Curcumin modulates the adipose FBN1–Asprosin axis and improves metabolic dysfunction in a rat model of type 2 diabetes

Abstract

Background

Asprosin, a glucogenic adipokine derived from the C-terminal region of profibrillin-1 encoded by FBN1, has emerged as a potential regulator of glucose homeostasis and insulin resistance. However, the effects of curcumin on the adipose FBN1–asprosin axis in type 2 diabetes mellitus (T2DM) remain unclear. This study investigated whether curcumin supplementation modulates adipose tissue FBN1 expression and circulating asprosin in a rat model of T2DM.

Methods

Forty male Wistar rats were randomly allocated to four groups (n = 10/group): control, curcumin, T2DM, and T2DM + curcumin. T2DM was induced by high-fat diet feeding followed by low-dose streptozotocin administration. Diabetic rats received curcumin (300 mg/kg/day) by oral gavage for eight weeks. Body weight, fasting blood glucose, fasting insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) were assessed. Serum asprosin concentrations were determined using ELISA, and FBN1 gene expression in subcutaneous adipose tissue was quantified using real-time PCR.

Results

Compared with controls, diabetic rats exhibited significantly higher body weight, fasting blood glucose, fasting insulin, HOMA-IR, adipose tissue FBN1 expression, and serum asprosin concentrations (all P < 0.0001). Curcumin supplementation significantly reduced body weight, fasting blood glucose, fasting insulin, and HOMA-IR in diabetic rats (P < 0.05). Moreover, curcumin significantly attenuated adipose tissue FBN1 expression (P = 0.0028) and circulating asprosin levels (P = 0.0014) compared with untreated diabetic rats.

Conclusion

Curcumin supplementation improves metabolic abnormalities and attenuates the adipose FBN1–asprosin axis in experimental T2DM. These findings suggest that modulation of FBN1–asprosin signaling may contribute to the metabolic effects of curcumin and warrants further mechanistic investigation.

1. Introduction

Type 2 diabetes mellitus (T2DM) constitutes a prevalent chronic metabolic disorder of multifactorial etiology that has emerged as a major global health challenge, affecting millions worldwide. Primarily characterized by insulin resistance, pancreatic β-cell dysfunction, and sustained hyperglycemia, it predisposes individuals to serious long-term sequelae such as cardiovascular disorders, neuropathy, nephropathy, and retinopathy [1,2]. The onset of T2DM arises from intricate interplay among genetic predispositions, environmental influences, and lifestyle factors, culminating in dysregulated glucose homeostasis and chronic systemic inflammation [3].

Curcumin, the principal bioactive polyphenol from turmeric (Curcuma longa) demonstrates robust antioxidant effects by directly neutralizing reactive oxygen species (ROS) and reactive nitrogen species (RNS)-such as O₂^.-, HO^., NO^., and ONOO^.--while indirectly enhancing key antioxidant enzymes including catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and heme oxygenase-1 (HO-1) to safeguard cells and sustain metabolic homeostasis [4]. Curcumin supplementation improves insulin sensitivity via activation of AMP-activated protein kinase (AMPK), a key regulator of energy balance and glucose uptake. It promotes the expression and translocation of glucose transporter proteins (e.g., GLUT4), thereby enhancing glucose uptake in skeletal muscle and adipose tissue [5,6]. Additionally, curcumin inhibits hepatic gluconeogenesis to curb endogenous glucose output. By suppressing nuclear factor-kappa B (NF-κB), it exerts potent anti-inflammatory effects, lowering proinflammatory cytokines such as TNF-α and IL-6, which are typically upregulated in diabetes [7].

Romere et al. identified a novel adipokine in a study on progeroid syndrome in newborns, primarily secreted by white adipose tissue, and thus termed it asprosin. Asprosin represents the C-terminal cleavage product of the fibrillin-1 (FBN1) precursor protein, comprising 140 amino acids encoded by exons 65 and 66. While predominantly produced by white adipose tissue, asprosin exerts its effects across multiple organs body-wide; its receptors are chiefly expressed in the hypothalamic arcuate nucleus of the brain, as well as in the liver, pancreas, skeletal muscle, and myocardium [8]. Asprosin acts through the olfactory receptor OLFR734 to modulate hepatic glucose production and sustain glucose homeostasis [9]. It plays a role in diabetes pathogenesis by influencing glucose homeostasis, appetite, insulin secretion, and insulin sensitivity. It elevates blood glucose and insulin levels, with heightened concentrations observed in insulin-resistant humans and mice. Foundational research shows asprosin targets multiple organs-including the liver, brain, skeletal muscle, and pancreas-triggering hyperglycemia, heightened food intake, insulin resistance, and pancreatic islet inflammation and dysfunction [10,11].

Beyond its established role in promoting hepatic glucose production, asprosin contributes to T2DM pathogenesis through several interconnected mechanisms that collectively perpetuate metabolic deterioration. First, asprosin directly exacerbates insulin resistance by impairing insulin signaling in skeletal muscle, liver, and adipose tissue, thereby reducing glucose disposal and aggravating hyperglycemia [10,11]. Second, it promotes a pro-inflammatory state by elevating circulating levels of inflammatory cytokines such as TNF-α and IL-6, which are directly toxic to pancreatic β-cells and accelerate their functional decline. Third, asprosin participates in redox imbalance by diminishing endogenous antioxidant defenses and increasing oxidative stress, further compromising β-cell survival and insulin secretory capacity. Fourth, and critically, asprosin adversely modulates the lipid profile—raising triglyceride levels while perturbing cholesterol homeostasis—and given that hypertriglyceridemia itself reinforces insulin resistance, this creates a bidirectional vicious cycle that sustains metabolic dysregulation [10,11]. Collectively, these multifaceted actions position the adipose FBN1–asprosin axis as a central pathogenic hub in T2DM, making it an attractive target for therapeutic intervention.

