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. 2026 Jul 1;16:30223. doi: 10.1038/s41598-026-60052-5

Influence of high-fat diet and sex on connective tissue in carpal tunnel syndrome

Tomoyuki Kuroiwa 1, Hayman Lui 1, Koichi Nakagawa 1, Naoya Iida 1, Claire Desrochers 1, Rou Wan 1, Ken Nishimura 1, Elameen Adam 1, Dirk Larson 2, Peter Amadio 1,✉, Anne Gingery 1,3,4,✉
PMCID: PMC13623633  PMID: 42380228

Abstract

Carpal tunnel syndrome (CTS) is a common musculoskeletal disorder, characterized by thickening and fibrosis of the subsynovial connective tissue (SSCT). Risk factors for CTS includes sex, metabolic dysfunction and age. Interestingly although the overall prevalence of CTS is higher in women than in men, men exhibit a greater incidence under conditions of metabolic dysfunction. This suggests a focus on metabolic and sex specific therapeutic strategies for the treatment of patients with CTS. In this study we hypothesized that a high-fat diet (HFD), a common driver of metabolic dysfunction, would promote SSCT thickening in CTS and that this response would be sex dependent. To test this, we examined the effects of HFD and sex on SSCT thickening and markers of fibrosis using our established CTS rabbit model of SSCT thickening. Forty-eight mature adult rabbits (24 male and 24 female) were assigned to four groups including HFD or standard diet (STD), each with and without CTS induction. SSCT was collected for histological and gene expression analysis. Here we found that HFD promoted SSCT thickening and upregulated profibrotic genes, including TGF-β, with additional fibrotic genes exhibiting sex-specific differential expression.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1038/s41598-026-60052-5.

Keywords: Carpal tunnel syndrome, Sex, High-fat diet, Subsynovial connective tissue, Rabbit

Subject terms: Physiology, Ageing

Introduction

Carpal Tunnel Syndrome (CTS) is an idiopathic non-inflammatory fibrotic age-related disorder in which progressive fibrosis of the subsynovial connective tissue (SSCT) within the carpal tunnel is associated with progressive compression and dysfunction of the median nerve. Despite this prevalence, in most cases the underlying cause of CTS is unknown. Surgery is the only effective curative treatment1. A better understanding of the etiology of CTS is important, as this may lead to new nonsurgical treatments, targeting the underlying mechanism of disease.

Fibrosis and subsequent thickening of the SSCT is driven by transforming growth factor beta (TGF-β)-mediated signaling2–4. A significant risk factor for CTS is metabolic dysfunction5, which has been proposed to induce systemic inflammation that promotes fibrosis in various tissues and organs6. Multiple studies have reported that metabolic dysfunction and high fat diet (HFD) promotes TGF-β-mediated fibrosis7–14.

Another important consideration when evaluating the etiology of CTS is the marked sex difference in the prevalence, as CTS occurs approximately twice as often in women as in men15. Interestingly, men with metabolic dysfunction are more likely than women to have CTS16,17. Based on this information, we hypothesized that there is a sex difference in the relationship between CTS SSCT thickening, markers of fibrosis and metabolic dysfunction. We also hypothesized that HFD18–20 which drives metabolic dysfunction and induces SSCT thickening in the carpal tunnel in a sex dependent manner.

We used our established rabbit model of CTS which is the smallest animal with human-like SSCT21. Briefly, the model is created by injecting hypertonic dextrose into the carpal tunnel synovium22,23. The resulting fibrosis of the SSCT recapitulates the fibrosis found in CTS patient SSCT2–4. To test our hypotheses, we conducted a comparative study to evaluate SSCT thickening and markers of fibrosis in mature male and female rabbits fed a HFD or standard normal diet (STD), with or without CTS fibrosis induction (Fig. 1)23–25.

Fig. 1.

Fig. 1

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Experimental design. Forty-eight rabbits were divided into four groups (n = 6 per group) based on diet—high fat diet (HFD) or standard diet (STD) and procedure—CTS induction (CTS) or Sham (n = 6 per group). Rabbits were maintained on their respective diets prior to CTS or Sham procedures. Animals were sacrificed six weeks after the first CTS or Sham injection, and blood analyses were performed at the time of sacrifice. Three rabbits died during the study: one STD-female (unknown cause), and two HFD rabbits (one male and female) due to liver failure.

Results

Metabolic dysfunction

Blood analyses were completed at sacrifice. The results showed no significant interactions between diet and sex (Fig. 2). However HFD in both males and female rabbits had noted significantly higher cholesterol, triglycerides, and insulin levels and significant lower glucose levels as compared to STD rabbits (Fig. 2).

