scholarly journals Leptin sensitizing effect of 1,3-butanediol and its potential mechanism

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Masayo Isoda ◽  
Ken Ebihara ◽  
Nagisa Sawayama ◽  
Akiko Murakami ◽  
Chihiro Ebihara ◽  
...  
Keyword(s):  
Er Stress ◽  
Ketone Bodies ◽  
Leptin Resistance ◽  
Therapeutic Effects ◽  
Potential Mechanism ◽  
Collateral Evidence ◽  
Obese Subjects ◽  
Treatment Of Obesity ◽  
Sensitizing Effect ◽  
Obesity Drugs

AbstractLeptin is an adipocyte-derived hormone that regulates appetite and energy expenditure via the hypothalamus. Since the majority of obese subjects are leptin resistant, leptin sensitizers, rather than leptin itself, are expected to be anti-obesity drugs. Endoplasmic reticulum (ER) stress in the hypothalamus plays a key role in the pathogenesis of leptin resistance. ATP-deficient cells are vulnerable to ER stress and ATP treatment protects cells against ER stress. Thus, we investigated the therapeutic effects of oral 1,3-butanediol (BD) administration, which increases plasma β-hydroxybutyrate and hypothalamic ATP concentrations, in diet induced obese (DIO) mice with leptin resistance. BD treatment effectively decreased food intake and body weight in DIO mice. In contrast, BD treatment had no effect in leptin deficient ob/ob mice. Co-administration experiment demonstrated that BD treatment sensitizes leptin action in both DIO and ob/ob mice. We also demonstrated that BD treatment attenuates ER stress and leptin resistance at the hypothalamus level. This is the first report to confirm the leptin sensitizing effect of BD treatment in leptin resistant DIO mice. The present study provides collateral evidence suggesting that the effect of BD treatment is mediated by the elevation of hypothalamic ATP concentration. Ketone bodies and hypothalamic ATP are the potential target for the treatment of obesity and its complications.

scholarly journals Leptin, Obesity, and Leptin Resistance: Where Are We 25 Years Later?

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2704 ◽  
Author(s):  
Andrea G. Izquierdo ◽  
Ana B. Crujeiras ◽  
Felipe F. Casanueva ◽  
Marcos C. Carreira
Keyword(s):  
Body Weight ◽  
Blood Brain Barrier ◽  
Clinical Utility ◽  
Molecular Mechanisms ◽  
Brain Barrier ◽  
Leptin Resistance ◽  
Blood Brain ◽  
Obese Subjects ◽  
Treatment Of Obesity ◽  
New Strategies

Leptin, a hormone that is capable of effectively reducing food intake and body weight, was initially considered for use in the treatment of obesity. However, obese subjects have since been found to have high levels of circulating leptin and to be insensitive to the exogenous administration of leptin. The inability of leptin to exert its anorexigenic effects in obese individuals, and therefore, the lack of clinical utility of leptin in obesity, is defined as leptin resistance. This phenomenon has not yet been adequately characterized. Elucidation of the molecular mechanisms underlying leptin resistance is of vital importance for the application of leptin as an effective treatment for obesity. Leptin must cross the blood–brain barrier (BBB) to reach the hypothalamus and exert its anorexigenic functions. The mechanisms involved in leptin transportation across the blood–brain barrier continue to be unclear, thereby preventing the clinical application of leptin in the treatment of obesity. In recent years, new strategies have been developed to recover the response to leptin in obesity. We have summarized these strategies in this review.

scholarly journals Therapeutic effects of Gambi-jung for the treatment of obesity

2021 ◽  
Vol 141 ◽  
pp. 111838
Author(s):  
Yea-Jin Park ◽  
Divina C. Cominguez ◽  
Hyo-Jung Kim ◽  
Jong-Sik Jin ◽  
Duck-jae Koh ◽  
...  
Keyword(s):  
Therapeutic Effects ◽  
Treatment Of Obesity

scholarly journals 3,3′-Diindolylmethane Suppresses the Growth of Hepatocellular Carcinoma by Regulating Its Invasion, Migration and ER Stress-Mediated Mitochondrial Apoptosis

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1178
Author(s):  
Suvesh Munakarmi ◽  
Juna Shrestha ◽  
Hyun-Beak Shin ◽  
Geum-Hwa Lee ◽  
Yeon-Jun Jeong
Keyword(s):  
Hepatocellular Carcinoma ◽  
Er Stress ◽  
Hepatoma Cell ◽  
Biologically Active ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Huh7 Cells ◽  
Anti Cancer

