Ilex paraguariensis modulates fat metabolism in Caenorhabditis elegans through purinergic system (ADOR-1) and nuclear hormone receptor (NHR-49) pathways

Abstract

Ilex paraguariensis is a well-known plant that is widely consumed in South America, primarily as a drink called mate. Mate is described to have stimulant and medicinal properties. Considering the potential anti-lipid effects of I. paraguariensis infusion, we used an extract of this plant as a possible modulator of fat storage to control lipid metabolism in worms. Herein, the I. paraguariensis-dependent modulation of fat metabolism in Caenorhabditis elegans was investigated. C. elegans were treated with I. paraguariensis aqueous extract (1 mg/ml) from L1 larvae stage until adulthood, to simulate the primary form of consumption. Expression of adipocyte triglyceride lipase 1 (ATGL-1) and heat shock protein 16.2, lipid accumulation through C1-BODIPY-C12 (BODIPY) lipid staining, behavioral parameters, body length, total body energy expenditure and overall survival were analyzed. Total body energy expenditure was determined by the oxygen consumption rate in N2, nuclear hormone receptor knockout, nhr-49(nr2041), and adenosine receptor knockout, ador-1(ox489) strains. Ilex paraguariensis extract increased ATGL-1 expression 20.06% and decreased intestinal BODIPY fat staining 63.36%, compared with the respective control group, without affecting bacterial growth and energetic balance, while nhr-49(nr2041) and ador-1(ox489) strains blocked the worm fat loss. In addition, I. paraguariensis increased the oxygen consumption in N2 worms, but not in mutant strains, increased N2 worm survival following juglone exposure, and did not alter hsp-16.2 expression. We demonstrate for the first time that I. paraguariensis can decrease fat storage and increase body energy expenditure in worms. These effects depend on the purinergic system (ADOR-1) and NHR-49 pathways. Ilex paraguariensis upregulated the expression of ATGL-1 to modulate fat metabolism. Furthermore, our data corroborates with other studies that demonstrate that C. elegans is a useful tool for studies of fat metabolism and energy consumption.

Fat-lowering effects of isorhamnetin are via NHR-49-dependent pathway in Caenorhabditis elegans

“…Previously, it was reported that fenofibrate had lipolytic effects via PPARα-ATGL pathway in muscle tissue in rats ( Biswas et al., 2016 ). Consistently, yerba mate tea extract reduced fat accumulation via NHR-49-dependent pathway with the upregulation of atgl-1 in C. elegans ( Machado et al., 2018 ). Therefore, the lipolytic effects of isorhamnetin, particularly via atgl-1 upregulation, may contribute for its fat-lowering effects in C. elegans .…”

“…The lipases, atgl-1 (a homolog of the human adipose triglyceride lipase or patatin-like phospholipase domain-containing protein 2, PNPLA2) and hosl-1 (a homolog of the human hormone-sensitive lipase E, LIPE), are targets for anti-obesity agents due to their effects on lipolysis ( Farias-Pereira et al., 2018 , Liu et al., 2018 , Machado et al., 2018 ). Treatment of 200 μM isorhamnetin upregulated atgl-1 expression by 27% ( P = 0.0211), while hosl-1 expression was upregulated only by 6% in the 100 μM isorhamnetin-treated worms ( P = 0.0106) compared to the control ( Fig.…”

“…The anti-obesity mechanisms of action of dietary bioactives and plant extracts on lipid metabolism have various molecular targets in C. elegans ( Farias-Pereira et al., 2018 , Lin et al., 2019 , Liu et al., 2018 , Machado et al., 2018 , Shen et al., 2017 , Shen et al., 2018c , Sun et al., 2016 , Yue et al., 2019 ). It was reported that the inhibitory effects of NHR-49 on fatty acid desaturases (lipogenesis) were related to the fat-lowering effects of a saponin extract in C. elegans ( Lin et al., 2019 ).…”

“…Human lipid metabolism pathways are conserved in C. elegans , which help to identify the mechanisms of action of food components prior to vertebrate animals and/or humans ( Shen et al., 2018a , Shen et al., 2018b ). Previously, studies have examined the anti-obesity effects of plant extracts and food bioactive components in C. elegans , showing the relevance of this animal model for the mechanistic studies of prospective bioactives ( Bhattacharya et al., 2013 , Farias-Pereira et al., 2018 , Farias-Pereira et al., 2020 , Lin et al., 2019 , Liu et al., 2018 , Machado et al., 2018 , Shen et al., 2017 , Shen et al., 2018a , Shen et al., 2018b , Shen et al., 2018c , Sun et al., 2016 , Yue et al., 2019 ). Thus, the goal of this study was to determine the effects of isorhamnetin on lipid metabolism by using C. elegans as an animal model.…”

Application of Caenorhabditis elegans in Lipid Metabolism Research

“…This method preserves the worm’s anatomy and the native morphology of LDs but also allows for the quantification of the fat content per volume at the individual-worm level, facilitating the accurate screenings of fat storage mutants [ 163 ]. Several studies have used BODIPY-labeled FAs in nematode models to probe the fatty acid uptake and identify regulators of the fat mass [ 164 , 165 , 166 , 167 ]. Recently, many efficient probes labeling lipids such as benzothieno [7,6-b]-fused BODIPYs have been designed and synthesized for live cell imaging [ 168 , 169 , 170 ].…”