Agents For Treatment Of Obesity Research Articles

823-P: The Long-Acting Dual Amylin and Calcitonin Receptor Agonist KBP Has Increased Efficacy on Weight Loss and Glucose Control Compared with Cagrilintide in Obese and Diabetic Rats

Long-acting dual amylin and calcitonin receptor agonists (DACRAs) are novel candidates for treatment of type 2 diabetes (T2D) and obesity due to their beneficial effects on both body weight, glucose control and insulin action. Cagrilintide, which is currently in clinical trials, has shown promising effects on weight loss. In this study we compared a new long-acting DACRA (KBP) to cagrilintide in pre-clinical models of obesity and T2D. In vitro potencies were assessed using receptor assays. In vivo efficacies were investigated head-to-head in high fat diet (HFD) fed obese and T2D (ZDF) rat models. In vitro data showed that both peptides active both the amylin and the calcitonin receptor, with KBP being more potent on both receptors. This was further confirmed in vivo by assessment of acute effects on food intake and CTX suppression. KBP (1.5, 4.5 and 13.5 nmol/kg) and cagrilintide (10, 30 and 100 nmol/kg) induced a potent and dose-dependent weight loss in HFD rats, with the highest dose of KBP being superior to cagrilintide. In diabetic ZDF rats, DACRA treatment improved glucose control and preserved plasma insulin compared to vehicle. Interestingly, despite similar levels of plasma insulin, KBP treatment was superior to cagrilintide in improving glucose control. This was further reflected in the HbA1c levels at study end, where KBP treatment resulted in significantly lower levels compared to cagrilintide. In summary, both DACRAs induced weight loss and improved glucose tolerance, insulin action as well as glucose control. However, KBP treatment results in superior efficacy on both weight loss and glucose control. These findings highlight KBP as a promising once-weekly agent for treatment of obesity and T2D. Disclosure A.T.Larsen: Employee; Nordic Bioscience. N.Sonne: None. K.Mohamed: None. E.Bredtoft: None. F.Andersen: None. M.A.Karsdal: Employee; Nordic Bioscience A/S, Nordic Bioscience A/S, Nordic Bioscience A/S. K.Henriksen: Employee; Nordic Bioscience A/S, Stock/Shareholder; Nordic Bioscience A/S.

Indolepropionic acid reduces obesity-induced metabolic dysfunction through colonic barrier restoration mediated via tuft cell-derived IL-25.

Previous studies have indicated that indolepropionic acid (IPA), derived from dietary tryptophan via gut microbiota conversion, is negatively correlated with type 2 diabetes mellitus and systemic low-grade inflammation. However, the effects of IPA administration on obesity, as well as the underlying mechanisms, remain unclear. In the present study, we observed that obesity leads to a dramatic reduction in IPA levels in both the serum and colonic mucosa, and IPA supplementation exerted beneficial effects on weight, as well as on glucose and lipid metabolism disorders. In adipose tissue, IPA treatment had no direct effect on adipocyte differentiation, but it significantly ameliorated adipose inflammation, thus preventing adipocyte enlargement. Moreover, IPA administration promoted gut integrity, increased the expression of tight junction proteins, and downregulated colonic inflammation; these effects were demonstrated to have a poor relationship with gut microbiota composition. Mechanistically, IPA significantly promoted the expansion of the tuft cell lineage in the gut and increased the secretion of interleukin-25 both in vivo and ex vivo, which contributes to the integrity of the gut barrier. This may partly depend on the free fatty acid receptor 3 pathway in tuft cells. Overall, our results demonstrate that IPA supplementation prevents the development of high-fat diet-induced obesity and metabolic disorders by restoring tuft cell-interleukin-25-mediated colonic barrier integrity; hence, IPA could be a potential agent for treatment of obesity.

