were examined. A HFD elicited rapid and pronounced compensatory responses which were, however, insufficient to overcome the impact of the positive energy balance. Rapid and dynamic responses of c-fos expression throughout the brain were seen over the course of HFD exposure, with some regions showing linear-like responses and some regions exhibiting biphasic responses. The switch from HFD to chow resulted in metabolic compensations mitigating the effects of the negative energy balance and a heightened preference for sweet taste. Interestingly, this diet switch led to a significant c-fos activation in the lateral hypothalamus, an area unresponsive to HFD intervention. Plasticity exists in the extended brain networks facilitating rapid adaptations dependent on energy availability. Knowledge of these critical control points may provide novel antiobesity treatment targets.

Obesity self-management: knowledge, attitude, practice, and pharmaceutical use among healthy obese individuals in Saudi Arabia

Introduction: Obesity is a chronic disease that is increasing in Saudi Arabia (SA) and globally. Obesity self-management among individuals is essential for managing obesity and its complications. This study aimed to conduct an obesity knowledge, attitude, and practice (KAP) assessment and prevalence of used pharmaceutical anti-obesity medications among individuals with obesity in SA. Subjects and methods: This cross-sectional study was conducted between January and April 2021. The participants completed a validated online administered questionnaire using the Survey Monkey website. Potential participants were approached in governmental hospitals, leisure centers, and shopping malls. The chi-square test was used to assess associations between categorical variables. In addition, correlations between the participants' KAP and outcome variables were measured using the Pearson correlation coefficient (r). Results: In all, 410 obese individuals (mean age 40±14 years, range 18–80 years) were surveyed. Overall, 68% of participants reported good obesity knowledge, and 63% reported a good attitude, while 72% reported poor practice. In addition, there were significant positive linear correlations between knowledge and attitude (r=0.44, P&lt;0.001), knowledge and practice (r=0.14, P&lt;0.01), attitude and practice (r=0.11, P&lt;0.05), body mass index (BMI), and waist circumference (WC) (r=0.25, P&lt;0.01), while there were significant negative linear correlations between knowledge and BMI (r=−0.20, P&lt;0.001), attitude and BMI (r=−0.19, P&lt;0.001), practice and BMI (r=−0.67, P&lt;0.001), knowledge and WC (r=−0.10, P&lt;0.05), attitude and WC (r=−0.10, P&lt;0.05), and practice and WC (r=−0.45, P&lt;0.001). Interestingly, 67% of participants did not use any approved pharmaceutical anti-obesity medications due to a lack of anti-obesity treatment knowledge and safety. Conclusion: The participants reported good knowledge and attitudes toward obesity, although these were not reflected in their practice levels. The lack of pharmaceutical knowledge, safety, and use of anti-obesity medications contributed directly to poor practice levels. Health authorities should establish clinical and pharmaceutical health education programs incorporating the latest pharmaceutical anti-obesity medications, including their applications and safety, for enhancing self-management and awareness among obese individuals.

Strategies for Browning Agent Delivery.

Obesity expands as a global climbing epidemic that is often correlated to cardiovascular diseases and endocrine disorders. Converting white adipocytes to brown adipocytes for enhanced energy expenditure has recently emerged as a promising anti-obesity treatment. However, the conventional approaches to apply browning agents systematically suffer from off-target effects, multiple dosage requirements, and poor patient compliance. To date, various delivery strategies have been reported to deliver browning agents for obesity treatment in a safer and more controllable manner. This review will discuss the latest designs in browning agent delivery systems with a focus on nanomedicines and transdermal patches.

