Potential Treatment For Obesity Research Articles

Comparative insights into the inhibition of pancreatic lipase by quercetin using Mg-MOF-74 as nano-carrier: Inhibitory interaction, inhibition activity and conformational change

As one of the focus causes of death in the world, obesity has attracted much attention in recent years. Pancreatic lipase (PL), an outstanding target for obesity, is an enzyme which can decompose dietary lipids. Based on the good performance and drug loading effect of Mg-MOF-74, the interaction mechanism and inhibition mechanism of quercetin (Que) loaded with Mg-MOF-74 on PL were studied by multispectral technology and enzyme inhibition kinetic analysis. The effect of Mg-MOF-74 loaded Que on PL is a mix quenching process dominated by hydrophobic force. Fluorescence spectral data of the nanocomposite system were resolved by multivariate curve resolution-alternating least squares. The complex system equilibrated at a [Que]:[PL] ratio nearly 2. The conformation of PL changes under the influence of Mg-MOF-74 and Mg-MOF-74-Que were demonstrated through 3D fluorescence, Fourier transform infrared spectroscopy and circular dichroism spectrum. Molecular docking studies showed that more hydrogen bonds were formed and confirmed the stronger binding affinity of PL when Que loaded on Mg-MOF-74 (−103.17 kcal mol−1). Further analysis of the inhibition kinetics showed that PL-Que belonged to the mixed inhibition type, PL-Mg-MOF-74-Que belonged to the non-competitive inhibition type, and the inhibition constants were Ki, Que (16.63 ± 7.49 × 10−6 mol L−1) > Ki, Mg-MOF-74-Que (10.68 ± 2.04 × 10−6 mol L−1). Through investigating the inhibitory mechanism and interaction between Mg-MOF-74-Que and PL on a molecular level, it affords a new idea for the design of new PL inhibitors and a new method for the potential treatment of obesity.

A One-Year Weight Management Program for Difficult-to-Treat Asthma With Obesity: A Randomized Controlled Study

BackgroundObesity-associated asthma results in increased morbidity and mortality. We report one-year asthma outcomes with the Counterweight-Plus weight management programme (CWP) compared to usual care (UC) in a single-centre, randomised, controlled trial in patients with difficult-to-treat asthma and obesity. Research QuestionCan CWP use result in improved asthma control and quality of life compared to UC at one-year in patients with difficult-to-treat asthma and obesity? Study design and methodsWe randomised (1:1 CWP:UC) adults with difficult-to-treat asthma and body mass index ≥30kg/m2. CWP with dietitian support: 12-week total diet replacement phase (850kcal/day low-energy formula); food reintroduction and maintenance phases up to one-year. Outcomes include Asthma Control Questionnaire (ACQ-6), Asthma Quality of Life Questionnaire (AQLQ) and healthcare usage. Minimal clinically important difference (MCID) is 0.5 for ACQ-6 and AQLQ. ResultsOf 36 recruited, 29 attended at 52-weeks: 13 CWP, 16 UC. CWP resulted in greater weight change (median –14kg [IQR –15, –9]) compared to UC (2kg [-7, 8]; p=0.015) at 52-weeks. A greater proportion achieved MCID with CWP vs UC in AQLQ (71% vs 6% respectively; p<0.001). No between-group differences were observed in ACQ-6. Median exacerbation frequency reduced over 52-weeks with CWP from 4 (IQR 2, 5) to 0 (0, 2) (p<0.001), though no between-group difference was observed. 70% of the CWP group lost ≥10% body weight and had improvement in ACQ-6 (mean difference –1.1, 95%CI –1.9, -0.3; p=0.018) and AQLQ (1.2, 95%CI 0.4, 2.1; p=0.011) across 52-weeks. InterpretationUse of a dietitian-supported weight management programme results in sustained weight-loss and is a potential treatment for obesity in asthma. CWP resulted in a higher proportion achieving MCID improvement in AQLQ compared to UC. Within group differences in AQLQ and exacerbation frequency suggest potential with CWP. These encouraging signals justify a larger sample study to further assess asthma-related outcomes.

Madecassoside modulates lipid metabolism in visceral adipocytes: exploring the browning, lipolysis, and lipogenesis mechanisms for potential obesity treatment.