Glycyrrhizic acid suppresses early stage of adipogenesis through repression of MEK/ERK-mediated C/EBPβ and C/EBPδ expression in 3T3-L1 cells

Glycyrrhizic acid (GA), a major constituent of the root of licorice (Glycyrrhiza glabra), and has various biological activities, including anti-obesity property. However, the molecular mechanism of anti-adipogenic effect of GA is still unclear. In this study, we investigated the anti-adipogenic effects of GA in mouse adipocytic 3T3-L1 cells and elucidated its underlying molecular mechanism. GA decreased the intracellular triglyceride level. The expression levels of the adipogenic and lipogenic genes were lowered by treatment with GA in a concertation-dependent manner. In contrast, GA did not affect the lipolytic gene expression and the released glycerol level. GA suppressed the early stage of adipogenesis when it was added for 0–3 h after initiation of adipogenesis. Moreover, GA reduced the mRNA levels of CCAAT/enhancer binding protein (C/EBP) β and C/EBPδ, both of which activate the early stage of adipogenesis. Furthermore, GA decreased phosphorylation of extracellular signal-regulated kinase [ERK: p44/42 mitogen-activated protein kinase (MAPK)] in the early stage of adipogenesis. In addition, a MAPK kinase (MEK) inhibitor, PD98059 reduced the C/EBPβ and C/EBPδ gene expression. These results indicate that GA suppressed the early stage of adipogenesis through repressing the MEK/ERK-mediated C/EBPβ and C/EBPδ expression in 3T3-L1 cells. Thus, GA has an anti-adipogenic ability and a possible agent for treatment of obesity.

Once weekly semaglutide for treatment of obesity

Background: Once weekly (OW) semaglutide 0.5-1.0 mg is a glucagon-like type-1 receptor agonist (GLR-1 RA) approved for treatment of type 2 diabetes and is currently under evaluation for treatment of obesity at a higher dose of 2.4 mg OW. Objective: to provide an appraisal of WO semaglutide 2.4 mg for treatment of obesity. Methods: Pubmed research up to March 22. Randomized trials, pertinent animal studies, and reviews are included. Search terms were glucagon-like type 1 receptor agonists, weight loss, obesity, semaglutide, safety, efficacy. Results: WO semaglutide 2.4 mg was evaluated as a weight loss agent in 3 well-designed clinical trials of 68 week-duration. In one trial including patients with type 2 diabetes, the difference in weight loss from baseline to week 68 between OW semaglutide and placebo was - 6.2 percentage points (95% CI, -7.3 to -5.2; P<0.0001). In the other 2 studies that excluded patients with diabetes, the difference in weight loss between OW semaglutide and placebo ranged between -10.3% and -12.4%. A significantly higher proportion of participants in the semaglutide groups vs placebo groups achieved at least 5% of weight loss. The most common adverse effects of semaglutide were related to the gastrointestinal (GI) system. Across these 3 trials, premature discontinuation of OW semaglutide occurred in 6-7% vs 3% in placebo groups. Conclusions: OW semaglutide may be a promising agent for treatment of obesity irrespective of presence of type 2 diabetes. Further studies are needed to establish its long-term safety and efficacy.

Alisol A attenuates high-fat-diet-induced obesity and metabolic disorders via the AMPK/ACC/SREBP-1c pathway.

Obesity and its associated metabolic disorders such as diabetes, hepatic steatosis and chronic heart diseases are affecting billions of individuals. However there is no satisfactory drug to treat such diseases. In this study, we found that alisol A, a major active triterpene isolated from the Chinese traditional medicine Rhizoma Alismatis, could significantly attenuate high‐fat‐diet‐induced obesity. Our biochemical detection demonstrated that alisol A remarkably decreased lipid levels, alleviated glucose metabolism disorders and insulin resistance in high‐fat‐diet‐induced obese mice. We also found that alisol A reduced hepatic steatosis and improved liver function in the obese mice model.In addition, protein expression investigation revealed that alisol A had an active effect on AMPK/ACC/SREBP‐1c pathway. As suggested by the molecular docking study, such bioactivity of alisol A may result from its selective binding to the catalytic region of AMPK.Therefore, we believe that Alisol A could serve as a promising agent for treatment of obesity and its related metabolic diseases.

Dual targeting of Nur77 and AMPKα by isoalantolactone inhibits adipogenesis in vitro and decreases body fat mass in vivo.

