Revista Cienfica, FCV-LUZ / Vol. XXXV Recibido: 22/07/2025 Aceptado: 29/09/2025 Publicado: 28/10/2025 UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico 1 of 7 Revista Cienfica, FCV-LUZ / Vol. XXXV https://doi.org/10.52973/rcfcv-e35753 UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico Effects of Lactobacillus rhamnosus GG on some adipokine levels in rats fed Western diet Efectos de Lactobacillus rhamnosus GG sobre algunos niveles de adipocinas en ratas alimentadas con dieta occidental Atakan Ozturk 1 * , Mukadder Baylan 2 , Cemil Tumer 3 , Berjan DemirtaŞ 4 ¹Gaziantep Islam Science and Technology University, Faculty of Medicine, Department of Physiology1 (Gaziantep, Turkey). ²Dicle University, Faculty of Medicine, Department of Physiology. Diyarbakır 21280, Turkiye. ³Hatay Mustafa Kemal University, Faculty of Medicine, Department of Physiology. Hatay 31040, Turkiye. ⁴İstanbul University- Cerrahpaşa, Vocaonal School of Veterinary Medicine, Department of Plant and Animal Producon, Equine and Training Programme. Turkiye. *Corresponding author: dr.atakanozturk@gmail.com ABSTRACT Adipokines regulate energy homeostasis. High-fat Western diet leads to obesity and disrupts adipocyte metabolism. Probiocs such as Lactobacillus rhamnosus GG are effecve in obesity management. This study invesgates the effect of Lactobacillus rhamnosus GG on serum adipokine levels in rats fed a High-fat Western diet. Thirty 5-6 week old male Wistar albino rats (Raus norvegicus domesca) were randomly selected and divided into three groups: control (standard chow), W (45% fat), and a WLgroup supplemented orally with Lactobacillus rhamnosus GG in vegetable oil for 16 weeks. At the end of the study, blood samples were collected from rats via cardiac puncture, and serum adipokine levels were measured using ELISA kits. Body weight, naso-anal length, and BMI (body mass index) exhibited stascally significant increases in the W group. In the Lactobacillus rhamnosus GG-supplemented group (WL), body weight and BMI decreased, while naso-anal length increased. SFRP5 and CT1 levels were low, and asprosin and vaspin levels were high in the Wgroup. CT1, vaspin, and asprosin levels increased in the Lactobacillus rhamnosus GG- supplemented group. In conclusion, Lactobacillus rhamnosus GG alleviates obesity, increases naso-anal length, and reduces BMI in rats fed a High-fat Western diet. These results suggest that L. rhamnosus may regulate serum CT1, vaspin, and asprosin levels, but not omenn or SFRP5 in the High-fat Western diet model. Key words: Adipokine; high fat western diet; probioc; Lactobacillus rhamnosus RESUMEN Las adipocinas regulan la homeostasis energéca. La dieta occidental alta en grasas conduce a la obesidad y altera el metabolismo de los adipocitos. Los probiócos como Lactobacillus rhamnosus GG son eficaces en el manejo de la obesidad.Este estudio invesga el efecto de Lactobacillus rhamnosus GG en los niveles séricos de adipocinas en ratas alimentadas con una dieta occidental alta en grasas. Un total de 30 ratas macho Wistar albino (Raus norvegicus domesca) de 5-6 semanas de edad fueron seleccionadas y divididas aleatoriamente en tres grupos: control (pienso estándar), W(45% de grasa) y un WL grupo suplementado oralmente con Lactobacillus rhamnosus GG en aceite vegetal durante 16 semanas. Al final del estudio, se recolectaron muestras de sangre de las ratas mediante punción cardíaca y se midieron los niveles séricos de adipocinas ulizando kits ELISA. El peso corporal, la longitud naso-anal y el IMC (índice de masa corporal) mostraron aumentos estadíscamente significavos en el grupo W. En el grupo suplementado con LGG (WL), el peso corporal y el IMC disminuyeron, mientras que la longitud naso- anal aumentó. Los niveles de SFRP5 y CT-1 fueron bajos, y los niveles de asprosina y vaspina fueron altos en el grupo W. Los niveles de CT-1, vaspina y asprosina aumentaron en el grupo suplementado con Lactobacillus rhamnosus GG. En conclusión, Lactobacillus rhamnosus GG alivia la obesidad, aumenta la longitud naso-anal y reduce el IMC en ratas alimentadas con una dieta occidental alta en grasas. Estos resultados sugieren que L. rhamnosus puede regular los niveles séricos de CT-1, vaspina y asprosina, pero no los de omenna o SFRP5 en el modelo de dieta occidental alta en grasas. Palabras clave: Adipocina;dieta occidental alta en grasas; probióco, Lactobacillus rhamnosus