Madecassoside (MA) is a triterpene derived from Centella asiatica that has been recognized for its antioxidant and anti-inflammatory properties in various disease models. However, its direct impact on cultured white adipocytes and the underlying mechanisms, mainly through gene knockdown, have not been thoroughly explored. Western blot analysis was utilized to assess the expression levels of various proteins, while oil red O staining was used to measure lipid deposition. The adipocyte shapes were confirmed using H&E staining. MA treatment enhanced browning and lipolysis in 3T3-L1 adipocytes and adipose tissue from experimental mice while suppressing lipogenesis. Furthermore, MA treatment increased the expression of PPARα and FGF21 in 3T3-L1 adipocytes as well as the secretion of FGF21 into the culture medium. Knockdown of PPARα or FGF21 using siRNA diminished the effects of MA on lipid metabolism in cultured adipocytes. These findings demonstrate that MA promotes thermogenic browning and lipolysis while inhibiting adipocyte lipogenesis, thus showing the potential for attenuating obesity. The study suggested that MA could be a viable therapeutic approach for treating obesity.

Bioactive Peptides from Meretrix lusoria Enzymatic Hydrolysate as a Potential Treatment for Obesity in db/db Mice.

Obesity is acknowledged as a significant risk factor for cardiovascular disease, often accompanied by increased inflammation and diabetes. Bioactive peptides derived from marine animal proteins show promise as safe and effective anti-obesity agents by regulating adipocyte differentiation through the AMPK signaling pathway. Therefore, this study aims to investigate the anti-obesity and anti-diabetic effects of bioactive compounds derived from a Meretrix lusoria Protamex enzymatic hydrolysate (MLP) fraction (≤1 kDa) through a 6-week treatment (150 mg/kg or 300 mg/kg, administered once daily) in leptin receptor-deficient db/db mice. The MLP treatment significantly decreased the body weight, serum total cholesterol, triglycerides, and LDL-cholesterol levels while also exhibiting a beneficial effect on hepatic and serum marker parameters in db/db mice. A histological analysis revealed a reduction in hepatic steatosis and epididymal fat following MLP treatment. Furthermore, poor glucose tolerance was improved, and hepatic antioxidant enzyme activities were elevated in MLP-treated mice compared to db/db control mice. Western blot analysis showed an increased expression of the AMPK protein after MLP treatment. In addition, the expression of lipogenic genes decreased in db/db mice. These findings indicate that bioactive peptides, which are known to regulate blood glucose levels, lipid metabolism, and adipogenesis, could be beneficial functional food additives and pharmaceuticals.

Prolactin-Releasing Peptide, a Peptide with an Improper Name, but Proper Biological Activity for Obesity, Type-2 Diabetes, and Alzheimer's Disease Treatment

Obesity is an escalating epidemic, but an effective non-invasive therapy is still scarce. For the obesity treatment, anorexigenic neuropeptides represent promising tools, but their delivery from the periphery to the brain is complicated because peptides have a low stability and limited ability to cross the blood-brain barrier. Recently discovered anorexigenic neuropeptides, such as prolactin-releasing peptide, represent new trends in development of anti-obesity agents. They are released and acting directly in brain areas regulating food intake, but generally do not cross the blood-brain barrier if administered peripherally. We succeeded to design stable palmitoylated analogs of this neuropeptide with a prolonged acute anorexigenic effect after peripheral administration as shown in mice and rats. Repeated peripheral administration of the lipidized prolactin-releasing peptide analogs resulted in long-lasting anti-obesity and antidiabetic effects in rodent models of diet-induced obesity and insulin resistance. We proved that lipidation might be an effective way to transmit the desired effect to the central nervous system after peripheral administration, for a potential treatment of obesity and related complications such as type-2 diabetes. Besides the advanced age, type-2 diabetes and obesity were shown to be risk factors for Alzheimer's disease; therefore, compounds with glucose-lowering and/or anorexigenic properties were proposed to be neuroprotective. In our group, we studied a possible crosstalk between obesity, type-2 diabetes and Alzheimer's-like pathology. We also investigated if our novel palmitoylated analogs of prolactin-releasing peptide could have beneficial effect on neurodegeneration in several mouse models of Alzheimer's-like pathology and their age-matched wild type controls. We demonstrated that these lipidized analogs are potentially neuroprotective substances improving spatial memory, neurogenesis, synaptogenesis and attenuating neuroinflammation and two hallmarks of Alzheimer's disease, i.e., tau hyper-phosphorylation and β-amyloid plaques in different mouse models of Alzheimer's-like neurodegeneration.