Suppression of adipogenesis has been considered as a potential target for the prevention and treatment of obesity and associated metabolic disorders, and the nuclear receptor 4A1 (NR4A1/Nur77) and AMPKα are known to play important roles during early and intermediate stages of adipogenesis. Therefore, we hypothesized that dual targeting Nur77 and AMPKα would show strong inhibitory effect on adipogenesis. We screened a herbal medicine-based small molecule library to identify novel natural compounds dual targeting Nur77 and AMPKα, and the antiadipogenic effects and mechanisms of action of a "hit" compound were studied in 3T3-L1 cells. In vivo antiobesity effects of the compound were also investigated in high-fat diet (HFD)-induced obese mice. We identified isoalantolactone (ISO) as a new NR4A1 inactivator that also activates AMPKα in 3T3-L1 cells. ISO, as expected, inhibited adipogenic differentiation of 3T3-L1 preadipocytes, accompanied by reduced mitotic clonal expansion (MCE) which occurs in the early stage of adipogenesis and decreased expression of genes required for MCE and cell cycle markers including cyclin A, cyclin D1. Furthermore, ISO reduced body weight gain and fat mass (epididymal, subcutaneous, perirenal, and inguinal white adipose tissues) in the high-fat diet-fed C57BL/6 N mice. Serum levels of triglycerides, aspartate transaminase, and alanine transaminase and hepatic steatosis were also significantly improved in the ISO-treated group compared to the high-fat diet control group. These results suggest that ISO dual targeting Nur77 and AMPKα during adipogenesis represents a novel class of mechanism-based antiadipogenic agents for treatment of obesity and associated metabolic disorders, including hyperlipidemia and fatty liver.

Effect of CNTM on high‐fat diet‐induced obesity in C57BL/6J mice

Cirsium setidens Nakai, a wild perennial herb, grows mainly in Gangwon province, Korea, and it has been reported to contain bioactive ingredients with various medicinal activities including treat edema, bleeding and hemoptysis. In our previous studies have demonstrated that C. setidens nakai ethanolic extract had an anti‐adipogenic effect during the adipogenesis of 3T3‐L1 cells and beneficial effect on high‐fat diet (HFD)‐induced obesity in C57BL/6J mice. The purpose of this study describes a preliminary evaluation of the anti‐obesity activity on Cirsium setidens Nakai ethanolic extract containing test material (CNTM). Also, this study was to evaluate the effects of CNTM high‐fat diet‐induced obesity in C57BL/6J mice. To study for anti‐obesity agents effectively, we first examined the effect of CNTM on body weight gain and relative weight of the adipose tissue. In addition, we investigated the beneficial effect of CNTM on high‐fat diet (HFD)‐induced obesity in C57BL/6J mice. C57BL/6J mice were fed a high‐fat diet to induce obesity and were orally administered CNTM (160, 320 mg/kg) for 8 weeks. CNTM‐treated groups were reduced body weight, adipose tissue weight and improved serum lipid profiles and adiponectin protein expression in obese C57BL/6J mice fed a high‐fat diet. These results suggested that CNTM may have an anti‐obesity effect through the regulation of transcription factors related to adipogenesis, lipogenesis, and lipolysis. metabolism., hypertension, and diabetes. This study suggests that CNTM are potential candidates as anti‐obesity agents for treatment of obesity as non‐toxic natural resources.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of Baicalein on GLUT4 Translocation in Adipocytes of Diet-Induced Obese Mice

Background/Aims: Although baicalein has been shown to increase insulin sensitivity in liver of mice, there is no literature available about the effect of baicalein on glucose transporter 4 (GLUT4) translocation from intracellular membrane pools to plasma membranes in adipocytes of diet-induced obese mice. Methods: In the present study, the obese model was induced in mice fed a high fat diet (20% carbohydrates, 21% protein and 59% fat) for 16 weeks. The diet-induced obese mice were given 20mg/kg baicalein intraperitoneally (i.p.) once a day for 21 days. The plasma insulin was measured by enzyme-linked immunosorbent assay. Fasting blood glucose and insulin resistance indexes were measured by glucose tolerance test (GTT). The expression levels of PGC-1α, UCP1, GLUT4, PPARγ, pP38MAPK, pERK and pAKT in adipocytes were determined by quantitative real-time polymerase chain reaction and western blotting. Results: The present findings showed that administration of baicalein decreased pP38MAPK, pERK and PPARγ levels, but enhanced pAKT, PGC-1α and UCP1 contents as well as GLUT4 expression in adipocytes, and reversed high fat diet-induced glucose intolerance, hyperglycemia and insulin resistance in diet-induced obese mice. Moreover, baicalein treatment increased GLUT4 concentration in plasma membranes of adipocytes, i.e. baicalein may prevent insulin resistance through the GLUT4 translocation from intracellular membrane compartments to plasma membranes in adipocytes. Conclusion: These results suggest that baicalein is a powerful and promising agent for treatment of obesity and insulin resistance via Akt/GLUT4 pathway.