Type 2 diabetes mellitus (T2DM) remains a major global health crisis, driving the urgent need for novel therapeutic targets beyond conventional pathways. The recent discovery of asprosin—a glucogenic adipokine derived from the FBN1 precursor that promotes hepatic glucose production and insulin resistance—has identified this axis as a promising candidate for pharmacological intervention. Although curcumin is widely recognized for its potent anti-diabetic, anti-inflammatory, and antioxidant properties, no study to date has investigated its specific modulatory effects on the adipose FBN1–asprosin signaling cascade in T2DM. This study is of critical importance as it directly addresses this mechanistic knowledge gap. By elucidating whether curcumin supplementation can attenuate FBN1 expression and circulating asprosin levels, our findings may uncover a previously unrecognized molecular basis for curcumin's metabolic benefits and provide foundational evidence to support the asprosin axis as a viable adjunctive therapeutic target in the management of T2DM.

2. Materials and methods

2.1. Chemicals and reagents

Curcumin (purity ≥98%) and streptozotocin (STZ) were procured from Sigma-Aldrich (USA). The high-fat diet (HFD) containing 40% fat was custom-formulated by Behparvar Co. (Iran). Serum asprosin and insulin concentrations were determined using specific enzyme-linked immunosorbent assay (ELISA) kits obtained from Zellbio GmbH (Germany).

2.2. Animals and housing

Forty male white Wistar rats, weighing 220–240 g, were used in this study. They were maintained in a temperature- and humidity-controlled room (temperature: 22 ± 2 °C; relative humidity: 45 ± 5%) on a 12-h light/dark cycle, with ad libitum access to water and standard laboratory rodent chow. The ethical aspects of the study were approved by the Ethics Committee of Zahedan University of Medical Sciences (ethical code: IR.ZAUMS.AEC.1404.012). Following an acclimatization period, the rats were randomly allocated into four experimental groups (n = 10 per group).

2.3. Experimental groups

• -Group I (Healthy control): Untreated healthy rats.
• -Group II (Non-diabetic + Curcumin): Non-diabetic rats receiving curcumin at 300 mg/kg/day dissolved in 5% sodium carboxymethyl cellulose [12].
• -Group III (Diabetic control): Rats with induced type 2 diabetes mellitus (T2DM) receiving no intervention.

• -Group IV (Diabetic + Curcumin): Diabetic rats treated with curcumin (300 mg/kg/day) dissolved in 5% sodium carboxymethyl cellulose [12].
• -Group II (Non-diabetic + Curcumin): Non-diabetic rats receiving curcumin at 300 mg/kg/day dissolved in 5% sodium carboxymethyl cellulose. This group was included to assess (i) the safety and tolerability of curcumin at the chosen dose in healthy animals, and (ii) whether curcumin exerts any physiological effects on the FBN1–asprosin axis or metabolic parameters independent of the diabetic state. The dose of 300 mg/kg/day was selected based on previous studies demonstrating its safety and efficacy in rodent models of metabolic dysfunction [12].

2.4. Induction of type 2 diabetes

To induce T2DM, the animals were first fed a high-fat diet (HFD) containing 40% fat for four weeks. Subsequently, a single low-dose intraperitoneal injection of STZ (45 mg/kg body weight) dissolved in 0.05 mmol/L citrate buffer (pH 4.5) was administered [13,14]. One week after STZ injection, fasting blood glucose (FBG) levels were measured from tail vein blood. Rats with FBG levels exceeding 200 mg/dL were considered diabetic [14,15]. Body weight was recorded at the beginning of the study and then weekly until the end of the experiment.

2.5. Curcumin treatment and sample collection

Curcumin (300 mg/kg/day), dissolved in 5% sodium carboxymethyl cellulose, was administered daily to the respective groups via oral gavage for eight weeks [12]. The curcumin suspension was freshly prepared each day, and the final dosing volume was adjusted to 5 mL/kg body weight. At the end of the treatment period, animals were anesthetized by intraperitoneal injection of xylazine (10 mg/kg) and ketamine (100 mg/kg). Blood samples were collected via cardiac puncture for biochemical analyses. After serum separation, the samples were immediately stored at −70 °C until further analysis [16].

2.6. Measurement of asprosin, insulin, and HOMA-IR

Serum levels of asprosin and insulin were determined using commercial ELISA kits (Zellbio, Germany) according to the manufacturer's instructions. Absorbance was read using an ELISA microplate reader.

Insulin resistance was estimated using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). The index was calculated based on fasting blood glucose (mg/dL) and fasting serum insulin (μU/mL) using the following Equation (1) [16]:

$$\text{HOMA}‐\text{IR}=\frac{\text{glucose}\left(\text{mg}/\text{dL}\right)\times \text{insulin}\left(\mu \mathrm{U}/\text{ml}\right)}{405}$$ (1)

2.7. Measurement of lipid profile and TyG index

Serum triglycerides (TG) was measured using commercially available enzymatic colorimetric kits according to the manufacturer's instructions. The triglyceride-glucose (TyG) index was calculated as a surrogate marker of insulin resistance using the following formula: TyG = Ln [fasting TG (mg/dL) × fasting glucose (mg/dL)/2].

2.8. Statistical analysis

All data were analyzed using GraphPad Prism version 8.4. Comparisons among the four groups were performed by one-way analysis of variance (ANOVA) followed by Bonferroni's post-hoc test. A significance level of p < 0.05 was considered statistically significant.