Effects of L.rhamnosus on Adipokine Levels / Ozturk et al. UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico INTRODUCTION Obesity is a significant public health problem. This condion affects a large poron of the populaon worldwide. Obesity plays an important role in the development of many metabolic diseases such as diabetes, hypertension and heart diseases. Therefore, high-fat diets, cafeteria diets and high-calorie diets are models of obesity that have been used for experimental studies in animals [1]. It has been suggested that, among these models, High-fat Western diet (HFWD) are more similar to the human diet [1]. Evidence from long-term studies indicates that diets with a substanal caloric content prepared with high levels of fat and/ or sugar expand adipose ssue and cause obesity [2]. Adipose ssue accumulates surplus calories in the form of triacylglycerol and has been considered an endocrine organ, secreng adipokines [3 ,[4]. Adipokines, structurally similar to cytokines, are responsive to fluctuaons within adipocytes for triacylglycerol storage, exerng both local and systemic effects inflammatory processes [5],[6]. Gut microbiota modulate body weight, adipose ssue and low-grade inflammaon [7]. In addion to family genes, environment, drug use and nutrion play a major role in the change of microbiota types in the digesve system [8]. Dietary paerns cause changes in intesnal microbiotaand its metabolic funcons [9]. They may also affect the circulang adipokine levels [10]. Changes in intesnal structure or microbiota composion may affect adipokine levels [11]. There is increasing interest in modifying the composion or funcon of the gut microbiota to prevent obesity and related metabolic syndromes [12]. Administraon of probioc strains, including Bifidobacterium longum [13], Lactobacillus plantarum [14] and Lactobacillus casei [15 , 16], improves gut microbiota dysbiosis and consequently prevents obesity-related metabolic disorders. Lactobacillus rhamnosus (L. rhamnosus) is a representave strain of Lactobacillus. L. rhamnosus, which is a common probioc, has been shown to be effecve in combang obesity [17]. While the an-obesity effects of L. rhamnosus have been explored [18], the impact of L. rhamnosus on adipokine levels requires further in-depth invesgaon. Therefore, the aim of this study was to invesgate the effects of L. rhamnosus GG (LGG) on some adipokine levels (omenn, secreted frizzled-related protein 5 (SFRP-5), cardiotrophin-1 (CT- 1), vaspin, asprosin) in rats (Raus norvegicus) fed a HFWD. MATERIALS AND METHODS Experimental protocols were performed in accordance with the regulaons regarding the use of laboratory animals. Ethical approval was obtained from the Animal Experimentaon Commiee (2019/8-14), Hatay Mustafa Kemal University Experimental Research Center, Hatay, Turkey. Experimental design and animals Thirty male Wistar albino rats (Raus norvegicus), ages 5–6 weeks, weighing an average of 123.33 ± 20.14 g, were used in this invesgaon. Three to four rats per cage were kept in stainless steel cages with standardized lighng (12 h of light and 12 h of darkness), a constant temperature (22 ± 2 °C), and a humidity level of 55% ± 10%. Aſter one week of adaptaon, the rats were randomly divided into three groups. Each group consisted of ten rats. All animals survived unl the end of the experiment. The experiment lasted 16 weeks. During the experiment, food and water were provided ad libitum. Baseline and final measurements of body weight (OHAUS NVT 6201,Switzerland) and naso-anal length were obtained for all animals. The body mass index (BMI) of each animal was calculated as the rao of body weight (g) to the square of the naso-anal length (cm 2 ). The control group (C) of rats was fed a commercial normocaloric standard rat chow (Bil-yem®,Turkey), which consisted of 2.70 kcal/g including 12% fat, 60% carbohydrate and 28% protein. The first experimental group (W) of rats was fed only a HFWD consisng of 5.00 kcal/g including 45% fat, 35% carbohydrate and 20% protein created based on open data principles (D12451, Research Diets) [19]. The second experimental group served as the probioc (WL) group and received a HFWD supplemented with LGG. LGG (ATCC 53103) was purchased from the Menarini Group (Florance, Italy) (trade name Kaleidon). The probioc supplement was in liquid form and one probioc drop contained 1x10 9 CFU of LGG, sunflower oil and an emulsifier. One drop of LGG was mixed with 0.1 mL of vegetable oil and administered by gavage to the WL group, while rats in both the C and W groups received only 0.1 mL of vegetable oil daily (d) as a placebo for 16 weeks. Biochemical analysis Aſter the study was concluded, animals were euthanazied by cardiac puncture under anaesthesia (Xylazine 10 mg/kg (Rompun 2%, Bayer, Germany) and Ketamine HCl 75 mg/kg (Ketasol 10%, interhas, Turkey)). Blood samples were collected and allowed to clot at room temperature for 30 min. Subsequently, they were centrifuged at 1790 G units (NF800R Desktop Centrifuge, Nuve, Turkey) for 15 min at 4°C. Serum supernatants were separated and stored at -80°C (DF290 Deep Freezer, Nuve, Turkey) unl further analysis of serum adipokines. Serum omenn, SFRP-5, CT-1, vaspin, asprosin were determined by enzyme-linked immunosorbent assay (ELISA) kits. ELISA kits (Fine Test) for Omenn (Rat Intelecn1/Omenn/ ER1117), SFRP-5 (Rat SFRP-5/ER1945), CT-1 (Rat CT-1/ER0868), adipocyte/ER0249, Vaspin (Rat Vaspin/(Visceral Adipose Specific Serine Protease Inhibitor/ER1420), Asprosin (Rat Asprosin/ ER1944) were purchased from Fine Biological, Wuhan, China. All procedures were performed according to the manufacturer’s instrucons. Analyses were performed using a microplate reader at 450 nm (Spectrostar Nano, BMG Labtech, Germany). 2 of 7

Revista Cienfica, FCV-LUZ / Vol. XXXV UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico Stascal analysis For stascal evaluaons, the Windows SPSS 22.0 package program was used. One-way analysis of variance (ANOVA) followed by Duncan’s post-hoc test was used for mulple comparisons in parametric data sets. For non-parametric data, mulple comparisons were performed using the Kruskal-Wallis test followed by Tamhane’s test. Analysed data are presented as mean ± standard error of the mean. A significance level of P<0.05 was used for stascal analysis. RESULTS AND DISCUSSION The increasing prevalence of obesity worldwide is aracted the adminstraon of probiocs for the prevenon and treatment of obesity aenon [20]. The most obvious finding in HFWD studies is weight gain. Previous studies have shown that probioc supplementaon reduces weight gain [21 , 22]. At the beginning of the study, there were no differences in body weight among the groups (P>0.05). At the end of the study, the body weight of the W group was significantly higher than that of the C group (P<0.05). Conversely, the body weight of the WL group was found to be notably lower compared to the W group at the end of the study (P<0.05). No significant difference was observed between the WL and C groups at the end of the study (P>0.05) (TABLE I). In addion, these effects are occured by regulang adipogenesis and glucose metabolism, and reducing proinflammatory cytokines in adipose ssue [20]. TABLE I Baseline and final body weight changes of all animal groups Groups Parameter C W WL p Baseline Weight(g) 122.02±21.10 a 125.83±27.69 a 123.00±11,64 a 0.719 Final Weight(g) 488.06±36.77 b 550.88±61.95 a 502.28±23.14 b 0.001 Values are presented as mean ± SE (standard error) C: Control, W: fed a high-fat western diet (HFWD) and WL: fed a HFWD supplemented with L.rhamnosus GG. Superscripts (a, b, c) indicate significant differences across groups in the same row (p<0.05). Probioc supplements cause decreases in the (BMI as well as body weight by the same mechanism [23]. A stascally significant decrease in BMI was evident in the WL group relave to the other two groups within this study. BMI fluctuaons mirrored the changes seen in body weight (TABLE I) and naso-anal length (TABLE II). No significant differences in inial naso-anal lengths were observed among the groups (P>0.05). However, the naso-anal length of the WL group was significantly greater than that of both the W and C groups at the end of the study (both P<0.05) (TABLE II). This shows that probioc supplements also contribute to height increase. The study of a systemac meta-analysis showed that probiocs supported the development of weight and height gain in children with growth retardaon [24]. In addion, the relaonship between growth hormone and the gut microbiome may have a posive impact on gut and metabolic health [25]. In this study showed that the naso-anal lenghtsof the rats in the WL group was longer, consistent with the literature, and the difference was stascally significant contrast to other two groups. LGG supplementaon, butyrate producon in the intesne increased and trabecular bone volume increased [26]. In addion, the increase in height may be related to LGG count and duraon colonizaon and funcon in the animal’s gastrointesnal tract [27]. The current study findings are consistent with the studies conducted, and height and weight changes can be explained by the posive effects of L.rhamnosus GG supplemenon to the diet on the intesnal microbiota. TABLE II Baseline and final naso-anal lengths changes of all animal groups Groups