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide with limited treatment options. Biomarker-based active phenolic flavonoids isolated from medicinal plants might shed some light on potential therapeutics for treating HCC. 3,3′-diindolylmethane (DIM) is a unique biologically active dimer of indole-3-carbinol (I3C), a phytochemical compound derived from Brassica species of cruciferous vegetables—such as broccoli, kale, cabbage, and cauliflower. It has anti-cancer effects on various cancers such as breast cancer, prostate cancer, endometrial cancer, and colon cancer. However, the molecular mechanism of DIM involved in reducing cancer risk and/or enhancing therapy remains unknown. The aim of the present study was to evaluate anti-cancer and therapeutic effects of DIM in human hepatoma cell lines Hep3B and HuhCell proliferation was measured with MTT and trypan blue colony formation assays. Migration, invasion, and apoptosis were measured with Transwell assays and flow cytometry analyses. Reactive oxygen species (ROS) intensity and the loss in mitochondrial membrane potential of Hep3B and Huh7 cells were determined using dihydroethidium (DHE) staining and tetramethylrhodamine ethyl ester dye. Results showed that DIM significantly suppressed HCC cell growth, proliferation, migration, and invasion in a concentration-dependent manner. Furthermore, DIM treatment activated caspase-dependent apoptotic pathway and suppressed epithelial–mesenchymal transition (EMT) via ER stress and unfolded protein response (UPR). Taken together, our results suggest that DIM is a potential anticancer drug for HCC therapy by targeting ER-stress/UPR.

scholarly journals Pharmacological treatment of obesity

2006 ◽  
Vol 50 (2) ◽  
pp. 377-389 ◽  
Author(s):  
Marcio C. Mancini ◽  
Alfredo Halpern
Keyword(s):  
Insulin Resistance ◽  
Pharmacological Treatment ◽  
Energy Homeostasis ◽  
Extensive Review ◽  
Obesity Management ◽  
Physiological Mechanisms ◽  
Triggering Factor ◽  
Treatment Of Obesity ◽  
Obesity Drugs ◽  
Cannabinoid Agonist

This review offers an overview of physiological agents, current therapeutics, as well as medications, which have been extensively used and those agents not currently available or non-classically considered anti-obesity drugs. As obesity - particularly that of central distribution - represents an important triggering factor for insulin resistance, its pharmacological treatment is relevant in the context of metabolic syndrome control. The authors present an extensive review on the criteria for anti-obesity management efficacy, on physiological mechanisms that regulate central and/or peripheral energy homeostasis (nutrients, monoamines, and peptides), on beta-phenethylamine pharmacological derivative agents (fenfluramine, dexfenfluramine, phentermine and sibutramine), tricyclic derivatives (mazindol), phenylpropanolamine derivatives (ephedrin, phenylpropanolamine), phenylpropanolamine oxytrifluorphenyl derivative (fluoxetine), a naftilamine derivative (sertraline) and a lipstatine derivative (orlistat). An analysis of all clinical trials - over ten-week long - is also presented for medications used in the management of obesity, as well as data about future medications, such as a the inverse cannabinoid agonist, rimonabant.

Caffeine attenuated ER stress-induced leptin resistance in neurons

2014 ◽  
Vol 569 ◽  
pp. 23-26 ◽  
Author(s):  
Toru Hosoi ◽  
Keisuke Toyoda ◽  
Kanako Nakatsu ◽  
Koichiro Ozawa
Keyword(s):  
Er Stress ◽  
Leptin Resistance

Role of impulsivity and reward in the anti-obesity actions of 5-HT2C receptor agonists

2017 ◽  
Vol 31 (11) ◽  
pp. 1403-1418 ◽  
Author(s):  
Guy A Higgins ◽  
Fiona D Zeeb ◽  
Paul J Fletcher
Keyword(s):  
Lifestyle Modification ◽  
Conditioned Reward ◽  
Receptor Agonists ◽  
Subsequent Phase ◽  
Obese Subjects ◽  
Clinically Significant ◽  
Treatment Of Obesity ◽  
Phase Ii And Iii ◽  
Modest Effect

The selective 5-HT2C receptor agonist lorcaserin entered clinical obesity trials with the prevalent view that satiety was a primary mechanism of action. Subsequent Phase II and III trials demonstrated efficacy in terms of weight loss, although the overall effect size (~3% placebo-corrected change) is considered modest. Lorcaserin has been approved by the FDA for the treatment of obesity with lifestyle modification, but since its introduction in 2013 its sales are in decline, probably due to its overall modest effect. However, in some individuals, lorcaserin has a much more clinically significant effect (i.e. >10% placebo-corrected change), although what common features, if any, define these high responders is presently unknown. In the present article we highlight the evidence that alternative mechanisms to satiety may contribute to the anti-obesity effect of lorcaserin, namely effects on constructs of primary and conditioned reward and impulsivity. This may better inform the clinical evaluation of lorcaserin (and any future 5-HT2C receptor agonists) to subgroups of obese subjects characterized by overeating due to maladaptive impulsivity and reward mechanisms. One such population might be individuals diagnosed with binge eating disorder.

scholarly journals Phlorotannins from Ecklonia cava Attenuates Palmitate-Induced Endoplasmic Reticulum Stress and Leptin Resistance in Hypothalamic Neurons

Marine Drugs ◽  
2019 ◽  
Vol 17 (10) ◽  
pp. 570 ◽  
Author(s):  
Seyeon Oh ◽  
Myeongjoo Son ◽  
Junwon Choi ◽  
Chang Hu Choi ◽  
Kook Yang Park ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Leptin Receptor ◽  
Saturated Fatty Acids ◽  
Receptor Expression ◽  
Leptin Resistance ◽  
Ecklonia Cava ◽  
Hypothalamic Neurons ◽  
Potent Effect ◽  
Stress Markers