3. Results

3.1. FBN1 gene expression in adipose tissue

FBN1 gene expression (Fig. 1) was significantly upregulated in the diabetic group compared to both control groups (p < 0.0001). Treatment with curcumin significantly downregulated FBN1 expression in the diabetic group relative to the untreated diabetic animals (p = 0.0028). However, FBN1 expression in the Diab + Curcu group was still significantly higher than that observed in the control groups (p < 0.0001).

Fig. 1.

Effect of curcumin consumption on FBN1 gene expression in subcutaneous thigh fat tissue of different groups.

Data are expressed as mean ± SEM. Cont group: control rats group; Cont + Curcu: control rats group supplemented with curcumin treatment; Diab group: diabetic rats group; Diab + Curcu group: diabetic rats supplemented with curcumin.

*p = 0.0028 Diab + Curcu vs. Diab;

#p < 0.0001 Diab vs. Cont and Cont + Curcu.

3.2. Serum asprosin levels

Serum asprosin levels (Fig. 2) were significantly elevated in the diabetic group (Diab) compared to the control (Cont) and control + curcumin (Cont + Curcu) groups (p < 0.0001). Curcumin administration in diabetic rats (Diab + Curcu) resulted in a significant reduction in serum asprosin levels compared to the untreated diabetic group (p = 0.0014). Nevertheless, asprosin levels in the Diab + Curcu group remained significantly higher than those in both control groups (p < 0.0001).

Fig. 2.

Effect of curcumin consumption on serum asprosin levels in different groups.

Data are expressed as mean ± SEM. Cont group: control rats group; Cont + Curcu: control rats group supplemented with curcumin treatment; Diab group: diabetic rats group; Diab + Curcu group: diabetic rats supplemented with curcumin.

*p = 0.0014 Diab + Curcu vs. Diab; **p < 0.0001 Diab + Curcu vs. Cont and Cont + Curcu

#p < 0.0001 Diab vs. Cont and Cont + Curcu.

3.3. Fasting insulin levels

Fasting insulin levels (Fig. 3) were significantly increased in the diabetic group compared to the control groups (p < 0.0001). Curcumin supplementation significantly reduced fasting insulin levels in diabetic rats compared to the untreated diabetic group (p = 0.0072). Furthermore, insulin levels in the Diab + Curcu group were significantly higher than those in the Cont + Curcu group (p = 0.0054), but did not differ significantly from the simple control group.

Fig. 3.

Effect of curcumin consumption on serum fasting insulin levels of different groups.

Data are expressed as mean ± SEM. Cont group: control rats group; Cont + Curcu: control rats group supplemented with curcumin treatment; Diab group: diabetic rats group; Diab + Curcu group: diabetic rats supplemented with curcumin. *p = 0.0072 Diab + Curcu vs. Diab; **p = 0.0054 Diab + Curcu vs. Cont + Curcu

#p < 0.0001 Diab vs. Cont and Cont + Curcu.

3.4. Fasting blood glucose levels

Fasting blood glucose levels (Fig. 4) were significantly higher in the diabetic group relative to both control groups (p < 0.0001). Curcumin treatment led to a highly significant decrease in blood glucose levels in diabetic rats compared to the untreated diabetic group (p < 0.0001). Additionally, glucose levels in the Diab + Curcu group were significantly higher than those in both the Cont and Cont + Curcu groups (p < 0.0001).

Fig. 4.

Effect of curcumin consumption on fasting blood glucose levels of different groups.

Data are expressed as mean ± SEM. Cont group: control rats group; Cont + Curcu: control rats group supplemented with curcumin treatment; Diab group: diabetic rats group; Diab + Curcu group: diabetic rats supplemented with curcumin. *p < 0.0001 Diab + Curcu vs. Diab, Cont + Curcu and Cont.

#p < 0.0001 Diab vs. Cont and Cont + Curcu.

3.5. HOMA-IR and TyG index values

The HOMA-IR index (Fig. 5a) was significantly increased in the diabetic group compared to the control groups (p < 0.0001). Curcumin consumption significantly decreased HOMA-IR in the diabetic group relative to the untreated diabetic group (p < 0.05). Moreover, HOMA-IR values in the Diab + Curcu group were significantly higher than those in the Cont and Cont + Curcu groups (p < 0.05).

Fig. 5.

Effect of curcumin consumption on (a) HOMA-IR and (b) Triglyceride-glucose index levels of different groups.

Data are expressed as mean ± SEM. Cont group: control rats group; Cont + Curcu: control rats group supplemented with curcumin treatment; Diab group: diabetic rats group; Diab + Curcu group: diabetic rats supplemented with curcumin. a)*p < 0.05 Diab + Curcu vs. Diab, Cont + Curcu and Cont. #p < 0.0001 Diab vs. Cont and Cont + Curcu b) *p < 0.0001 Diab + Curcu vs. Diab, Cont + Curcu and Cont. #p < 0.0001 Diab vs. Cont and Cont + Curcu.

The TyG index (Fig. 5b) was markedly elevated in diabetic control rats compared with healthy controls (p < 0.001). Curcumin treatment significantly reduced the TyG index compared with untreated diabetic rats (p < 0.0001).

3.6. Body weight

Body weight (Fig. 6) was significantly increased in the diabetic group compared to the control groups (p < 0.0001). Curcumin treatment significantly reduced body weight in diabetic rats compared to the untreated diabetic group (p = 0.0011). Furthermore, body weight in the Diab + Curcu group was significantly higher than that in the Cont + Curcu group (p = 0.0014), but did not show a significant difference compared to the simple control group.