Parameter C W WL p Baseline naso-anal length (mm) 153.10±10.343 a 152.40±14.14 a 147.1±6.00 a 0.115 Final naso-anal length (mm) 248.40±4.718 c 253.50±4.58 b 266.9±4.61 a 0.000 Values are presented as mean ± SE (standard error) C: Control, W: fed a high-fat western diet (HFWD) and WL: fed a HFWD supplemented with L.rhamnosus GG. Superscripts (a, b, c) indicate significant differences across groups in the same row (p<0.05). By the end of the study, the W group, maintained on a HFWD, exhibited the highest BMI levels (P<0.05) (TABLE III). Both the probioc-supplemented WL group and the control group (C) displayed BMI values that were markedly lower than the W group (P<0.001). Addionally, a notable disncon was observed between the C group and the WL group (P<0.001). The finding that the WL group, which received probioc supplementaon, presented the lowest BMI value strongly suggests that probiocs can significantly contribute to lowering BMI. 3 of 7

Effects of L.rhamnosus on Adipokine Levels / Ozturk et al. UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico TABLE III Baseline and final Body mass index (BMI) changes of all animal groups Groups Parameter C W WL P Baseline BMI (gr/ cm 2 ) 0.52±0.06 a 0.55±0.14 a 0.57±0.06 a 0.507 Final BMI (g/ cm 2 ) 0.79±0.04 b 0.86±0.07 a 0.70±0.02 c 0.000 Values are presented as mean ± SE (standard error). Body mass index (BMI).C: Control, W: fed a high-fat western diet (HFWD) and WL: fed a HFWD supplemented with L.rhamnosus GG. Superscripts (a, b, c) indicate significant differences across groups in the same row (p<0.05). Lactobacillus probiocs have been reported to aenuate adiposity, improve lipid profiles, and prevent adverse alteraons in adipokine levels in animal models fed obesogenic diets [28]. Moreover, it increases the levels of an-inflammatory adipokines while simultaneously decreasing the levels of pro- inflammatory adipokines. An-inflammatory adipokines, such as adiponecn, omenn-1, SFRP5, and CT-1, play a crucial role in regulang energy metabolism. They contribute to improved energy ulizaon in key ssues, including the liver, skeletal muscle, pancreas, and adipose ssue itself [29]. Omenn-1 is highly expressed in visceral adipose ssue, while circulang levels of omenn are decreased in obese individuals [30]. In addion, especially exercise training result in a significant increase in the serum omenn-1 concentraons and insulin- sensizaon. In this study, no significant difference between three groups was seen in omenn levels. This result may indicate that L. rhamnosus supplementaon may not affect omenn-1 levels without exercise effect. Secreted frizzled-related protein 5 SFRP5 has beneficial effects on insulin sensivity and is a new marker of chronic inflammaon associated with adipose ssue. Serum SFRP5 levels are low in subjects with obesity and type 2 diabetes mellitus [31]. In the present study, SFRP-5 levels were decreased in the W and WL groups compared to the C group (TABLE IV). This finding may suggest that L. rhamnosus alone is not sufficient to correct this significant decrease. Serum concentraons of SFRP-5 have been increased in obese paents undergoing calorie restricon [32], 33 , 34 , 35]. The relaonship between CT-1 levels and obesity/metabolic diseases in humans remains elusive. While CT-1 gene expression levels are downregulated in white adipose ssue in diet-induced obese mice (Raus norvegicus) [36], plasma levels have been shown to be increased in individuals with obesity and metabolic syndrome [37]. TABLE IV Presents the adipokine levels in all groups at the end of the experimental period Groups Parameters C W WL P Omenn (ng/mL) 4.08±0.65 4.04±0.71 4.26±0.43 0.701 SFRP-5 (pg/mL) 9.16±1.65 a 5.55±0.43 b 5.86±2.05 b 0.000 CT-1 (pg/mL) 24.05±3.37 a 15.27±3.50 b 21.78±3.70 a 0.000 Vaspin (pg/mL) 155.77±11.48 c 281.93±100.32 b 536.64±99.25 a 0.000 Asprosin (pg/mL) 93.09±15.58 c 168.34±38.63 b 222.17±39.67 a 0.000 Values are presented as mean ± SE (standard error) . C: Control, W: fed a high-fat western diet (HFWD) and WL: fed a HFWD supplemented with L.rhamnosus GG.Superscripts (a, b, c) indicate significant differences across groups in the same row (P<0.05). On the contrary, some studies are showed that CT-1 levels are lower in overweight and obese individuals compared to normal weight individuals [38]. In the present study, CT-1 levels decreased in the W group. On the other hand, increased CT-1 levels in the C and WL groups were also consistent with decreased weight gain and BMI (TABLE IV). CT-1 is a protein that belongs to theinterleukin-6 (IL-6) cytokine family [39]. While