Foxj3 Regulates Thermogenesis of Brown and Beige Fat Via Induction of PGC-1α.

Enhancing the development and thermogenesis in brown and beige fat represents a potential treatment for obesity. In the present study, we show that Foxj3 expression in fat is stimulated by cold exposure and a β-adrenergic agonist. Adipose-specific Foxj3 knockout impairs the thermogenic function of brown fat, leading to morphological whitening of brown fat and obesity. Adipose Foxj3-deficient mice display increased fasting blood glucose levels and hepatic steatosis on a chow diet. Foxj3 deficiency inhibits the browning of inguinal white adipose tissue (iWAT) following β3-agonist treatment of mice. Furthermore, depletion of Foxj3 in primary brown adipocytes reduces the expression of thermogenic genes and cellular respiration, indicating that the Foxj3 effects on the thermogenic program are cell autonomous. In contrast, Foxj3 overexpression in primary brown adipocytes enhances the thermogenic program. Moreover, AAV-mediated Foxj3 overexpression in brown fat and inguinal WAT increases energy expenditure and improves systemic metabolism on either a chow diet or a high-fat diet. Finally, Foxj3 deletion in fat inhibits the β3 agonist-mediated induction of WAT browning and brown adipose tissue thermogenesis. Mechanistically, cold-inducible Foxj3 stimulates the expression of PGC-1α and UCP1, subsequently promoting energy expenditure. The present study identifies Foxj3 as a critical regulator of fat thermogenesis, and targeting Foxj3 in fat might be a therapeutic strategy for treating obesity and metabolic diseases.

Liver-Selective Imidazolopyrazine Mitochondrial Uncoupler SHD865 Reverses Adiposity and Glucose Intolerance in Mice.

Excess body fat is a risk factor for metabolic diseases and is a leading preventable cause of morbidity and mortality worldwide. There is a strong need to find new treatments that decrease the burden of obesity and lower the risk of obesity-related comorbidities including cardiovascular disease and type 2 diabetes. Pharmacologic mitochondrial uncouplers represent a potential treatment for obesity through their ability to increase nutrient oxidation. Herein, we report the in vitro and in vivo characterization of compound SHD865, the first compound to be studied in vivo in a newly discovered class of imidazolopyrazine mitochondrial uncouplers. SHD865 is a derivative of the furazanopyrazine uncoupler BAM15. SHD865 is a milder mitochondrial uncoupler than BAM15 that results in a lower maximal respiration rate. In a mouse model of diet-induced adiposity, six-week treatment with SHD865 completely restored normal body composition and glucose tolerance to levels like those of chow-fed controls without altering food intake. SHD865 treatment also corrected liver steatosis and plasma hyperlipidemia to normal levels comparable with chow-fed controls. SHD865 has maximal oral bioavailability in rats and slow clearance in human microsomes and hepatocytes. Collectively, these data identify the potential of imidazolopyrazine mitochondrial uncouplers as drug candidates for the treatment of obesity-related disorders.

Celastrol attenuates HFD-induced obesity and improves metabolic function independent of adiponectin signaling

Backgound: Celastrol, a leptin sensitiser, has been shown to inhibit food intake and reduce body weight in diet-induced obese mice, making it a potential treatment for obesity and metabolic diseases. Adiponectin signalling has been reported to play an important role in the treatment of obesity, inflammation, and non-alcoholic fatty liver disease. Materials and methods: Wild-type (WT) and AdipoR1 knockout (AdipoR1-/-) mice were placed on a chow diet or a high-fat diet (HFD) and several metabolic parameters were measured. Celastrol was then administered to the HFD-induced mice and the response of WT and AdipoR1-/- mice to celastrol in terms of body weight, blood glucose, and food intake was also recorded. Results: AdipoR1 knockout caused elevated blood glucose and lipids, impaired glucose tolerance and insulin resistance in mice, as well as increased susceptibility to HFD-induced obesity. After 14 days of treatment, WT and AdipoR1-/- mice showed significant reductions in body weight and blood glucose and improvements in glucose tolerance. Conclusion: The present study demonstrated that AdipoR1 plays a critical role in metabolic regulation and that the improvement of weight and metabolic function by celastrol is independent of the AdipoR1-mediated signalling pathway.