Fig. 6.

Effect of curcumin consumption on weight of different groups.

Data are expressed as mean ± SEM. Cont group: control rats group; Cont + Curcu: control rats group supplemented with curcumin treatment; Diab group: diabetic rats group; Diab + Curcu group: diabetic rats supplemented with curcumin. *p = 0.0011 Diab + Curcu vs. Diab; **p = 0.0014 Diab + Curcu vs. Cont + Curcu;

#p < 0.0001 Diab vs. Cont and Cont + Curcu.

4. Discussion

The present study provides novel evidence that curcumin supplementation modulates the adipose tissue FBN1–asprosin axis in a rat model of type 2 diabetes mellitus (T2DM). In the diabetic rats, FBN1 gene expression in subcutaneous adipose tissue and circulating asprosin concentrations were markedly increased compared with non-diabetic controls. These molecular changes were accompanied by pronounced hyperglycemia, hyperinsulinemia, increased HOMA-IR, and increased body weight. Importantly, eight weeks of curcumin supplementation at 300 mg/kg/day significantly reduced adipose FBN1 expression and serum asprosin concentrations in diabetic rats, while simultaneously improving fasting blood glucose, fasting insulin, HOMA-IR, and body weight. However, none of these parameters was completely normalized to the levels observed in the healthy control groups.

The principal novelty of these findings lies in the simultaneous assessment of adipose FBN1 expression and circulating asprosin following curcumin administration. Although the metabolic effects of curcumin have been extensively investigated, relatively little is known regarding its potential effects on the FBN1–asprosin endocrine pathway. The present findings therefore extend the existing literature by suggesting that this pathway may be responsive to pharmacological or nutritional improvement of the diabetic metabolic state.

Asprosin is a fasting-induced glucogenic and orexigenic protein hormone derived from the C-terminal portion of profibrillin-1, the protein encoded by the FBN1 gene. Profibrillin undergoes proteolytic processing to generate mature fibrillin-1 and the C-terminal fragment asprosin [17]. White adipose tissue is considered the major source of circulating asprosin [18]. The discovery of asprosin provided an important mechanistic link between adipose tissue energy stores and systemic glucose regulation. Following secretion from adipose tissue, asprosin acts primarily on the liver to stimulate glucose production through a cAMP-dependent signaling pathway. Li et al. subsequently identified OLFR734 as a hepatic receptor for asprosin and demonstrated that disruption of OLFR734 attenuated asprosin-induced hepatic glucose production and improved insulin sensitivity [19]. Thus, excessive asprosin signaling has the potential to promote hyperglycemia, particularly in conditions characterized by obesity and insulin resistance. Asprosin also exerts central effects on energy homeostasis. Duerrschmid et al. demonstrated that circulating asprosin can cross the blood–brain barrier and activate orexigenic AgRP neurons, thereby stimulating appetite and promoting adiposity [20]. More recent work has further characterized the neuronal mechanisms through which asprosin regulates feeding behavior [21]. Therefore, the biological actions of asprosin extend beyond hepatic glucose production and include regulation of appetite, energy balance, and body composition. This biological background is particularly relevant to the current study because diabetic rats exhibited simultaneous elevations in FBN1 expression and circulating asprosin. The observed increase in serum asprosin may therefore represent an endocrine component of the metabolic abnormalities induced by the HFD/STZ model.

A major finding of the present study was the significant upregulation of FBN1 gene expression in subcutaneous thigh adipose tissue in diabetic rats. Compared with both non-diabetic groups, diabetic animals demonstrated a highly significant increase in FBN1 expression (p < 0.0001). Curcumin administration significantly reduced FBN1 expression compared with untreated diabetic rats (p = 0.0028), although expression remained significantly higher than in the control groups. The increase in FBN1 expression is potentially important because FBN1 provides the precursor from which asprosin is generated. However, FBN1 is primarily an extracellular matrix protein, and its metabolic significance extends beyond its role as the precursor of asprosin [17]. Fibrillin-1 contributes to the organization of extracellular microfibrils and participates in regulation of tissue growth-factor signaling [22]. Consequently, altered FBN1 expression may reflect changes in adipose tissue extracellular matrix remodeling accompanying metabolic dysfunction [17].

The relationship between FBN1 and asprosin has recently received increasing attention. A review focusing specifically on the FBN1-derived nature of asprosin emphasized that asprosin is encoded by the terminal exons of FBN1 and generated through furin-mediated cleavage of profibrillin [17,21]. This provides a biological basis for investigating adipose FBN1 expression in parallel with circulating asprosin. Most importantly, the present observation is consistent with a recent experimental study by Dashtkar et al., which examined the FBN1–asprosin system in HFD/STZ-induced diabetic rats [14]. They reported increased FBN1 gene expression in white adipose tissue and increased serum asprosin concentrations in diabetic animals; metformin treatment significantly reduced both parameters [14]. The close agreement between their findings and those of the present study supports the possibility that dysregulation of the FBN1–asprosin axis is reproducible in experimental T2DM. Nevertheless, an important distinction should be made between FBN1 transcription and asprosin biosynthesis. Increased FBN1 mRNA does not necessarily establish increased production of mature asprosin because asprosin generation depends on post-translational processing of profibrillin. Therefore, the present findings demonstrate parallel alterations in FBN1 expression and circulating asprosin rather than a direct causal relationship between FBN1 transcription and asprosin secretion.