Capsaicin and capsiate could be appropriate agents for treatment of obesity: A meta-analysis of human studies

ABSTRACTConsumption of capsaicin or its nonpungent analogues, capsinoids has been reported to affect energy expenditure and fat oxidation, although available data are still controversial. The aim of the present study was to conduct a meta-analysis regarding the effects of these substances on energy expenditure and respiratory quotient, with special emphasis on the role of body mass index (BMI) of the participants. Medical databases were systematically searched for papers. Of the 627 trials identified, 9 provided results suitable to be included in analysis. Data analysis showed that after ingestion of capsaicin or capsinoids the energy expenditure increased (245 kJ/day, 58.56 kcal/day, p = 0.030) and the respiratory quotient decreased (by 0.216; p = 0.031) indicating a rise in fat oxidation. Studies with mean BMI of the participants below 25 kg/m2 failed to report any effect of capsaicin or capsinoids on the energy expenditure (p = 0.718) or on the respiratory quotient (p = 0.444), but studies with mean BMI exceeding 25 kg/m2 demonstrated an increase in energy expenditure (292 kJ/day, 69.79 kcal/day, p = 0.023) and a marked decrease in respiratory quotient (−0.257, p = 0.036). Our data clearly suggest that capsaicin or capsiate could be a new therapeutic approach in obesity promoting a negative energy balance and increased fat oxidation.

Baicalin against obesity and insulin resistance through activation of AKT/AS160/GLUT4 pathway

Obesity may cause several metabolic complications, including insulin resistance and type 2 diabetes mellitus. Despite great advances in medicine, people still keep exploring novel and effective drugs for treatment of obesity and insulin resistance. The aim of this study was to survey if baicalin might ameliorate obesity-induced insulin resistance and to explore its signal mechanisms in skeletal muscles of mice. Diet-induced obese (DIO) mice were given 50 mg/kg baicalin intraperitoneally (i.p.) once a day for 21 days, and C2C12 myotubes were treated with 100, 200, 400 μM baicalin for 12 h in this study. Then insulin resistance indexes and insulin signal protein levels in skeletal muscles were examined. We discovered that administration of baicalin decreased food intake, body weight, HOMA-IR and NT-PGC-1α levels, but enhanced GLUT4, PGC-1α, pP38MAPK, pAKT and pAS160 contents, as well as GLUT4 mRNA, PGC-1α mRNA, PPARγ mRNA, GLUT1 mRNA expression in skeletal muscles of obese mice and myotubes of C2C12 cells, and reversed high fat diet-induced glucose and insulin intolerance, hyperglycemia and insulin resistance in the mice. These results suggest that baicalin is a powerful and promising agent for treatment of obesity and insulin resistance via Akt/AS160/GLUT4 and P38MAPK/PGC1α/GLUT4 pathway.

3,5-Diiodo-L-thyronine (3,5-t2) exerts thyromimetic effects on hypothalamus-pituitary-thyroid axis, body composition, and energy metabolism in male diet-induced obese mice.

Effective and safe antiobesity drugs are still needed in face of the obesity pandemic worldwide. Recent interventions in rodents revealed 3,5-diiodo-L-thyronine (3,5-T2) as a metabolically active iodothyronine affecting energy and lipid metabolism without thyromimetic side effects typically associated with T3 administration. Accordingly, 3,5-T2 has been proposed as a potential hypolipidemic agent for treatment of obesity and hepatic steatosis. In contrast to other observations, our experiments revealed dose-dependent thyromimetic effects of 3,5-T2 akin to those of T3 in diet-induced obese male C57BL/6J mice. 3,5-T2 treatment exerted a negative feedback regulation on the hypothalamus-pituitary-thyroid axis, similar to T3. This is demonstrated by decreased expression of genes responsive to thyroid hormones (TH) in pituitary resulting in a suppressed thyroid function with lower T4 and T3 concentrations in serum and liver of 3,5-T2-treated mice. Analyses of hepatic TH target genes involved in lipid metabolism revealed T3-like changes in gene expression and increased type I-deiodinase activity after application of 3,5-T2 (2.5 μg/g body weight). Reduced hepatic triglyceride and serum cholesterol concentrations reflected enhanced lipid metabolism. Desired increased metabolic rate and reduction of different fat depots were, however, compromised by increased food intake preventing significant body weight loss. Moreover, enlarged heart weights indicate potential cardiac side effects of 3,5-T2 beyond hepatic thyromimetic actions. Altogether, the observed thyromimetic effects of 3,5-T2 in several mouse TH target tissues raise concern about indiscriminate administration of 3,5-T2 as powerful natural hormone for the treatment of hyperlipidemia and pandemic obesity.