Fig. 2.

Fig. 2

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Blood analysis. Cholesterol, triglycerides, glucose, and insulin levels of rabbits at sacrifice were measured. Interactions between diet and CTS were not significant. The main effect of diet significantly regulated cholesterol, triglycerides, glucose, and insulin levels. Additionally significant sex differences were found in insulin levels. P values for the main or interaction comparisons (diet and sex) are shown.

SSCT histology

SSCT thickness, a marker of SSCT fibrosis, was measured (Fig. 3). A representative image of hematoxylin-eosin SSCT measurement is shown in Fig. 3a. The overall average SSCT thickness (mean ± s.d) was 0.16 ± 0.03 mm, 0.31 ± 0.03 mm, 0.33 ± 0.03 mm, and 0.33 ± 0.026 mm in the STD+Sham, STD + CTS, HFD+Sham, and HFD + CTS groups, respectively. The analysis showed that there was a significant interaction between diet and CTS induction and that both main effects of induction and diet were significant in affecting SSCT thickness (Fig. 3b). In male rabbits, the interaction effects were significant (Fig. 3c). In contrast, CTS induction alone in female rabbits was found to be the main driver of SSCT fibrosis (Fig. 3d).

Fig. 3.

Fig. 3

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SSCT thickness. (a) Representative histological cross-sectional images of the carpal tunnel inlet (H&E staining) in STD+Sham and HFD+Sham groups. Subsynovial connective tissues (SSCT) thickness between flexor digitorum superficialis (FDS2) and flexor digitorum profundus (FDP). (b) Average SSCT thickness in CTS and Sham induced group treated with high fat diet (HFD) or standard diet (STD). n = 11. The interaction between diet and CTS induction was significant. (c) Assessment in male rabbits showed significant interaction between diet and CTS induction. (d) Female rabbit CTS did not have significant interaction between diet and induction but separately showed that CTS induction drove increases in SSCT thickness. Means ± standard errors are depicted. P values for the main or interaction comparisons (CTS induction and diet) are shown. *, and ** indicate significant differences between the respective groups with p value < 0.05, and < 0.01, respectively. (n = 5–6 per group).

SSCT Gene expression

Fibrotic gene expression differences between CTS treatments were reported comparing CTS fibrosis induction or sham and diet (Fig. 4). High fat diet (HFD) and standard diet (STD) were assessed using RT2 Profiler™ PCR Fibrosis Arrays (Fig. 4a-d). Significant interaction effects (diet and CTS induction) were found for multiple fibrosis-promoting genes, including Itga1, Itgb1, Tgfbr1, Ilk, Stat6, and Vegfa were upregulated in the combination of CTS induction and HFD (Table S-2). Significant main effects of induction (45 genes) and diet (17 genes) were also found (Table S-2). These include fibrosis-promoting genes, including Il1a, Itgav, Tgfb3, Tgfbr1, Timp1 and Smad7 which were upregulated by CTS induction alone. Furthermore, it was observed that HFD fibrosis-promoting genes including Ctgf and Cxcr4 were upregulated, and genes such as Dcn and Ifng were down-regulated in HFD rabbits. (Fig. 4e and Table S-2).

Fig. 4.

Fig. 4

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Gene expression changes following CTS induction and diet. Relative gene expressions were measured from SSCT following CTS or Sham induction and HFD or STD diets. (a–d) Scatter plots of effect of CTS induction (a), effect of HFD (b), effect of HFD on CTS induction (c) and effect of CTS induction with HFD (d). Yellow dots indicate genes that were significantly expressed at 1.5-fold or greater change relative to STD+Sham, HFD+Sham, or STD + CTS group. Down regulated genes in blue indicate genes significantly downregulated 0.5-fold or less change. P < 0.05 was considered a significant difference, (n = 5–6 per group). (e) Fold expression of select genes normalized to STD+Sham. Interaction indicates the significance of the interaction between CTS induction and diet. Means ± standard errors are depicted. P values for the main or interaction comparisons (CTS induction and diet) are shown. *, and ** indicate significant differences between the respective groups.

In analysis comparing sex, it was observed that the combination of male sex and a HFD resulted in 8 significantly upregulated genes, including Cul1, Cxcr4, Eng, Fli1, Prkcd, Stat6, Tgfbr1, and Timp4 (Table S-3). In contrast, female interaction between sex and diet demonstrated only one upregulated gene (Illb) (Table S-3). No shared down-regulated genes were observed in HFD in both sexes (Table S-3). In males, significant main effects of CTS induction were found in 28 genes and in diet 3 regulated genes. In females, significant main effects of CTS induction were found in 4 genes and main effects in diet identified 13 regulated genes. Of the 46 genes that demonstrated significant main effects, only two genes had the same main effect in both males and females (Itgav and Tgfb3) (Fig. 5 and Table S-3).