The diabetic animals in the present study exhibited a highly significant elevation in serum asprosin compared with both non-diabetic groups (p < 0.0001). Curcumin treatment significantly decreased circulating asprosin compared with untreated diabetic animals (p = 0.0014), although serum asprosin remained significantly higher than in the control groups. This finding is consistent with the established relationship between elevated asprosin and metabolic dysfunction. The original description of asprosin demonstrated that insulin-resistant humans and rats exhibit pathologically elevated circulating asprosin and that reduction of asprosin signaling can lower glucose and insulin concentrations [14,23,24]. Subsequent studies have reported elevated asprosin concentrations in obesity and metabolic disorders and have suggested that circulating asprosin may serve as a biomarker of insulin resistance [23,25]. A recent systematic review and meta-analysis further evaluated circulating asprosin in individuals with T2DM, metabolic syndrome, and obesity and concluded that asprosin concentrations are generally elevated in these metabolic conditions [26]. More recent clinical evidence has also demonstrated positive associations between circulating asprosin and HOMA-IR, adiposity, oxidative stress, and inflammatory markers in adults with obesity [24]. These observations strengthen the biological relevance of the increased serum asprosin observed in the diabetic animals in the present study. The elevation of asprosin may contribute to hyperglycemia through increased hepatic glucose production. Activation of OLFR734 by asprosin promotes cAMP signaling and hepatic glucose output, whereas genetic deletion of OLFR734 attenuates these metabolic effects [19]. Therefore, increased circulating asprosin in the diabetic group could plausibly contribute to maintenance of elevated fasting glucose. However, the present experimental design does not allow determination of whether increased asprosin is a primary driver of insulin resistance or a consequence of the diabetic metabolic environment. Because asprosin is physiologically induced by fasting and contributes to glucose availability during energy deprivation, its elevation in T2DM may represent an exaggerated or dysregulated physiological response rather than an initiating event.

The simultaneous elevation of asprosin, fasting insulin, fasting glucose, and HOMA-IR in the diabetic group is particularly noteworthy. The diabetic rats demonstrated a highly significant increase in fasting insulin compared with controls, whereas curcumin significantly reduced fasting insulin in diabetic animals (p = 0.0072). This pattern is compatible with compensatory hyperinsulinemia resulting from insulin resistance. Human studies provide additional support for an association between asprosin and insulin resistance. In obese individuals, circulating asprosin has been positively correlated with several indirect measures of insulin resistance, including TyG-based indices [23,25]. A recent study additionally demonstrated associations between asprosin and HOMA-IR, TyG, hepatic insulin resistance markers, oxidative stress, and inflammation [24]. The mechanistic relationship may be bidirectional. Increased asprosin can stimulate hepatic glucose production, thereby increasing the metabolic demand for insulin. Conversely, insulin resistance and adipose tissue dysfunction may increase adipose-derived asprosin secretion. The current study cannot distinguish these possibilities. Nevertheless, the parallel reduction in asprosin and HOMA-IR following curcumin treatment suggests that modulation of this endocrine pathway may accompany improvement in insulin sensitivity.

The inclusion of the TyG index provides a valuable complementary perspective on insulin resistance that extends beyond the glucose-insulin dynamics captured by HOMA-IR. While HOMA-IR primarily reflects hepatic insulin resistance, the TyG index integrates both glycemic and lipid components and is increasingly recognized as a reliable surrogate for peripheral and whole-body insulin resistance. In our study, curcumin treatment significantly lowered the TyG index in diabetic rats, paralleling the reduction in HOMA-IR. This concurrent improvement in both indices suggests that curcumin's beneficial effects extend beyond glycemic control to encompass lipid-associated metabolic derangements. Given that FBN1 is predominantly expressed in adipose tissue, and that adipose tissue dysfunction is intimately linked to both dyslipidemia and insulin resistance, our findings raise the intriguing possibility that curcumin-mediated downregulation of adipose FBN1 expression and circulating asprosin may contribute to the simultaneous improvement in glucose and lipid metabolism. The positive correlation between reduced asprosin and improved TyG index supports the concept that the FBN1–asprosin axis serves as an integrative node linking lipid metabolism to systemic insulin sensitivity.

The reduction in FBN1 expression following curcumin supplementation represents one of the most important novel observations of the present study. Diabetic rats receiving curcumin exhibited significantly lower FBN1 expression than untreated diabetic rats (p = 0.0028). However, expression remained significantly above that of healthy animals. Direct evidence regarding curcumin-mediated regulation of FBN1 in adipose tissue is currently limited. Consequently, the present observation cannot be directly compared with a large body of previous research. Rather, it should be interpreted in the context of curcumin's established effects on adipose tissue inflammation, oxidative stress, insulin signaling, and adipokine secretion. High-fat feeding promotes adipose tissue expansion, inflammation, oxidative stress, and insulin resistance. In a rat model, curcumin supplementation reduced body weight, adipose tissue mass, fasting glucose, insulin, HOMA-IR, inflammatory markers, and oxidative stress [27]. Similarly, curcumin attenuated inflammation, oxidative stress, and insulin resistance in fructose-fed Wistar rats through modulation of stress-sensitive kinases and insulin signaling [28]. These observations raise the possibility that the reduction in FBN1 expression in the present study may reflect improvement of the adipose metabolic environment. Curcumin may indirectly influence FBN1 transcription through attenuation of oxidative stress and inflammatory signaling rather than acting as a direct FBN1 transcriptional inhibitor. This distinction is important because the present study measured FBN1 at the mRNA level only. It did not evaluate FBN1 protein abundance, profibrillin processing, furin activity, or extracellular matrix architecture. Therefore, the observed reduction should be interpreted as evidence of altered FBN1 gene expression rather than definitive evidence of reduced FBN1 protein or reduced asprosin biosynthesis.

