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Trends in Obesity Research and Anti-Obesity Therapeutics

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Pharmacokinetics and Pharmacodynamics".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 21085

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Special Issue Editors

Prof. Dr. Han-Joo Maeng

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Guest Editor

College of Pharmacy, Gachon University, 191 Hambakmoe-ro, Yeonsu-gu, Incheon 21936, Republic of Korea
Interests: pharmacokinetics; biopharmaceutics; absorption; drug transporters; metabolic enzymes; drug delivery; nanoparticles
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Kwang-Hoon Chun

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Guest Editor

College of Pharmacy, Gachon University, Incheon 21936, Korea
Interests: obesity; adipocyte differentiation; target identification; drug development; gene expression

Special Issue Information

Dear Colleagues,

The obese population is increasing rapidly worldwide. In 2016, more than 1.9 billion adults were overweight, of which more than 650 million were obese.

Obesity is a main cause of cardiovascular disease, diabetes, musculoskeletal disease, and some types of cancer. The increase in obesity reduces quality of life and increases medical and social costs. In order to solve these problems, the prevention of obesity and the development of effective novel drug treatments are essential. On the other hand, safe and effective surgical and drug treatment methods for obesity have not been established so far. Currently, intensive studies are being conducted for the understanding of the cause and mechanism in developing obesity and the approaches for its prevention and treatment.

This Special Issue focuses on the latest research on the identification of molecular targets, nutritional and environmental factors causing obesity, and the development of various pharmacotherapeutics including small molecules, biologics, and cell therapy and their pharmacological, pharmacokinetics and formulation studies.

Prof. Dr. Han-Joo Maeng
Prof. Dr. Kwang-Hoon Chun
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

obesity
adipose tissue
obesity genes
anti-obesity drugs
post-transcriptional regulations
pharmacotherapeutics

Published Papers (6 papers)

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Research

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16 pages, 2369 KiB

Open AccessArticle

l-Arginine Induces White Adipose Tissue Browning—A New Pharmaceutical Alternative to Cold

by Andjelika Kalezic, Aleksandra Korac, Bato Korac and Aleksandra Jankovic

Pharmaceutics 2022, 14(7), 1368; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14071368 - 28 Jun 2022

Viewed by 3018

Abstract

The beneficial effects of l-arginine supplementation in obesity and type II diabetes involve white adipose tissue (WAT) reduction and increased substrate oxidation. We aimed to test the potential of l-arginine to induce WAT browning. Therefore, the molecular basis of browning was investigated in retroperitoneal WAT (rpWAT) of rats exposed to cold or treated with 2.25% l-arginine for 1, 3, and 7 days. Compared to untreated control, levels of inducible nitric oxide (NO) synthase protein expression and NO signaling increased in both cold-exposed and l-arginine-treated groups. These increases coincided with the appearance of multilocular adipocytes and increased expression levels of uncoupling protein 1 (UCP1), thermogenic and beige adipocyte-specific genes (Cidea, Cd137, and Tmem26), mitochondriogenesis markers (peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α, mitochondrial DNA copy number), nuclear respiratory factor 1, PPARα and their respective downstream lipid oxidation enzymes after l-arginine treatment. Such browning phenotype in the l-arginine-treated group was concordant with end-course decreases in leptinaemia, rpWAT mass, and body weight. In conclusion, l-arginine mimics cold-mediated increases in NO signaling in rpWAT and induces molecular and structural fingerprints of rpWAT browning. The results endorse l-arginine as a pharmaceutical alternative to cold exposure, which could be of great interest in obesity and associated metabolic diseases. Full article

(This article belongs to the Special Issue Trends in Obesity Research and Anti-Obesity Therapeutics)

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19 pages, 3197 KiB

Open AccessArticle

Ginsenoside Compound K Protects against Obesity through Pharmacological Targeting of Glucocorticoid Receptor to Activate Lipophagy and Lipid Metabolism

by Siwen Yang, Ting Liu, Chenxing Hu, Weili Li, Yuhan Meng, Haiyang Li, Chengcheng Song, Congcong He, Yifa Zhou and Yuying Fan

Pharmaceutics 2022, 14(6), 1192; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14061192 - 02 Jun 2022