Effects of a long-acting secretin peptide analog alone and in combination with a GLP-1R agonist in a diet-induced obesity mouse model

ObjectiveObesity is a major global health problem which can be targeted with new mechanistic diverse pharmacological interventions. Here we evaluate a new long-acting secretin receptor agonist as a potential treatment for obesity. MethodsBI-3434 was designed as a secretin analog with stabilized peptide backbone and attached fatty acid-based half-life extension group. The peptide was evaluated in vitro for its ability to stimulate cAMP accumulation in a cell line stably expressing recombinant secretin receptor. On the functional level, stimulation of lipolysis in primary adipocytes after treatment with BI-3434 was determined. The ability of BI-3434 to activate secretin receptor in vivo was assessed in a cAMP reporter CRE-Luc mouse model. Furthermore, a diet-induced obesity mouse model was used to test the effects of BI-3434 on body weight and food intake following repeated daily subcutaneous administration alone and in combination with a GLP-1R agonist. ResultsBI-3434 potently activated human secretin receptor. However, lipolysis was only weakly induced in primary murine adipocytes. BI-3434 had an extended half-life compared to endogenous secretin and activated target tissues like pancreas, adipose tissue, and stomach in vivo. BI-3434 did not lower food intake in lean or diet-induced obese mice, but it increased energy expenditure after daily administration. This led to a loss of fat mass, which did not translate in a significant effect on body weight. However, treatment in combination with a GLP-1R agonist led to a synergistic effect on body weight loss. ConclusionsBI-3434 is a highly potent and selective agonist of secretin receptor with an extended pharmacokinetic (PK) profile. Increased energy expenditure after daily treatment with BI-3434 suggests that secretin receptor is involved in metabolic regulation and energy homeostasis. Targeting secretin receptor alone may not be an efficient anti-obesity treatment, but could be combined with anorectic principles like GLP-1R agonists.

Treatment sequencing using the dual amylin and calcitonin receptor agonist KBP-336 and semaglutide results in durable weight loss

ObjectiveLong-acting dual amylin and calcitonin receptor agonists (DACRAs) hold great promise as potential treatments for obesity and its associated comorbidities. These agents have demonstrated beneficial effects on body weight, glucose control, and insulin action mirroring the effects observed with glucagon-like peptide-1 (GLP-1) agonist treatment. Strategies aimed at enhancing and prolonging treatment efficacy include treatment sequencing and combination therapy. Here, we sought to investigate the impact of switching between or combining treatment with the DACRA KBP-336 and the GLP-1 analog semaglutide in fed rats with obesity induced by a high-fat diet (HFD). MethodsTwo studies were performed in which HFD-induced obese Sprague Dawley rats were switched between treatment with KBP-336 (4.5 nmol/kg, Q3D) and semaglutide (50 nmol/kg, Q3D) or a combination of the two. Treatment efficacy on weight loss and food intake was evaluated, and glucose tolerance was assessed by oral glucose tolerance tests. ResultsKBP-336 and semaglutide monotherapy resulted in a similar reduction in body weight and food intake. Treatment sequencing resulted in continuous weight loss and all monotherapies resulted in similar weight loss independent of the treatment regimen (P < 0.001 compared to vehicle). The combination of KBP-336 and semaglutide significantly improved the weight loss compared to either monotherapy alone (P < 0.001), which was evident in the adiposity at the study end. All treatments improved glucose tolerance, with the KBP-effect on insulin sensitivity as the dominant response. ConclusionsThese findings highlight KBP-336 as a promising anti-obesity therapy both alone, in treatment sequencing, and in combination with semaglutide or other incretin-based therapies.

Associations of dietary antioxidant micronutrients with the prevalence of obesity in adults.