inially idenfied for its role in cardiac hypertrophy, emerging evidence suggests potenal involvement of CT-1 in regulang glucose and lipid metabolism [40]. The increased CT-1 levels in the WL group (TABLE IV), which was fed the same diet as the W group but supplemented with LGG, may indicate the beneficial effect of LGG on these pathway. The other two adipokines evaluated in the current study are vaspin and aspirosin. Although they are linked to obesity and insulin resistance and are considered inflammatory adipokines, it has been stated that increases in these two parameters may be a protecve mechanism against metabolic syndrome [41], 42]. Vaspin is elevated in obese and streptozotocin-induced diabetes mellitus fed a high-fat diet [43]. On the contrary, it has been shown to enhance glucose tolerance and insulin sensivity and inhibit the expression of genes associated with insulin resistance [44]. Similarly, asprosin levels are increased in obesity with insulin resistance [45]. The results of the current study were similar to these and vaspin and aspirosin levels increased and were stascally significant in the two experimental groups fed HFWD compared to the control group. However, this increase was stascally significant and higher in the WL group compared to the W group (Table IV). Vaspin administraon reduces food intake [46]. Asprosin, which smulates food intake, is a centrally acng oroxygenic hormone. [47 , 48]. Asprosin levels exhibit a posive correlaon with body mass index [49]. Despite all these negave data, asprosin is thought to play a role in the regulaon of glucose homeostasis [45]. The change in vaspin concentraons with nutrion indicates that it may be a contribung factor in the regulaon of body weight homeostasis [50]. 4 of 7

Revista Cienfica, FCV-LUZ / Vol. XXXV UNIVERSIDAD DEL ZULIA Serbiluz Sistema de Servicios Bibliotecarios y de Información Biblioteca Digital Repositorio Académico In this study, both adipokine levels were significantly higher in the WL group compared to the other two groups (TABLE IV). The lower BMI and body weight in this group despite higher adipokine levels suggest that LGG contributes to the maintenance of homeostasis despite HFWD feeding. CONCLUSIONS In the current study, it was shown that the strain-specific probioc (L. rhamnosus) was effecve in improving obesity- related adipokines. On the other hand, the effecveness of a high-fat western diet and L. rhamnosus applicaon on omenn, Secreted frizzled-related protein 5, cardiotrophin-1 and vaspin, aspirosin was invesgated for the first me. L. rhamnosus was determined to have beneficial effects on a high-fat western protein feeding by prevenng the decrease in serum cardiotrophin-1 levels. It also supports the effects of two adipokines on hunger and feed intake by causing a significant increase in vaspin and asprosin levels. L. rhamnosus supplementaon together with a high-fat western protein provides the preservaon of body mass index and body weight by acng on certain adipokines. However, further studies are needed to understand the physiological pathways of this effect. ACKNOWLEDGEMENTS We would like to thank Dicle University Scienfic Research Projects Coordinaon Office for their support in conducng the experiments. Authors contrıbuons AO, MB and CT designed the experiments. AO performed the tests and collected the samples. MB and CT were present at all stages of the studies. AO prepared Elisa’s analyses and stascs. BD contributed to the preparaon of the arcle for publicaon. AO was the author of the arcle. All authors contributed to the study and approved the final version of the manuscript for publicaon. Fundıng ınformaon This study was funded by The Scienfic Research Projects Coordinatorship of Dicle University of Turkey (TIP.20.013). Conflıct of ınterest The authors declared no conflict of interest. Ethical approval This study was approved by the Hatay Mustafa Kemal University Local Ethics Commiee (2019/8-14) and the experimental methods were carried out in accordance with ethical rules. BIBLIOGRAPHIC REFERENCES [1] Bortolin RC, Vargas AR, Gasparoo J, Chaves PR, Schnorr CE, Marnello KB, Silveira AK, Rabelo TK, Gelain DP, Moreira JCF. A new animal diet based on human Western diet is a robust diet-induced obesity model: comparison to high-fat and cafeteria diets in term of metabolic and gut microbiota disrupon. Int. J. Obes. [Internet]. 2018; 42(3):525-534. doi: hps://doi.org/gdbp39 [2] Vileigas DF, de Souza-Borges SL, Corrêa CR, Silva CCVA, de Campos DHS, Padovani CR, Cicogna AC. 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