Intermittent cold exposure improves glucose homeostasis despite exacerbating diet‐induced obesity in mice housed at thermoneutrality

Ambient cold exposure is often regarded as a promising anti-obesity treatment in mice. However, most preclinical studies aimed at treating obesity via cold-induced thermogenesis have been confounded by subthermoneutral housing temperatures. Therefore, the ability of ambient cold to combat diet-induced obesity in mice housed under humanized thermoneutral conditions is currently unknown. Moreover, mammals such as mice are rarely exposed to chronic ambient cold without reprieve, yet mice are often subjected to experimental conditions of chronic rather than intermittent cold exposure (ICE), despite ICE being more physiologically relevant. In the present study, we provide novel evidence that thermoneutral housing uncouples the effects of ICE on glucose and energy homeostasis suggesting that ICE, despite improving glucose tolerance, is not an effective obesity treatment when mice are housed under humanized thermoneutral conditions. The present study examines whether a physiologically relevant model of ambient cold exposure, intermittent cold exposure (ICE), could ameliorate the metabolic impairments of diet-induced obesity in male and female mice housed under humanized thermoneutral conditions. Male and female C57BL/6J mice housed at thermoneutrality (29°C) were fed a low-fat diet or high-fat diet for 6weeks before being weight matched into groups that remained unperturbed or underwent ICE for 4 weeks (4°C for 60minday-1 ; 5daysweek-1 ) when being maintained on their respective diets. ICE induced rapid and persistent hyperphagia exacerbating rather than attenuating high-fat diet-induced obesity over time. These ICE-induced increases in adiposity were found to be energy intake-dependent via pair-feeding. Despite exacerbating high-fat diet-induced obesity, ICE improved glucose tolerance, independent of diet, in a sex-specific manner. The effects of ICE on glucose tolerance were not attributed to improvements in whole-body insulin tolerance, tissue specific insulin action, nor differences in markers of hepatic insulin clearance or pancreatic beta cell proliferation. Instead, ICE increased serum concentrations of insulin and C-peptide in response to glucose, suggesting that ICE may improve glucose tolerance by potentiating pancreatic glucose-stimulated insulin secretion. These data suggest that ICE, despite improving glucose tolerance, is not an effective obesity treatment in mice housed under humanized conditions.

Running the Obstacle Course: Improving the Utilization of Bariatric Surgery in Adolescent Obesity

The obesity epidemic in the adolescent population continues to worsen despite increased awareness. Although there is an improved understanding of the role of bariatric surgery in the treatment of obesity in adolescents, a number of barriers still prevent its widespread utilization. The lack of formal obesity-focused education in the training curricula of primary care providers (PCPs), coupled with variable distribution of comprehensive resources, creates an inhospitable environment for effective anti-obesity treatment in adolescents. In addition, racial disparities and variability in insurance coverage contribute to the complexity of this problem. The coronavirus disease 2019 (COVID-19) pandemic has exacerbated the rate of childhood obesity and emphasized the need for bariatric surgery as an adjunctive treatment. This article highlights 3 barriers to bariatric surgery: (1) hesitation to refer for surgery; (2) limitation in available resources; and (3) racial disparities in anti-obesity treatment. Potential systemic solutions to such obstacles are examined.

Obstetrician-Gynecologists' Strategies for Patient Initiation and Maintenance of Antiobesity Treatment with Glucagon-Like Peptide-1 Receptor Agonists.

Obesity is a chronic disease affecting women at higher rates than men. In an obstetrics and gynecology setting, frequently encountered obesity-related complications are polycystic ovary syndrome, fertility and pregnancy complications, and increased risk of breast and gynecological cancers. Obstetrician-gynecologists (OBGYNs) are uniquely positioned to diagnose and treat obesity, given their role in women's primary health care and the increasing prevalence of obesity-related fertility and pregnancy complications. The metabolic processes of bodyweight regulation are complex, which makes weight-loss maintenance challenging, despite dietary modifications and exercise. Antiobesity medications (AOMs) can facilitate weight loss by targeting appetite regulation. There are four AOMs currently approved for long-term use in the United States, of which liraglutide 3.0 mg is among the most efficacious. Liraglutide 3.0 mg, a glucagon-like peptide-1 receptor agonist (GLP-1 RA), is superior to placebo in achieving weight loss and improving cardiometabolic profile, in both clinical trial and real-world settings. In addition, women with fertility complications receiving liraglutide 1.8–3.0 mg can benefit from improved ovarian function and fertility. Liraglutide 3.0 mg is generally well tolerated, but associated with transient gastrointestinal side effects, which can be mitigated. In this review, we present the risks of obesity and benefits of weight loss for women, and summarize clinical development of GLP-1 RAs for weight management. Finally, we provide practical advice and recommendations for OBGYNs to open the discussion about bodyweight with their patients, initiate lifestyle modification and GLP-1 RA treatment, and help them persist with these interventions to achieve optimal weight loss with associated health benefits.