Fig. 5.

Fig. 5

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Gene expression changes following CTS induction, diet in male and females. Relative gene expressions were measured from SSCT following CTS or Sham induction and HFD or STD diets separated by males and females. Fold changes normalized to male STD+Sham or female STD+Sham groups. Interactions between induction and diet are reported. Means ± standard errors are presented. P values for the main or interaction comparisons (induction and diet) are shown. *, and ** indicate significant differences between the respective groups. (n = 5–6 per group).

Discussion

CTS is an idiopathic non-inflammatory fibrotic age-related disorder in which progressive thickening of the SSCT within the carpal tunnel can result in the progressive compression and dysfunction of the median nerve3,26–29. Incidence of CTS is associated with metabolic dysfunction, age and sex15–17.

In this study a rabbit model of CTS thickening and HFD was used to assess the role of metabolic dysfunction and CTS22,25,30–32. All rabbits exhibited induced hypercholesterolemia with HFD. CTS induction and HFD upregulated many fibrosis-inducing genes including Tgfbr1, a receptor protein of the TGF-β family, as well as fibrosis-associated integrin-related genes (Itga1, Itgb1, Ilk)2,33–35, Stat 636, and Vegfa28,37. Additionally CTS fibrosis induction and HFD significantly increased SSCT thickness.

Given the high prevalence of CTS and metabolic dysfunction in middle-aged patients, we selected mature animals to more accurately represent the clinical condition studied. While the CTS model robustly recapitulates SSCT fibrosis, the HFD rabbit model does have inherent constraints. The use of an herbivorous species to model metabolic changes found in omnivorous populations is a limitation. In our work and in prior studies this HFD model has shown sensitivity to diet-induced changes that are relevant to patient populations. It should be noted that the markedly elevated cholesterol levels observed in this model exceed those typically seen in patients and that the triglyceride levels are at the high end of patient reported levels but remain within physiological range. The model does recapitulate patient CTS and the HFD treated rabbits used in this study developed hypercholesterolemia and hypertriglyceridemia similar to what has been found in previous reports25. Interestingly we did not find a significant increase in blood glucose levels. This difference may be attributable to age, as the present study used mature rabbits, whereas previous metabolic studies used young rabbits. This finding that HFD blood glucose levels are not significantly increased in mature rabbits is consistent with trends observed in other HFD animal studies using both young and aged animals which also report a significant elevation in blood glucose levels only in young animals but not in mature animals38,39. This underscores the importance of using mature preclinical models to recapitulate patient conditions more accurately.

It is well established that metabolic dysfunction promotes fibrosis in many tissues/organs6,40. Clinically, metabolic dysfunction has been reported as one of the risk factors for CTS5,41–43, and the results reported here provide support for HFD driving SSCT thickening. Interestingly, subgroup analysis of sex showed that the HFD induced SSCT thickening in male rabbits only and that the regulated gene profiles are different between treatments. Similarly previous studies have reported that mature male rats and mice were also more vulnerable to the effects of the HFD than females44,45. Our findings are consistent with clinical studies have reported that metabolic dysfunction is a risk factor for CTS5,41–43,46, and that this incidence is higher in males16,17.

We and others have shown that Ctgf is a known mediator of TGF-β induced fibrosis4,29,47,48. In this study, HFD resulted in significant increases in Ctgf. This response has been observed in previous HFD animal studies49–51 and in analysis of SSCT tissue of patients with CTS2,3. Additionally, Tgfbr1 and integrin-related genes were observed to be significantly upregulated in both CTS induction and HFD animals. Tgfbr2 encodes a receptor that binds to Tgf-β protein, promotes Tgf-β signaling, and has also been found to be upregulated with metabolic dysfunction4,12,29,48,52,53. A subset of the integrin family has been reported to play an important role in the protein activation of latent TGFβ-1, which drives fibrosis in multiple conditions.34,35,54,55. The significant upregulation of these genes is consistent with the results of the SSCT thickness assessment.

In contrast, the expression of anti-fibrotic genes such as Ifng56,57 and Dcn58–60 were noted to be significantly downregulated in HFD rabbits. Interferon-γ, encoded by Ifng, is an immune-regulatory cytokine that also serves as a strong anti-fibrotic agent57. IFN-γ also inhibits fibroblast proliferation and collagen deposition and downregulates Tgfb expression56. The combination of both upregulation of fibrotic genes and downregulation of anti-fibrotic genes in HFD rabbits suggests that metabolic dysfunction induces gene expression changes that may drive SSCT fibrosis.