The significant reduction in circulating asprosin following curcumin treatment represents another important finding. Although asprosin has increasingly been investigated as a metabolic hormone, relatively few studies have evaluated nutritional or pharmacological interventions that modify this pathway. The present results indicate that curcumin reduced serum asprosin by approximately the same direction as the reduction in adipose FBN1 expression. This parallel response is biologically plausible because asprosin is derived from the FBN1-encoded profibrillin precursor [17,18]. An interpretation is that curcumin improved adipose tissue function, leading to simultaneous reductions in FBN1 expression and asprosin secretion. Curcumin has been demonstrated to modulate several adipokines in humans. For example, a randomized controlled trial reported beneficial effects of curcumin on circulating adiponectin and leptin concentrations [29]. Meta-analytic evidence has similarly suggested that curcumin supplementation can increase adiponectin concentrations [29] and decrease leptin concentrations [30]. These findings support the broader concept that curcumin can alter adipose-derived endocrine signals. The present study extends this concept to asprosin, a glucogenic adipokine derived from FBN1.

The reduction in fasting blood glucose following curcumin supplementation was significant (p < 0.0001). Nevertheless, glucose concentrations remained higher in curcumin-treated diabetic rats than in both control groups. This partial normalization is consistent with an improvement rather than complete reversal of the diabetic phenotype. Previous experimental studies have consistently reported glucose-lowering effects of curcumin. In diabetic db/db mice, curcumin significantly reduced blood glucose and HbA1c, improved glucose tolerance and HOMA-IR, and modified hepatic enzymes involved in glucose metabolism [16]. Curcumin also reduced fasting glucose, insulin, HOMA-IR, lipid abnormalities, inflammation, and oxidative stress in high-fat-fed rats [27]. The antidiabetic effects of curcumin may involve multiple mechanisms. A review of experimental evidence concluded that curcumin can influence hepatic glucose production, GLUT expression, AMPK activation, PPAR signaling, pancreatic function, and insulin sensitivity [5]. Furthermore, curcumin has been reported to improve hepatic insulin signaling through PI3K/Akt-related mechanisms in experimental diabetes [12]. Curcumin may also reduce hepatic gluconeogenesis. In diabetic db/db mice, curcumin increased hepatic glucokinase activity while decreasing glucose-6-phosphatase and phosphoenolpyruvate carboxykinase activities [16]. Because asprosin independently promotes hepatic glucose production, simultaneous suppression of asprosin may provide an additional mechanism through which curcumin could contribute to improved fasting glucose.

The diabetic group exhibited a marked increase in HOMA-IR compared with both control groups (p < 0.0001), while curcumin significantly reduced HOMA-IR compared with untreated diabetic animals. However, HOMA-IR remained higher than in the healthy groups. These findings are consistent with experimental evidence showing that curcumin can improve insulin sensitivity. In high-fat-fed rats, curcumin significantly reduced fasting insulin and HOMA-IR and attenuated inflammatory and oxidative abnormalities [27]. In fructose-fed Wistar rats, curcumin improved insulin resistance through attenuation of IRS-1 serine phosphorylation and enhancement of IRS-1 tyrosine phosphorylation [28]. Curcumin has also been investigated in human T2DM. A randomized controlled trial in overweight/obese patients with T2DM found that curcuminoids significantly reduced fasting glucose, HbA1c, and HOMA-IR, accompanied by reductions in circulating free fatty acids [31]. Another randomized trial using piperine-supplemented Curcuma longa reported reductions in glycemia, HbA1c, HOMA index, and triglycerides [32]. A systematic review and meta-analysis of randomized controlled trials similarly reported significant improvements in HOMA-IR and HbA1c following curcumin supplementation in people with T2DM [33]. Another systematic review of randomized clinical trials involving individuals with T2DM found that curcumin improved fasting blood glucose and HbA1c, with reductions in HOMA-IR observed in several studies [34]. More recent evidence further supports these findings. In a randomized controlled trial involving obese patients with T2DM, 12 months of curcumin supplementation reduced fasting blood glucose, HbA1c, HOMA-IR, body mass index, and leptin while increasing adiponectin [35]. A recent dose-response meta-analysis including randomized controlled trials also reported significant reductions in fasting glucose, HbA1c, fasting insulin, and HOMA-IR following curcumin/turmeric supplementation [36]. Thus, the improvement in HOMA-IR observed in the present animal model is consistent with both experimental and clinical evidence.

Inflammation and oxidative stress are plausible intermediates linking curcumin administration to the FBN1–asprosin pathway. Chronic metabolic inflammation contributes to adipose tissue dysfunction and systemic insulin resistance. Curcumin has demonstrated anti-inflammatory activity through modulation of NF-κB and other inflammatory signaling pathways [5]. In high-fat-fed rats, curcumin reduced TNF-α, C-reactive protein, oxidative stress markers, and hepatic lipid accumulation [27]. In fructose-fed rats, curcumin reduced TNF-α, CRP, COX-2, PKCθ, ERK1/2, and p38 signaling while preventing IκBα degradation [28]. These findings indicate that curcumin can interfere with several stress-sensitive pathways implicated in insulin resistance. At the adipocyte level, curcumin has also been shown to influence inflammatory and oxidative responses. Curcuma longa polyphenols reduced ROS, TNF-α, IL-6, MCP-1, and NF-κB while improving adiponectin secretion and PPAR-γ expression in oxidatively stressed adipocytes [37]. Furthermore, curcumin has been investigated in hypoxic adipocytes, a model relevant to dysfunctional expanding adipose tissue, with evidence of attenuation of inflammatory and insulin-resistant responses [38]. These effects provide a plausible framework in which curcumin-induced improvement of adipose tissue homeostasis could reduce abnormal FBN1 expression and asprosin secretion. Nevertheless, because inflammatory cytokines and oxidative stress markers were not measured in the present study, this proposed mechanism remains inferential.