Roflumilast Suppresses Adipogenic Differentiationvia AMPK Mediated Pathway.

Obesity and related disorders have increasingly become global health problems over the years. In recent years, obesity has been recognized as the most important risk factor for a variety of diseases including cardiovascular diseases, type 2 diabetes, steatohepatitis, and cancer. The medical anti-obesity treatment is to intervene in the metabolic process of adipocytes by suppressing adipogenesis and promoting lipolysis. The Phosphodiesterase-4 (PDE4) pathway is involved in fat mass control and metabolic regulation. The present study aimed to investigate the effects of Roflumilast, a selective PDE4 inhibitor, on the differentiation of 3T3-L1 cells and the high fat diet-induced obesity in mice. We showed that treatment with Roflumilast inhibited lipid accumulation and triglycerides storage in mature 3T3-L1 cells, suggesting that Roflumilast suppressed adipogenesis. Mechanistically, we found that Roflumilast decreased the differentiation-induced expression of the adipogenesis genes including SREBP1C, FABP4, and Glut4, as well as their regulators including PPAR-γ and C/EBPα. Moreover, we proved that the effect of Roflumilast was dependent on the activation of the metabolic regulator AMPKα. The treatment with Roflumilast remarkably decreased the animals’ body weight, visceral adipose tissue weight, and adipocyte size in high fat diet-induced obese mice. In conclusion, our study revealed that Roflumilast suppressed adipogenesis and promoted lipolysis in cell culture and mice models via AMPK-mediated inhibition of PPAR-γ and C/EBPα. These findings imply roflumilast could have therapeutic potential in obesity-related diseases.

Ammonium Salts of 5-(3-Chromenyl)-5H-chromeno[2,3-b]pyridines

The ammonium salts of many drugs have significantly improved the solubility and, accordingly, the bioavailability of medicinal substances in the human body. 5-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-5H-chromeno[2,3-b]pyridines are potential NPY1R ligands, which are attractive for antiobesity treatment. Ammonium salts of 5H-chromeno[2,3-b]pyridines were previously unknown. In this communication, it was found that the four-component reaction of salicylaldehyde, 2-aminoprop-1-ene-1,1,3-tricarbonitrile, 4-Hydroxy-2H-chromen-2-one and amines results in the formation of ammonium salts of 5-(3-chromenyl)-5H-chromeno[2,3-b]pyridines. The structure of these previously unknown compounds was confirmed by means of 1H, 13C NMR and IR spectroscopy, mass spectrometry and elemental analysis.

The Role of AMPK Signaling in Brown Adipose Tissue Activation.

Obesity is becoming a pandemic, and its prevalence is still increasing. Considering that obesity increases the risk of developing cardiometabolic diseases, research efforts are focusing on new ways to combat obesity. Brown adipose tissue (BAT) has emerged as a possible target to achieve this for its functional role in energy expenditure by means of increasing thermogenesis. An important metabolic sensor and regulator of whole-body energy balance is AMP-activated protein kinase (AMPK), and its role in energy metabolism is evident. This review highlights the mechanisms of BAT activation and investigates how AMPK can be used as a target for BAT activation. We review compounds and other factors that are able to activate AMPK and further discuss the therapeutic use of AMPK in BAT activation. Extensive research shows that AMPK can be activated by a number of different kinases, such as LKB1, CaMKK, but also small molecules, hormones, and metabolic stresses. AMPK is able to activate BAT by inducing adipogenesis, maintaining mitochondrial homeostasis and inducing browning in white adipose tissue. We conclude that, despite encouraging results, many uncertainties should be clarified before AMPK can be posed as a target for anti-obesity treatment via BAT activation.