Leptin resistance in the hypothalamus has an essential role in obesity. Saturated fatty acids such as palmitate bind to Toll-like receptor 4 (TLR4) and lead to endoplasmic reticulum (ER) stress and leptin resistance. In this study, we evaluated whether extracts of Ecklonia cava would attenuate the ER stress induced by palmitate and reduce leptin resistance in hypothalamic neurons and microglia. We added palmitate to these cells to mimic the environment induced by high-fat diet in the hypothalamus and evaluated which of the E. cava phlorotannins—dieckol (DK), 2,7-phloroglucinol-6,6-bieckol (PHB), pyrogallol-phloroglucinol-6,6-bieckol (PPB), or phlorofucofuroeckol-A (PFFA)—had the most potent effect on attenuating leptin resistance. TLR4 and NF-κB expression induced by palmitate was attenuated most effectively by PPB in both hypothalamic neurons and microglia. ER stress markers were increased by palmitate and were attenuated by PPB in both hypothalamic neurons and microglia. Leptin resistance, which was evaluated as an increase in SOCS3 and a decrease in STAT3 with leptin receptor expression, was increased by palmitate and was decreased by PPB in hypothalamic neurons. The culture medium from palmitate-treated microglia increased leptin resistance in hypothalamic neurons and this resistance was attenuated by PPB. In conclusion, PPB attenuated leptin resistance by decreasing ER stress in both hypothalamic neurons and microglia.

scholarly journals Oxytocin Administration Alleviates Acute but Not Chronic Leptin Resistance of Diet-Induced Obese Mice

2018 ◽  
Vol 20 (1) ◽  
pp. 88 ◽  
Author(s):  
Mehdi Labyb ◽  
Chloé Chrétien ◽  
Aurélie Caillon ◽  
Françoise Rohner-Jeanrenaud ◽  
Jordi Altirriba
Keyword(s):  
Body Weight ◽  
Weight Gain ◽  
Food Intake ◽  
Body Weight Gain ◽  
Leptin Resistance ◽  
Obese Mice ◽  
Short Term ◽  
Continuous Administration ◽  
Pre Treatment ◽  
Treatment Of Obesity

Whereas leptin administration only has a negligible effect on the treatment of obesity, it has been demonstrated that its action can be improved by co-administration of leptin and one of its sensitizers. Considering that oxytocin treatment decreases body weight in obese animals and humans, we investigated the effects of oxytocin and leptin cotreatment. First, lean and diet-induced obese (DIO) mice were treated with oxytocin for 2 weeks and we measured the acute leptin response. Second, DIO mice were treated for 2 weeks with saline, oxytocin (50 μg/day), leptin (20 or 40 µg/day) or oxytocin plus leptin. Oxytocin pre-treatment restored a normal acute leptin response, decreasing food intake and body weight gain. Chronic continuous administration of oxytocin or leptin at 40 µg/day decreased body weight in the presence (leptin) or in the absence (oxytocin) of cumulative differences in food intake. Saline or leptin treatment at 20 µg/day had no impact on body weight. Oxytocin and leptin cotreatments had no additional effects compared with single treatments. These results point to the fact that chronic oxytocin treatment improves the acute, but not the chronic leptin response, suggesting that this treatment could be used to improve the short-term satiety effect of leptin.

scholarly journals Obesity changes the human gut mycobiome

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
M. Mar Rodríguez ◽  
Daniel Pérez ◽  
Felipe Javier Chaves ◽  
Eduardo Esteve ◽  
Pablo Marin-Garcia ◽  
...  
Keyword(s):  
Hdl Cholesterol ◽  
Caproic Acid ◽  
Fungal Species ◽  
Human Gut ◽  
Body Fatness ◽  
Diverse Range ◽  
Obese Subjects ◽  
Metabolically Healthy ◽  
Treatment Of Obesity ◽  
Novel Target

Abstract The human intestine is home to a diverse range of bacterial and fungal species, forming an ecological community that contributes to normal physiology and disease susceptibility. Here, the fungal microbiota (mycobiome) in obese and non-obese subjects was characterized using Internal Transcribed Spacer (ITS)-based sequencing. The results demonstrate that obese patients could be discriminated by their specific fungal composition, which also distinguished metabolically “healthy” from “unhealthy” obesity. Clusters according to genus abundance co-segregated with body fatness, fasting triglycerides and HDL-cholesterol. A preliminary link to metabolites such as hexadecanedioic acid, caproic acid and N-acetyl-L-glutamic acid was also found. Mucor racemosus and M. fuscus were the species more represented in non-obese subjects compared to obese counterparts. Interestingly, the decreased relative abundance of the Mucor genus in obese subjects was reversible upon weight loss. Collectively, these findings suggest that manipulation of gut mycobiome communities might be a novel target in the treatment of obesity.

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