Antioxidant micronutrients have a therapeutic potential for clinical treatment of obesity. NO research, however, has examined the connection between the complex level of dietary antioxidants and obesity. We mainly aimed to investigate the relationship between a combination of antioxidants and obesity using the database of the national health and nutrition examination survey (NHANES). This cross-sectional study contains a survey of 41,021 people (≥18 years) in total ranging from 2005 to 2018. Multivariate logistic and weighted quantile sum (WQS) regression were performed to investigate the associations between these antioxidants, both individually and collectively, and the prevalence of obesity. The restricted cubic spline (RCS) regression was also utilized to analyze the linearity of these associations. According to multivariate logistic models, we found that the levels of most antioxidants in the highest quartile were independently related to a lower prevalence of obesity, while a reverse result was observed in selenium (p for trend <0.05). The WQS index revealed that a total of the 11 antioxidants is negatively related to the prevalence of obesity and abdominal obesity (all p<0.001), and iron/vitamin C have the greatest weight in the negative associations between antioxidant complex and obesity, as well as abdominal obesity. In addition, the RCS regression showed that retinol, vitamin A, α-carotene, β-carotene, β-cryptoxanthin, vitamin C, iron, and copper all had a non-linear association with obesity. Threshold effect analysis demonstrated that the inflection points of retinol, vitamin A, α-carotene, β-carotene, β-cryptoxanthin, vitamin C, iron, and cooper were 235.57, 374.81, 58.89, 891.44, 30.70, 43,410.00, 11,240.00, and 990.00 μg/day, respectively. Our study found that a high level of a complex of 11 dietary antioxidants is related to a lower prevalence of obesity and abdominal obesity, among this inverse associations iron and vitamin C have the greatest weight.

Active Glycogen Synthase in the Liver Prevents High-Fat Diet-Induced Glucose Intolerance, Decreases Food Intake, and Lowers Body Weight.

Many lines of evidence demonstrate a correlation between liver glycogen content and food intake. We previously demonstrated that mice overexpressing protein targeting to glycogen (PTG) specifically in the liver-which have increased glycogen content in this organ-are protected from high-fat diet (HFD)-induced obesity by reduced food intake. However, the use of PTG to increase liver glycogen implies certain limitations. PTG stimulates glycogen synthesis but also inhibits the enzyme responsible for glycogen degradation. Furthermore, as PTG is a regulatory subunit of protein phosphatase 1 (PP1), which regulates many cellular functions, its overexpression could have side effects beyond the regulation of glycogen metabolism. Therefore, it is necessary to determine whether the direct activation of glycogen synthesis, without affecting its degradation or other cellular functions, has the same effects. To this end, we generated mice overexpressing a non-inactivatable form of glycogen synthase (GS) specifically in the liver (9A-MGSAlb mice). Control and 9a-MGSAlb mice were fed a standard diet (SD) or HFD for 16 weeks. Glucose tolerance and feeding behavior were analyzed. 9A-MGSAlb mice showed an increase in hepatic glycogen in fed and fasting conditions. When fed an HFD, these animals preserved their hepatic energy state, had a reduced food intake, and presented a lower body weight and fat mass than control animals, without changes in energy expenditure. Furthermore, 9A-MGSAlb animals showed improved glucose tolerance when fed an SD or HFD. Moreover, liver triacylglycerol levels that were increased after HFD feeding were lower in these mice. These results confirm that increased liver glycogen stores contribute to decreased appetite and improve glucose tolerance in mice fed an HFD. On the basis of our findings, strategies to preserve hepatic glycogen stores emerge as potential treatments for obesity and hyperglycemia.

Astragalus polysaccharide prevents heart failure-induced cachexia by alleviating excessive adipose expenditure in white and brown adipose tissue

BackgroundAstragalus polysaccharide (APS) is a key active ingredient isolated from Astragalus membranaceus that has been reported to be a potential treatment for obesity and diabetes by regulating lipid metabolism and adipogenesis, alleviating inflammation, and improving insulin resistance. However, whether APS regulates lipid metabolism in the context of cachexia remains unclear. Therefore, this study analysed the effects of APS on lipid metabolism and adipose expenditure in a heart failure (HF)-induced cardiac cachexia rat model. MethodsA salt-sensitive hypertension-induced cardiac cachexia rat model was used in the present study. Cardiac function was detected by echocardiography. The histological features and fat droplets in fat tissue and liver were observed by H&E staining and Oil O Red staining. Immunohistochemical staining, Western blotting and RT‒qPCR were used to detect markers of lipolysis and adipose browning in white adipose tissue (WAT) and thermogenesis in brown adipose tissue (BAT). Additionally, sympathetic nerve activity and inflammation in adipose tissue were detected.ResultsRats with HF exhibited decreased cardiac function and reduced adipose accumulation as well as adipocyte atrophy. In contrast, administration of APS not only improved cardiac function and increased adipose weight but also prevented adipose atrophy and FFA efflux in HF-induced cachexia. Moreover, APS inhibited HF-induced lipolysis and browning of white adipocytes since the expression levels of lipid droplet enzymes, including HSL and perilipin, and beige adipocyte markers, including UCP-1, Cd137 and Zic-1, were suppressed after administration of APS. In BAT, treatment with APS inhibited PKA-p38 MAPK signalling, and these effects were accompanied by decreased thermogenesis reflected by decreased expression of UCP-1, PPAR-γ and PGC-1α and reduced FFA β-oxidation in mitochondria reflected by decreased Cd36, Fatp-1 and Cpt1. Moreover, sympathetic nerve activity and interleukin-6 levels were abnormally elevated in HF rats, and astragalus polysaccharide could inhibit their activity.ConclusionAPS prevented lipolysis and adipose browning in WAT and decreased BAT thermogenesis. These effects may be related to suppressed sympathetic activity and inflammation. This study provides a potential approach to treat HF-induced cardiac cachexia.