Evidence for thyromimetic action of 3,5-T2 in diet-induced obese mice

The thyroid hormones (TH) L-thyroxine (T4) and 3,5,3'- triiodothyronine (T3) are strong modulators of energy homeostasis. TH exert their classical, non-acute effects on metabolic pathways through gene-specific modulation of transcriptional activity of T3 receptors (TR). Recent findings revealed 3,5-diiodo-L-thyronine (3,5-T2) as a metabolically active iodothyronine affecting energy and lipid metabolism without thyromimetic side effects as typically caused by T3. Accordingly, 3,5-T2 is proposed to be a potential hypolipidemic agent for treatment of obesity and its associated secondary diseases, especially in liver. The objective of the present study was to investigate if chronic 3,5-T2 treatment affects the HPT axis and liver energy and lipid metabolism in a pattern similar to T3. High fat diet-induced obese adult male mice received for 2 weeks a daily application of two different doses of 3,5-T2 (0.25 and 2.5 µg/g bw), T3 (0.03 µg/g bw) or saline. Treatment with 3,5-T2 led to a negative feedback regulation of the HPT axis, similar to T3 as demonstrated by decreased gene expression of Trhr, Dio2 and Tshb in pituitary resulting in a suppressed thyroid function as obvious from lower T4 levels in serum and liver. Analyses of hepatic TH target genes involved in lipid metabolism (e.g. Me1, Scd1, Cyp7a1) revealed changes in gene expression level after 2.5 µg/g bw of 3,5-T2 similar to T3 treatment. Besides enhanced hepatic mRNA level of nuclear respiratory factor 1 and mitochondrial transcription factor A an increase in protein expression of cytochrome c and cytochrome c oxidase IV indicates that 2.5 µg/g bw 3,5-T2, like T3, stimulates mitochondrial metabolism. The results show similar thyromimetic effects of 3,5-T2 and T3, suggesting that chronic 3,5-T2 action is mainly mediated by nuclear-based TR and 3,5-T2 mimics T3 action by interfering with the HPT axis and expression of T3-responsive genes.

A loop matters for FTO substrate selection

Recent studies have unequivocally established the link between FTO and obesity. FTO was biochemically shown to belong to the AlkB-like family DNA/RNA demethylase. However, FTO differs from other AlkB members in that it has unique substrate specificity and contains an extended C-terminus with unknown functions. Insight into the substrate selection mechanism and a functional clue to the C-terminus of FTO were gained from recent structural and biochemical studies. These data would be valuable to design FTO-specific inhibitors that can be potentially translated into therapeutic agents for treatment of obesity or obesity-related diseases.

Therapeutic potential of antiangiogenic agents for prevention and treatment of obesity

Accumulating evidence demonstrates that growing adipose tissues produce various pro-angiogenic factors, cytokines and adipokines, which induce neovascularization. Similar to malignant tissue growth, expansion of fat mass would not be achieved without switching on an angiogenic phenotype. Several recent studies using mouse genetic and high caloric diet-fed obese models validate this concept of preventing obesity by delivery of angiogenesis inhibitors. It is predicted, although it needs to be further proved, that antiangiogenic agents might be used either alone or in combinations with other existing therapeutic agents for the treatment of obesity. This review article focuses on discussing molecular mechanisms of angiogenesis in adipose tissues, defining vascular therapeutic targets, and employing antiangiogenic agents for prevention and treatment of obesity.

Can we prevent Parkinson’s disease with n-3 polyunsaturated fatty acids?

Accumulating evidence demonstrates that growing adipose tissues produce various proangiogenic factors, cytokines and adipokines, which induce neovascularization. Similar to malignant tissue growth, expansion of fat mass would not be achieved without switching on an angiogenic phenotype. Several recent studies using mouse genetic and high caloric diet-fed obese models validate this concept of preventing obesity by delivery of angiogenesis inhibitors. It is predicted, although it needs to be further proved, that antiangiogenic agents might be used either alone or in combinations with other existing therapeutic agents for the treatment of obesity. This review article focuses on discussing molecular mechanisms of angiogenesis in adipose tissues, defining vascular therapeutic targets, and employing antiangiogenic agents for prevention and treatment of obesity.