The effects of curcumin on FBN1 and asprosin may be part of a broader modulation of adipose endocrine function. Adipose tissue secretes multiple hormones and adipokines, including adiponectin, leptin, resistin, and asprosin, that influence systemic glucose and lipid metabolism. A randomized clinical trial found that curcumin supplementation increased adiponectin and modified leptin concentrations [29]. A meta-analysis of randomized controlled trials reported a significant increase in circulating adiponectin following curcumin supplementation [39], while another meta-analysis found a significant reduction in leptin [30]. A more recent GRADE-assessed systematic review also evaluated the effects of curcumin on both adiponectin and leptin [40]. The regulation of adipokines is relevant to the present findings because improved adipose tissue endocrine function could reduce pathological asprosin secretion. However, asprosin should not simply be considered another conventional adipokine because it is derived from FBN1 and possesses distinct endocrine actions on hepatic glucose production and central appetite regulation.

The diabetic animals had significantly greater body weight than the control groups, whereas curcumin significantly reduced body weight compared with untreated diabetic rats (p = 0.0011). Body weight in curcumin-treated diabetic animals remained higher than in the non-diabetic curcumin group but was not significantly different from the untreated control group. The reduction in body weight may have contributed to the decline in serum asprosin. Asprosin is predominantly secreted from white adipose tissue and has been shown to promote appetite and adiposity [20]. Elevated asprosin concentrations have also been associated with obesity indices in humans [23]. Experimental and clinical studies have demonstrated modest weight-related effects of curcumin. Curcumin reduced body weight and adipose tissue mass in high-fat-fed rats [27]. In humans, randomized clinical trials and meta-analyses have also suggested modest improvements in body weight or adiposity-related indices following curcumin supplementation [35]. However, the direction of causality again remains uncertain. Reduced adiposity could decrease asprosin secretion, while reduced asprosin could theoretically influence appetite and energy balance. Because food intake, adipose tissue mass, and adipocyte size were not directly assessed in the present study, further studies are required to clarify this relationship.

The similarity between the present findings and those reported following metformin treatment is particularly noteworthy. Dashtkar et al. demonstrated that metformin reduced both FBN1 expression in adipose tissue and serum asprosin in HFD/STZ-induced diabetic rats [14]. This parallel suggests that FBN1 and asprosin may represent downstream metabolic markers that respond to improvement in diabetic metabolic dysfunction. Other antidiabetic agents have also been shown to modify adipokine profiles. Saad et al. reported that metformin and sitagliptin improved insulin resistance and altered adiponectin and leptin concentrations in HFD/STZ diabetic rats [13]. These observations reinforce the concept that improvement of insulin sensitivity can be accompanied by remodeling of adipose endocrine signaling. Importantly, the similarity between curcumin and metformin should not be interpreted as evidence of a common direct molecular target. Curcumin has multiple biological activities, whereas metformin has a distinct pharmacological profile. Rather, FBN1 and asprosin may represent components of a metabolic network that is normalized when insulin sensitivity and adipose tissue function improve.

4.1. Potential mechanistic model

Taken together, the findings support a working model in which HFD/STZ-induced diabetes promotes adipose tissue dysfunction, increased FBN1 expression, and increased circulating asprosin. Elevated asprosin may subsequently contribute to hepatic glucose production and impaired glucose homeostasis through OLFR734-dependent signaling [18,19]. Curcumin may intervene at several levels of this network. Its antioxidant and anti-inflammatory effects may improve adipose tissue metabolic homeostasis, while its effects on insulin signaling and glucose metabolism may reduce the metabolic stimuli associated with abnormal adipokine secretion. These changes could be accompanied by reduced FBN1 expression and decreased circulating asprosin. The reduction in asprosin may, in turn, decrease excessive hepatic glucose production, thereby contributing to improved fasting glucose and insulin resistance. The current study establishes that curcumin treatment is associated with simultaneous reductions in FBN1 expression, serum asprosin, fasting glucose, insulin, HOMA-IR, and body weight.

Asprosin has emerged as a multifaceted pathogenic mediator in type 2 diabetes mellitus, exerting its effects through four key mechanisms that collectively perpetuate metabolic dysfunction. First, asprosin directly promotes insulin resistance by impairing insulin signaling in peripheral tissues, including skeletal muscle, liver, and adipose tissue, thereby reducing glucose disposal and exacerbating hyperglycemia. Second, asprosin contributes to chronic low-grade inflammation by elevating pro-inflammatory cytokines such as TNF-α and IL-6, which are directly toxic to pancreatic β-cells and accelerate their functional decline. Third, asprosin participates in redox imbalance by diminishing endogenous antioxidant defenses and increasing oxidative stress, further compromising β-cell survival and insulin secretory capacity. Fourth, asprosin adversely modulates lipid metabolism by elevating triglycerides and perturbing cholesterol homeostasis, and given that hypertriglyceridemia itself reinforces insulin resistance, this creates a bidirectional vicious cycle that sustains metabolic dysregulation. Collectively, these multifaceted actions position the adipose FBN1–asprosin axis as a central pathogenic hub in T2DM. The present study demonstrates that curcumin—a natural polyphenol with well-established anti-inflammatory, antioxidant, and insulin-sensitizing properties [41,42]—can simultaneously attenuate adipose FBN1 expression and circulating asprosin levels, thereby interrupting this pathogenic cascade and improving multiple facets of metabolic dysfunction."

