Abstract
Background
The global rise in obesity and type 2 diabetes highlights the need for safe and effective therapeutic interventions. Enhalus acoroides is a tropical seagrass rich in carotenoids and other bioactives. Its potential for metabolic regulation has been suggested in vitro, but in vivo efficacy and molecular mechanisms remain unexplored. This study aimed to evaluate the anti-obesity and anti-diabetic effects of Enhalus acoroides extract (SEAE) in a zebrafish model of diet- and glucose-induced metabolic dysfunction.
Methods
Adult zebrafish were subjected to overfeeding and glucose immersion, after overfeeding and 14 days of glucose immersion to induce diabetes, adult zebrafish were randomized into three groups: untreated diabetic, SEAE-treated (5 mg/L), and metformin-treated (3.3 mg/L) for 20 days. Body weight, fasting blood glucose, lipid profile, gene expression (GLP-1, PPARγ, SREBP-1c), and gut microbiota profiles via 16 S rRNA sequencing were assessed.
Results
SEAE significantly reduced body weight and blood glucose in diabetic zebrafish (p < 0.05), with efficacy comparable to or exceeding Metformin. It upregulated GLP-1 and downregulated PPARγ and SREBP-1c. SEAE also reduced total cholesterol, triglycerides, and LDL levels, while increasing HDL levels. Moreover, SEAE restored the Firmicutes/Bacteroidetes ratio, increased alpha diversity, and shifted beta diversity toward healthy controls. SEAE-treated fish showed microbial profiles closer to normal than those treated with Metformin.
Conclusions
SEAE exhibits strong anti-obesity and anti-hyperglycemic effects by modulating key metabolic pathways and restoring gut microbial homeostasis. These findings highlight SEAE as a promising marine-derived therapeutic candidate for metabolic syndrome and warrant further investigation as a functional food or nutraceutical.
Introduction
The global rise in diabetes mellitus and obesity represents a significant public health concern. In 2024, over 589 million people worldwide were affected by diabetes, a number projected to reach 852.5 million by 2050 [1]. This increase parallels the growing prevalence of obesity, one of the primary risk factors for type 2 diabetes, which impacted 988 million individuals in 2020 and is estimated to affect 1.91 billion by 2035 [2]. Addressing obesity is, therefore, crucial in mitigating the diabetes epidemic.
At the molecular level, these metabolic disorders involve complex dysregulation of pathways controlling energy balance, glucose metabolism, and lipid storage. Several key regulators include glucagon-like peptide-1 (GLP-1), peroxisome proliferator-activated receptor gamma (PPARγ), and sterol regulatory element-binding protein-1c (SREBP-1c). GLP-1 promotes insulin secretion and satiety, PPARγ enhances insulin sensitivity and lipid storage, and SREBP-1c stimulates lipogenesis in the liver and adipose tissue [3,4,5]. In metabolic disorders such as obesity and type 2 diabetes, these pathways are often disrupted, leading to insulin resistance, hyperglycemia, dyslipidemia, and increased adiposity.
While existing therapies target some of these mechanisms, their limitations —such as poor compliance and the lack of multi-targeted mechanism of action— have prompted the search for safer, more comprehensive alternatives. One promising candidate is Enhalus acoroides (E. acoroides), a tropical seagrass native to coastal waters of the Indian and Western Pacific oceans, which is rich in bioactive compounds with reported antioxidant, antidiabetic, and anti-obesity properties [6, 7]. E. acoroides seeds have been used especially by coastal populations as a flour substitute, and showed nutritional properties similar to wheat, cassava, and rice. On the other hand, marine plants like E. acoroides have shown the potential to modulate metabolic pathways and gut microbiota, offering a novel therapeutic approach. Our prior in silico and in vitro study employed ultrasound-assisted extraction (UAE) to isolate several potent carotenoids from E. acoroides, including fucoxanthin (C1), lutein (C2), astaxanthin (C3), canthaxanthin (C4), zeaxanthin (C5), β-cryptoxanthin (C6), and β-carotene (C7), all of which are associated with key metabolic and regulatory functions [7].
This study investigates the effects of E. acoroides extract in a zebrafish model of diet- and glucose-induced diabetes. The focus has been set on its regulatory effects on GLP-1, PPARγ, and SREBP-1c pathways, along with its influence on gut microbial composition, to explore its potential for future functional food development targeting metabolic dysfunction. To the best of our knowledge, this is the first in vivo study to demonstrate the dual therapeutic effects of E. acoroides extract on both glucose and lipid metabolism through modulation of GLP-1, PPARγ, and SREBP-1c expression, as well as restoration of gut microbiota composition and diversity in a zebrafish model of overfeeding- and glucose-induced diabetes. This research integrates molecular, metabolic, and microbiome-based mechanisms, highlighting E. acoroides as a promising candidate for marine-derived functional foods targeting metabolic syndrome.
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Extraction of E. acoroides
The powdered E. acoroides material was subjected to ultrasound-assisted extraction (UAE), an environmentally friendly technique designed to enhance the recovery of bioactive compounds. Two hundred grams of the simplicia powder was sonicated in 2 L of deionized water at 40 °C for 30 min using a Branson 2510 ultrasonic bath (St. Louis, MO, USA) operating at 400 W. The resulting mixture was filtered and re-extracted to maximize compound yield. The filtrate was concentrated using a rotary evaporator at 100 °C to obtain a thick extract. This UAE-derived E. acoroides extract (E-UAE) was then stored in aluminum foil at 4 °C in a dry, dark environment until further phytochemical and pharmacological analyses were performed.
Kadharusman, M.M., Syahputra, R.A., Kurniawan, R. et al. Seagrass Enhalus acoroides extract mitigates obesity and diabetes via GLP-1, PPARγ, SREBP-1c modulation and gut microbiome restoration in diabetic zebrafish. Diabetol Metab Syndr 17, 235 (2025). https://doi.org/10.1186/s13098-025-01823-4
