A new use for old drugs: identifying compounds with an anti-obesity effect using a high through-put semi-automated Caenorhabditis elegans screening platform

Haerkens, Freek; Kikken, Charlotte; Kirkels, Laurens A. M. H.; Amstel, Monique van; Wouters, Willemijn; Doornmalen, Els van; Francke, Christof; Hughes, Sam

doi:10.1016/j.heliyon.2022.e10108

Cited by 5 publications

(5 citation statements)

References 65 publications

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“…Therefore, they can be applied in epidemiology to make up for the limitations of traditional epidemiology [ 41 ]. Moreover, they can be used to study reproductive toxicity [ 42 ], germ cell mutagenicity [ 43 ], lipid metabolism and obesity metabolic disruption [ 44 , 45 ], degenerative neurological diseases [ 46 ], aging process acceleration [ 47 ], and Alzheimer’s disease genetic research [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

Toxicity of Per- and Polyfluoroalkyl Substances to Nematodes

Pan

Wang

et al. 2023

Toxics

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Per- and polyfluoroalkyl substances (PFASs) are a class of compounds that persist in the environment globally. Besides being transported to the soil and sediments, which act as their sinks, PFASs can be transferred to several species of higher organisms directly or via bacteria, eliciting a wide range of adverse effects. Caenorhabditis elegans has been widely used in toxicological studies and life science research owing to its numerous advantages over traditional vertebrate models; notably, C. elegans has 65% conserved human-disease-associated genes and does not require ethical approvals for experimental use. This review covers a range of topics, from reported accumulation characteristics and lethal concentrations of PFAS in C. elegans to the mechanisms underlying the toxicity of PFAS at different levels, including reproductive, developmental, cellular, neurologic, oxidative, metabolic, immune, and endocrine toxicities. Additionally, the toxicity levels of some PFAS substitutes are summarized. Lastly, we discuss the toxicological mechanisms of these PFAS substitutes and the importance and promising potential of nematodes as in vivo models for life science research, epidemiological studies (obesity, aging, and Alzheimer’s disease research), and toxicological investigations of PFASs and other emerging pollutants compared with other soil animals or model organisms.

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Section: Discussionmentioning

confidence: 99%

Toxicity of Per- and Polyfluoroalkyl Substances to Nematodes

Pan

Wang

et al. 2023

Toxics

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“…Fasting, dietary restriction, and calorie restriction exemplify variants of weightreduction strategies that have been proven to further mitigate inflammation associated with obesity, and to contribute to enhanced metabolism and overall well-being [5,12,45]. During calorie restriction, several vital metabolic sensors such as AMPK and SIRT1 are modulated to increase energy expenditure by mobilizing and oxidizing lipids [24,45,46]. However, for the majority of individuals diagnosed with obesity, altering dietary patterns alone may not be sufficient for significant weight reduction.…”

Section: Discussionmentioning

confidence: 99%

“…For the following experiments, a standard hypochlorite bleaching method of gravid adults was used to obtain an age-synchronized worm population [21,[23][24][25][26][27]. Next, the nematodes were maintained on NGM plates supplemented with 2% glucose to model increased lipid accumulation [18,26,27].…”

Section: Caenorhabditis Elegans Maintenance and Treatmentmentioning

confidence: 99%

“…The functionally conserved genes involved in lipid and carbohydrate metabolism between C. elegans and mammals play a crucial role in obesity research [22,23]. The high extent of homology between key human energy regulators such as AMP-activated protein kinase (AMPK), sirtuins (SIRT1), SREBPs, PPARs, and PPAR-gamma coactivator 1 alpha (PGC-1α), and those in C. elegans-AAK-1/-2, SIR2.1, SBP-1, NHR-49, and MDT-15, respectively, provides additional rationale for a deep mechanistic investigation of the modulation of lipid metabolism [24][25][26][27]. Furthermore, it has been described that AAK-2 stimulates lipid mobilization in C. elegans [7,21,26].…”

Section: Introductionmentioning

confidence: 99%

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Maackiain Mimics Caloric Restriction through aak-2-Mediated Lipid Reduction in Caenorhabditis elegans

Mladenova,

Todorova,

Savova

et al. 2023

IJMS

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Obesity prevalence is becoming a serious global health and economic issue and is a major risk factor for concomitant diseases that worsen the quality and duration of life. Therefore, the urgency of the development of novel therapies is of a particular importance. A previous study of ours revealed that the natural pterocarpan, maackiain (MACK), significantly inhibits adipogenic differentiation in human adipocytes through a peroxisome proliferator-activated receptor gamma (PPARγ)-dependent mechanism. Considering the observed anti-adipogenic potential of MACK, we aimed to further elucidate the molecular mechanisms that drive its biological activity in a Caenorhabditis elegans obesity model. Therefore, in the current study, the anti-obesogenic effect of MACK (25, 50, and 100 μM) was compared to orlistat (ORST, 12 μM) as a reference drug. Additionally, the hybrid combination between the ORST (12 μM) and MACK (100 μM) was assessed for suspected synergistic interaction. Mechanistically, the observed anti-obesogenic effect of MACK was mediated through the upregulation of the key metabolic regulators, namely, the nuclear hormone receptor 49 (nhr-49) that is a functional homologue of the mammalian PPARs and the AMP-activated protein kinase (aak-2/AMPK) in C. elegans. Collectively, our investigation indicates that MACK has the potential to limit lipid accumulation and control obesity that deserves future developments.

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“…In line with these principles, the utilization of lower-order organisms, such as the nematode Caenorhabditis elegans , can serve as a valuable tool for pharmacological assessments of anti-obesity agents. 7 This approach allows for initial screening and evaluation of drug efficacy prior to advancing to more complex animal models.…”

Section: Dear Editormentioning

confidence: 99%