Plant-based diet for obesity treatment.

Obesity rates continue to rise, resulting in a global epidemic that shows no sign of slowing down. Our understanding of this complex disease is also constantly evolving, requiring healthcare providers to stay up to date with best practices. The application of plant-based diets (PBDs) may hold the key to a successful weight-control strategy. PBD refers to any dietary pattern that emphasizes the consumption of plant foods while excluding the consumption of most or all animal products. The purpose of this mini-review is to report on the application of PBDs as a potential treatment for obesity. PBDs have also been shown to be beneficial in the treatment of other non-communicable diseases, such as the prevention and treatment of type 2 diabetes. Many of the reported RCTs were of short duration. Longer-term studies, as well as studies focusing on strict adherence to the PBD regime, are needed. PBD is a beneficial approach to improving health, particularly in obese patients. Benefits include weight loss, improved cardiovascular health, lower blood pressure, and improved glucose metabolism.

1318-P: Repetitive Transcranial Magnetic Stimulation: A Potential Treatment for Obesity in Patients with Prader-Willi Syndrome

Prader-Willi Syndrome (PWS) is the most common syndromic type of human obesity. Multiple endocrine abnormalities due to hypothalamic dysfunction as well as cognitive and behavioral disorders occur in PWS. Hypothalamic dysfunction, dysregulated mesocorticolimbic reward system, and impaired prefrontal cortex (PFC) function are implicated in the pathophysiology of hyperphagia and obesity in PWS. All available therapeutic tools have not fully targeted at counteract the mechanisms underlying obesity in PWS. Previously, we demonstrated the safety and efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) in inducing weight loss in obesity by modulating the brain dopaminergic system and enhancing the inhibitory activity of the PFC on eating behaviour (Ferrulli et al, DOM 2019) . In this case-report, for the first time, we tested the efficacy and safety of rTMS in a 23-year-old patient with PWS, in whom repeated interventions aimed at inducing weight loss have failed. A 5-week high frequency (18 Hz) rTMS treatment, associated with diet, resulted in a 3.5% weight loss (127.4 vs. 123 Kg, BMI: 50.4 vs. 48.6 Kg/m2, WHR: 1.14 vs. 1.12) . Concerning the metabolic parameters, an improvement in lipid profile has been shown (CHO/HDL/LDL/TG: 212/40/142/152 vs. 190/40/124/131 mg/dL) . While no significant changes emerged in the psychometric assessment of food craving, impulsiveness, quality of life, self-esteem, interestingly, a robust improvement in the Mini-Mental State Examination score (corrected for age and schooling) has been found [from 22 (severe impairment) to 27 (moderate impairment) ]. The improvement in the cognitive status assessed through the Montreal Cognitive Assessment was weaker (17/30 to 19/30) . In view of the urgent need of novel effective interventions for obesity in PWS, these findings support a potential role of rTMS in reducing food drive and behaviors impacting hyperphagia and obesity in PWS, with a possible impact also on cognitive functions. Disclosure A.Ferrulli: None. D.Cannavaro: None. C.Macrì: None. S.Massarini: None. L.Luzi: Advisory Panel; Eli Lilly and Company, Speaker’s Bureau; Eli Lilly and Company, Novo Nordisk. Funding IRCCS Multimedica - Ricerca Corrente

Design, synthesis and preclinical evaluation of bio-conjugated amylinomimetic peptides as long-acting amylin receptor agonists