Cited by 10 | Viewed by 2165

Abstract

(1) Background: The glucocorticoid receptor (GR) plays a key role in lipid metabolism, but investigations of GR activation as a potential therapeutic approach have been hampered by a lack of selective agonists. Ginsenoside compound K (CK) is natural small molecule with a steroid-like structure that offers a variety of therapeutic benefits. Our study validates CK as a novel GR agonist for the treatment of obesity. (2) Methods: By using pulldown and RNA interference, we determined that CK binds to GR. The anti-obesity potential effects of CK were investigated in obese mice, including through whole-body energy homeostasis, glucose and insulin tolerance, and biochemical and proteomic analysis. Using chromatin immunoprecipitation, we identified GR binding sites upstream of lipase ATGL. (3) Results: We demonstrated that CK reduced the weight and blood lipids of mice more significantly than the drug Orlistat. Proteomics data showed that CK up-regulated autophagy regulatory proteins, enhanced fatty acid oxidation proteins, and decreased fatty acid synthesis proteins. CK induced lipophagy with the initial formation of the phagophore via AMPK/ULK1 activation. However, a blockade of autophagy did not disturb the increase in CK on lipase expression, suggesting that autophagy and lipase are independent pathways in the function of CK. The pulldown and siRNA experiments showed that GR is the critical target. After binding to GR, CK not only activated lipophagy, but also promoted the binding of GR to the ATGL promoter. (4) Conclusions: Our findings indicate that CK is a natural food candidate for reducing fat content and weight. Full article

(This article belongs to the Special Issue Trends in Obesity Research and Anti-Obesity Therapeutics)

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18 pages, 3083 KiB

Open AccessArticle

Pentamethylquercetin Regulates Lipid Metabolism by Modulating Skeletal Muscle-Adipose Tissue Crosstalk in Obese Mice

by Jianzhao Wu, Jingxia Du, Zhi Li, Wei He, Min Wang, Manwen Jin, Lei Yang and Hui Liu

Pharmaceutics 2022, 14(6), 1159; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14061159 - 29 May 2022

Cited by 4 | Viewed by 2430

Abstract

Irisin is an exercise-induced hormone that regulates lipid metabolism. The present study investigates whether the anti-obesity effect of the natural flavonoid pentamethylquercetin (PMQ) is related to irisin secretion from skeletal muscle in whole animals and cultured cells. Obese mice induced by monosodium glutamate were administered oral PMQ to determine blood irisin level and in vivo parameters of lipid metabolism, and cultured mouse C2C12 myoblasts and 3T3-L1 preadipocytes were employed to investigate the related molecular identities. PMQ increased circulating irisin and decreased bodyweight, insulin, and lipid levels accompanied with increasing brown-like adipocyte formation in obese mice. The brown adipocyte marker uncoupling protein 1 (UCP-1) and other brown-like adipocyte-specific genes and/or markers were increased in mouse white fat tissue, while PMQ treatment reversed the above changes. PMQ also dose-dependently increased the reduced levels of AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), and fibronectin type III domain-containing 5 (FNDC5) signal molecules in obese mice. Interestingly, the irisin level was increased in the culture medium of C2C12 cells treated with PMQ, and the conditioned medium stimulated the brown-like transition of 3T3-L1 preadipocytes with the increased expression of PGC-1α, FNDC5, UCP-1, and other brown-like adipocyte-specific genes. The effects of conditioned culture medium were abolished in C2C12 cells with silenced PGC-1α. On the other hand, PMQ-induced upregulation of PGC-1α and FNDC5 expression was reduced by AMPK inhibitor Compound C in C2C12 cells. Our results demonstrate the novel information that PMQ-induced irisin secretion from skeletal muscle involves the improvement of metabolic dysfunction in obese mice via activating the AMPK/PGC-1α/FNDC5 signal pathway, suggesting that PMQ modulates skeletal muscle-adipose tissue crosstalk and may be a promising drug candidate for treating obesity and obesity-related metabolic diseases. Full article

(This article belongs to the Special Issue Trends in Obesity Research and Anti-Obesity Therapeutics)

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13 pages, 2029 KiB

Open AccessArticle

Acute Inflammation Is a Predisposing Factor for Weight Gain and Insulin Resistance

by Edson Mendes de Oliveira, Jacqueline C. Silva, Thais P. Ascar, Silvana Sandri, Alexandre F. Marchi, Silene Migliorini, Helder T. I. Nakaya, Ricardo A. Fock and Ana Campa

Pharmaceutics 2022, 14(3), 623; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14030623 - 11 Mar 2022

Cited by 4 | Viewed by 2304

Abstract

In the course of infection and intense endotoxemia processes, induction of a catabolic state leading to weight loss is observed in mice and humans. However, the late effects of acute inflammation on energy homeostasis, regulation of body weight and glucose metabolism are yet to be elucidated. Here, we addressed whether serial intense endotoxemia, characterized by an acute phase response and weight loss, could be an aggravating or predisposing factor to weight gain and associated metabolic complications. Male Swiss Webster mice were submitted to 8 consecutive doses of lipopolysaccharide (10 mg/kg LPS), followed by 10 weeks on a high-fat diet (HFD). LPS-treated mice did not show changes in weight when fed standard chow. However, when challenged by a high-fat diet, LPS-treated mice showed greater weight gain, with larger fat depot areas, increased serum leptin and insulin levels and impaired insulin sensitivity when compared to mice on HFD only. Acute endotoxemia caused a long-lasting increase in mRNA expression of inflammatory markers such as TLR-4, CD14 and serum amyloid A (SAA) in the adipose tissue, which may represent the key factors connecting inflammation to increased susceptibility to weight gain and impaired glucose homeostasis. In an independent experimental model, and using publicly available microarray data from adipose tissue from mice infected with Gram-negative bacteria, we performed gene set enrichment analysis and confirmed upregulation of a set of genes responsible for cell proliferation and inflammation, including TLR-4 and SAA. Together, we showed that conditions leading to intense and recurring endotoxemia, such as common childhood bacterial infections, may resound for a long time and aggravate the effects of a western diet. If confirmed in humans, infections should be considered an additional factor contributing to obesity and type 2 diabetes epidemics. Full article