The improvement in insulin resistance observed following curcumin treatment in our diabetic rats warrants particular attention in the context of the FBN1–asprosin axis [43]. Curcumin has been recognized as a potent modulator of insulin sensitivity through multiple mechanisms, including activation of AMPK, enhancement of GLUT4 translocation, suppression of hepatic gluconeogenesis, and inhibition of NF-κB-mediated inflammatory signaling [44,45]. Our findings extend this established framework by demonstrating that curcumin-mediated improvement in insulin resistance is accompanied by parallel reductions in adipose FBN1 expression and circulating asprosin. This suggests that the beneficial effects of curcumin on insulin sensitivity may be partially mediated through downregulation of the asprosin pathway, thereby reducing asprosin-driven hepatic glucose production, inflammation, oxidative stress, and lipid dysregulation. Importantly, the concurrent improvement in HOMA-IR and TyG index following curcumin treatment supports the concept that curcumin exerts pleiotropic effects that encompass both glycemic and lipid components of insulin resistance.

4.2. Strengths and limitations

The principal strength of the present study is the simultaneous evaluation of adipose FBN1 gene expression and circulating asprosin in a controlled experimental model of T2DM. The four-group design also allowed differentiation between the effects of diabetes and curcumin treatment in diabetic and non-diabetic animals. The diabetic model was maintained for eight weeks at a defined curcumin dose. Several limitations should nevertheless be acknowledged. First, FBN1 was evaluated at the mRNA level rather than at the protein level. Consequently, it remains unknown whether the reduction in FBN1 mRNA was accompanied by reduced FBN1 protein or altered profibrillin processing. Second, serum asprosin was measured, but tissue asprosin production and downstream signaling were not assessed. In particular, measurement of hepatic OLFR734 and downstream cAMP/PKA signaling would provide stronger mechanistic evidence. Third, inflammatory cytokines, oxidative stress markers, adipose tissue histology, adipocyte size, and extracellular matrix remodeling were not evaluated. Therefore, the proposed involvement of inflammation, oxidative stress, and adipose tissue remodeling in the curcumin-induced regulation of FBN1 and asprosin remains hypothetical.

In addition, only a single dose of curcumin (300 mg/kg/day) was evaluated in the present study. While this dose was selected based on previous studies demonstrating its efficacy and safety in rodent models of metabolic dysfunction [5,12,27], the absence of a dose–response analysis limits our ability to determine the optimal therapeutic dose, the minimum effective dose, and the dose-dependent nature of curcumin's effects on the FBN1–asprosin axis. Future studies incorporating multiple dose levels—ranging from sub-therapeutic to potentially maximal effective doses—would be valuable to establish the dose–response relationship and to guide the selection of appropriate doses for clinical translation.

4.3. Future directions

Future studies should determine whether curcumin directly regulates FBN1 transcription or whether the reduction in FBN1 expression is secondary to improvement in adipose tissue metabolic homeostasis. Measurement of FBN1 protein, profibrillin, furin activity, tissue asprosin, and extracellular matrix remodeling would be particularly informative. It would also be important to determine whether curcumin modifies the hepatic response to asprosin. Measurement of OLFR734 expression and downstream cAMP/PKA/CREB signaling could establish whether the reduction in circulating asprosin is accompanied by reduced asprosin signaling. Causal experiments would provide even stronger evidence. For example, pharmacological or genetic inhibition of asprosin, FBN1 manipulation, or restoration of asprosin during curcumin treatment could determine whether the FBN1–asprosin axis is necessary for the metabolic effects of curcumin. Finally, dose-response studies and comparisons of conventional curcumin with formulations having improved bioavailability should be considered. Translation of these findings to humans will require clinical studies assessing whether curcumin supplementation modifies circulating asprosin and whether such changes are associated with improvements in insulin resistance and glycemic control.

5. Conclusion

In conclusion, the present study provides compelling evidence that curcumin supplementation significantly attenuates adipose FBN1 expression and circulating asprosin concentrations in a rat model of T2DM, while simultaneously improving fasting glucose, fasting insulin, HOMA-IR, TyG index, and body weight. These findings identify, for the first time, the adipose FBN1–asprosin axis as a previously unrecognized molecular target of curcumin's metabolic actions. The parallel improvements across both glycemic and lipid parameters underscore the pleiotropic nature of curcumin's antidiabetic effects and support the concept that the FBN1–asprosin axis serves as an integrative metabolic sensor linking adipose tissue dysfunction to systemic insulin resistance. While further mechanistic studies—including direct manipulation of the asprosin pathway—are required to establish causality, our findings position curcumin as a promising adjunctive therapeutic agent and the FBN1–asprosin axis as a viable target for comprehensive metabolic intervention in T2DM. These results provide a strong foundation for future clinical investigations evaluating whether curcumin supplementation can modulate asprosin levels in humans and whether such modulation translates to improved metabolic outcomes.

CRediT authorship contribution statement

Abdolvahed Safarzaei: Project administration, Formal analysis. Hamid Hafezinouri: Project administration, Formal analysis. Hamed Fanaei: Writing – original draft, Methodology, Funding acquisition.

Ethics declaration

This study was conducted in accordance with the ARRIVE (Animal Research: Reporting of In Vivo Experiments) guidelines. This study was approved by Ethics Committee of Zahedan University of Medical Sciences (ethical code: IR.ZAUMS.AEC.1404.012).

Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

Funding sources

This study was financially supported by the Office of the Vice-Chancellor for Research and Information Technology at Zahedan University of Medical Sciences, Zahedan, Iran (Grant No. 12070).

Declaration of competing interest

All authors declare that they have no actual or potential conflict of interest.