Pramlintide is an equipotent amylin analogue that reduces food intake and body weight in obese subjects and has been clinically approved as an adjunctive therapy for the treatment of adult diabetic patients. However, due to its extremely short half-life in vivo, a regimen of multiple daily administrations is required for achieving clinical effectiveness. Herein is described the development of prototypical long-acting pramlintide bioconjugates, in which pramlintide's disulfide-linked macrocycle was replaced by a cyclic thioether motif. This modification enabled stable chemical conjugation to a half-life extending antibody. In contrast to pramlintide (t1/2 < 0.75 h), bioconjugates 35 and 38 have terminal half-lives of ∼2 days in mice and attain significant exposure levels that are maintained up to 7 days. Single dose subcutaneous administration of 35 in lean mice, given 18–20 h prior to oral acetaminophen (AAP) administration, significantly reduced gastric emptying (as determined by plasma AAP levels). In a separate study, similar administration of 35 in fasted lean mice effected a reduction in food intake for up to 48 h. These data are consistent with durable amylinomimetic responses and provide the basis for further development of such long-acting amylinomimetic conjugates for the potential treatment of obesity and associated pathologies.

Comparative Study on Anti-obesity Effects of Pyungwi-san, Magnolia officinalis, and Atractylodes chinensis in High-fat Diet-induced Obese Mouse Model

Objectives Obesity is considered a global epidemic that greatly affects general population health, and there has been a growing interest in the development of anti-obesity drugs worldwide. There are many hepatic and gastrointestinal diseases for which obesity is the direct cause or is a serious risk factor. Pyungwi-san (PWS) is a traditional oriental herbal prescription used to treat gastrointestinal disorders. Atractylodes chinensis (DC.) Koidzumi (AC) and Magnolia officinalis Rehder & E.H. Wilson (MO) are main components of PWS. In this present study, anti-obesity effects of PWS, MO, and AC were investigated in high-fat diet (HFD)-induced obese mouse model. Methods Eight-week-old male C57BL/6N were fed 45% HFD for 8 weeks. For comparison of PWS, MO, and AC for obesity, the body weight, food intake, and white adipose tissue (WAT) weights were checked. In addition, hematoxylin and eosin staining for histological examination were performed to observe lipid droplets in epididymal WAT and liver tissue. Results Among them, AC had powerful effects on reduction of body weight, epididymal and visceral WAT weight, and regulation of the levels of serum total cholesterol and triglyceride. In addition, PWS, MO, and AC treatment ameliorated the HFD-induced histological changes in the epididymal WAT and liver tissue. Conclusions These findings demonstrate that AC has anti-obesity effects and would be evaluated as a potential treatment for obesity.

Caffeine and EGCG Alleviate High-Trans Fatty Acid and High-Carbohydrate Diet-Induced NASH in Mice: Commonality and Specificity.

Caffeine and epigallocatechin-3-gallate (EGCG), which respectively, are the main functional extracts from coffee and green tea, and present protective effects against non-alcoholic fatty liver diseases (NAFLD). These two beverages and their functional extracts are highly recommended as potential treatments for obesity and NAFLD in clinics; however, their pharmacodynamic effects and pharmacological mechanisms in non-alcoholic steatohepatitis (NASH) remain unclear. Therefore, the aim of this study was to explore the commonality and specificity of the pharmacodynamic effects and pharmacological mechanisms of caffeine and EGCG on NASH mice, which were fed with a high-trans fatty acid/high-carbohydrate (HFHC) diet. C57BL/6J mice were fed a normal diet (control group) or an HFHC diet (HFHC group) for 24 weeks. HFHC group mice were additionally treated with caffeine (75 mg/kg) or EGCG (100 mg/kg) for 6 weeks, using obeticholic acid (OCA,10 mg/kg) as a positive control group. The pharmacological effects of the drugs, including effects on glucose and lipid metabolism and liver inflammation and fibrosis, were evaluated. Gene expression in liver tissue samples from the different groups were assessed. Both caffeine and EGCG significantly reduced the liver manifestations of NASH induced by HFHC. The pathological aspects of liver lipid deposition, inflammation, and liver fibrosis in both groups were strongly ameliorated. Of note, most indexes were strongly reversed in the caffeine group, although AST activity, fasting blood glucose, and the HOMA-IR index were improved in the ECGC group. There were 714 differentially expressed genes between the caffeine and HFHC groups and 268 differentially expressed genes between the EGCG and HFHC groups. Twenty and 17 NASH-related KEGG signaling pathways were enriched by caffeine and EGCG. This study confirmed that 75 mg/kg caffeine and 100 mg/kg EGCG could significantly improve liver lipid deposition, glucose metabolism, inflammation, and fibrosis in a mouse model of NASH induced by HFHC. The bioinformatics platform we built for caffeine and EGCG in NASH disease found that the two drugs may greatly overlap in improving the mechanism related to NASH inflammation. However, caffeine may have better potential in regulating glucose metabolism and EGCG may have better potential in regulating lipid metabolism.