(This article belongs to the Special Issue Trends in Obesity Research and Anti-Obesity Therapeutics)

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14 pages, 23068 KiB

Open AccessArticle

Palmitoylethanolamide Promotes White-to-Beige Conversion and Metabolic Reprogramming of Adipocytes: Contribution of PPAR-α

by Chiara Annunziata, Claudio Pirozzi, Adriano Lama, Martina Senzacqua, Federica Comella, Antonella Bordin, Anna Monnolo, Alessandra Pelagalli, Maria Carmela Ferrante, Maria Pina Mollica, Angelo Iossa, Elena De Falco, Giuseppina Mattace Raso, Saverio Cinti, Antonio Giordano and Rosaria Meli

Pharmaceutics 2022, 14(2), 338; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14020338 - 31 Jan 2022

Cited by 9 | Viewed by 5400

Abstract

The potential role of brown and beige adipose tissue against obesity has been recognized. Browning, or beiging of white adipose tissue (WAT) is associated with the remodeling of adipocytes and the improvement of their metabolic and secretory functions. Here, palmitoylethanolamide (PEA) restore the plasticity of brown and white adipocytes impaired in mice on a high-fat diet (HFD). Young male C57Bl/6J mice were fed with control (STD) diet or HFD for 12 weeks. Ultramicronized PEA (30 mg/kg/die p.o.) was administered for an additional 7 weeks, together with HFD. PEA recovered interscapular brown fat morphology and function, increasing UCP1 positivity, noradrenergic innervation, and inducing the mRNA transcription of several specialized thermogenic genes. PEA promotes the beige-conversion of the subcutaneous WAT, increasing thermogenic markers and restoring leptin signaling and tissue hormone sensitivity. The pivotal role of lipid-sensing peroxisome proliferator-activated receptor (PPAR)-α in PEA effects was determined in mature 3T3-L1. Moreover, PEA improved mitochondrial bioenergetics in mature adipocytes measured by a Seahorse analyzer and induced metabolic machinery via AMPK phosphorylation. All these outcomes were dampened by the receptor antagonist GW6471. Finally, PEA induced adipogenic differentiation and increased AMPK phosphorylation in human adipose-derived stromal cells (ASCs) obtained from subcutaneous WAT of normal-weight patients and patients with obesity. We identify PEA and PPAR-α activation as the main mechanism by which PEA can rewire energy-storing white into energy-consuming brown-like adipocytes via multiple and converging effects that restore WAT homeostasis and metabolic flexibility. Full article

(This article belongs to the Special Issue Trends in Obesity Research and Anti-Obesity Therapeutics)

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Review

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26 pages, 1804 KiB

Open AccessReview

Biomaterial-Based Therapeutic Strategies for Obesity and Its Comorbidities

by Jing Li, Hongli Duan, Yan Liu, Lu Wang and Xing Zhou

Pharmaceutics 2022, 14(7), 1445; https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics14071445 - 11 Jul 2022

Cited by 8 | Viewed by 4873

Abstract

Obesity is a global public health issue that results in many health complications or comorbidities, including type 2 diabetes mellitus, cardiovascular disease, and fatty liver. Pharmacotherapy alone or combined with either lifestyle alteration or surgery represents the main modality to combat obesity and its complications. However, most anti-obesity drugs are limited by their bioavailability, target specificity, and potential toxic effects. Only a handful of drugs, including orlistat, liraglutide, and semaglutide, are currently approved for clinical obesity treatment. Thus, there is an urgent need for alternative treatment strategies. Based on the new revelation of the pathogenesis of obesity and the efforts toward the multi-disciplinary integration of materials, chemistry, biotechnology, and pharmacy, some emerging obesity treatment strategies are gradually entering the field of preclinical and clinical research. Herein, by analyzing the current situation and challenges of various new obesity treatment strategies such as small-molecule drugs, natural drugs, and biotechnology drugs, the advanced functions and prospects of biomaterials in obesity-targeted delivery, as well as their biological activities and applications in obesity treatment, are systematically summarized. Finally, based on the systematic analysis of biomaterial-based obesity therapeutic strategies, the future prospects and challenges in this field are proposed. Full article

(This article belongs to the Special Issue Trends in Obesity Research and Anti-Obesity Therapeutics)

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