S1270 Utilization of Chronic Cecal Distention to Induce a Colo-Gastric Brake Effect as a Potential Obesity Treatment: A Canine Feasibility Study

Introduction: There is a need for novel obesity therapy. The “colo-gastric brake” is a known physiologic process in which cecal distention causes anorexia and delayed gastric/small bowel emptying. In this study we explored an innovative obesity approach, i.e. using cecal distention to trigger the colo-gastric brake, to induce anorexia and weight loss in a canine model. Methods: 3 dogs had daily food intake, weights and activity monitored for 2 weeks. The dogs underwent colonoscopy with placement of a novel self-expanding Nitinol stent (Biomerics, Park, MN), 8.5 cm diameter, and wall pressure 0.136 atm, into each cecum via the biopsy channel. Clips secured the stents. Stent location and expansion were imaged weekly for 4 weeks. Post-procedure, animals resumed their diet with activity and food intake measured daily; weights were taken weekly. High-caloric supplements were provided for excess weight loss. At day 90 animals underwent a 2nd colonoscopy; stents photographed and the animals sacrificed, tissues were harvested and gross/histologic analysis was performed. Results: Stents were deployed into each cecum with full radial expansion by 1 week, and no migration. Following implant, animals recovered well and exhibited normal behavior throughout the study with no adverse events. Water intake was normal throughout the study, but inappetence was noted immediately post-implant beginning on day 1 and persisted throughout the study. Food intake as a group decreased below 50% of baseline at the end of week 1, recovered to around 70% at week 3, then dropped precipitously to 25% of baseline from week 4 to the end of the study (p< 0.009). Severe weight loss by day 25 (15.8-20.6%) prompted high-caloric supplementation; some weight was regained after supplementation however there was still marked weight loss (11.2-16.1%; p< .015) at the end of 90 days. At necropsy, the cecal implants demonstrated full distention; histology showed a mixed chronic-active cellular response in the mucosa and mild fibrosis. Conclusion: Chronic cecal distention is feasible and appeared to trigger a colo-gastric brake effect in a canine model. Device implant was associated with normal activity, no complications, normal water intake, but immediate and persistent loss of appetite, with markedly decreased food intake and significant weight loss. Test devices maintained cecal position without tissue damage. Although a small animal trial, these results suggest that cecal distention may represent an option for obesity treatment.Figure 1.: Representative longitudinal radiographic images of the cecal implant devices. Left Image, Animal 1. A fractured implant wire is visible (arrow) in the image. Middle Image, Animal 2. A fractured implant wire is visible (arrow) in the image. Right Image, Animal 3. Implant wires appear intact. Note: The connector end orientation for animal 1 is opposite that of animals 2 and 3.

Repetitive Transcranial Magnetic Stimulation: A Potential Treatment for Obesity in Patients with Schizophrenia

Obesity is highly prevalent in patients with schizophrenia and, in association with metabolic syndrome, contributes to premature deaths of patients due to cardiovascular disease complications. Moreover, pharmacologic, and behavioral interventions have not stemmed the tide of obesity in schizophrenia. Therefore, novel effective interventions are urgently needed. Repetitive transcranial magnetic stimulation (rTMS) has shown efficacy for inducing weight loss in obese non-psychiatric samples but this promising intervention has not been evaluated as a weight loss intervention in patients with schizophrenia. In this narrative review, we describe three brain mechanisms (hypothalamic inflammation, dysregulated mesocorticolimbic reward system, and impaired prefrontal cortex function) implicated in the pathogenesis and pathophysiology of obesity and emphasize how the three mechanisms have also been implicated in the neurobiology of schizophrenia. We then argue that, based on the three overlapping brain mechanisms in obesity and schizophrenia, rTMS would be effective as a weight loss intervention in patients with schizophrenia and comorbid obesity. We end this review by describing how deep TMS, relative to conventional TMS, could potentially result in larger effect size for weight loss. While this review is mainly conceptual and based on an extrapolation of findings from non-schizophrenia samples, our aim is to stimulate research in the use of rTMS for weight loss in patients with schizophrenia.