Gene expression levels also differed between males and females. In male rabbits, CTS induction significantly upregulated Cav1 and Smad7. Cav1 is overexpressed in adipose tissue of obese patients and is positively correlated with body fat and body mass index61. Cav1 has also been reported to suppress fibrosis in various organs via suppression of TGF-β/Smad signaling62,63. Smad7, a Smad inhibitory protein, is a key regulator that binds to regulatory SMADs and acts in to inhibit TGF-β signaling. Smad7 overexpression has been shown to antagonize TGF-β-mediated fibrosis and inflammation64,65. Therefore, the observed elevation in Cav1 and Smad7 expression in male rabbits may be a compensatory response to ongoing fibrosis in the SSCT.

Furthermore, Dcn, another negative regulator of TGF-β signaling, was significantly down regulated in HFD males only. Decorin, a small leucine-rich proteoglycan encoded by Dcn, regulates collagen fibrillogenesis during development. It exerts a protective effect against fibrosis in various tissues by directly blocking the bioactivity of Tgfb158–60. The loss of this important TGF-β regulator in conditions of metabolic dysfunction may contribute to increased SSCT fibrosis in males.

Another gene that was regulated by diet in males was plasminogen activator encoded by Plat. Plat is a component of the plasminogen system that is important for proteolytic remodeling of extracellular matrix. Plasminogen activators can act to attenuate the action of plasminogen activator inhibitors (PAI-1) that can drive fibrosis and extracellular matrix deposition66. Expression of Plat could be a compensatory mechanism to attenuate fibrosis. Plat also has been shown to limit activation of Tgfb167,68.

In contrast, HFD significantly upregulated Mmp2 and downregulated Smad ubiquitin regulatory factor 2 (Smurf2) in females only. MMP2 has been shown to have anti-fibrotic effects69,70 and Smurf2 negatively regulates TGF-β signaling by ubiquitinating TGF-β receptors (TβR) and Smad proteins. Together, these significant disparities in gene expression may provide a mechanistic explanation for the disparate response to CTS induction and diet in males and females.

In this study, female rabbits were housed two to a cage, whereas male rabbits were housed 1 to a cage, as required by our IACUC. This difference in housing may have caused differences in exercise and other behaviors. HFD rabbits were maintained on HFD for 12 weeks, in contrast the STD rabbits were induced for CTS or Sham after the standard 1 week of acclimation at Mayo Clinic. The effect of the difference in length of housing in our facility is likely to be negligible, as the duration of housing in our facility for the treatment phase was identical in all four groups. Subsequent use of this model could explore modifications to the high-fat diet to more closely approximate the lipid levels found in patients with metabolic dysfunction. Our future work includes assessment of sex differences in the gene and protein regulation of Cav1, Dcn, Mmp2, Plat, Smad7, Smurf2 in patient CTS SSCT biopsies.

In summary, the effect of HFD and its interaction with sex on SSCT thickening in a CTS animal model was studied. HFD resulted in increased fibrotic gene expression and SSCT thickness compared to STD rabbits. This is consistent with previous analysis of the SSCT in CTS patients23,71. In addition, the combination of HFD and CTS induction in males resulted in significantly greater SSCT thickening when compared to females. This is supportive of previous reports indicating that men with metabolic dysfunction are more likely to develop CTS16,17. This study has shown a potential mechanism for the observed differential sex-based development of CTS in patients with metabolic dysfunction.

Materials and methods

Animals

Mayo Clinic Institutional Animal Care and Use Committee (IACUC A5660) approved this study, and all procedures were performed in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals and in accordance with the ARRIVE guidelines. Animals were anesthetized with an intramuscular injection of Ketamine (35–40 mg/kg) and Xylazine (5 mg/kg), maintained on Isoflurane (1.5-3%) for duration of the procedures. Animals were sacrificed with an overdose of pentobarbital IV (100 mg/kg). All efforts were made to minimize suffering.

The CTS SSCT fibrosis rabbit model was created by our group and is the smallest animal with human-like SSCT22,23,71,72. CTS and the subsequent SSCT fibrosis is induced in this model by injecting 0.05 ml of 10% dextrose solution into the carpal tunnel through a small incision. Localization of the carpal tunnel is facilitated in the rabbit as the flexor retinaculum contains an easily palpated fibrocartilaginous disc. The dextrose solution is injected into the synovium around the middle-digit flexor digitorum superficialis (FDS) tendon, using a 30-gauge needle. A second injection is given by an identical method 1 week later. Saline injected rabbits were used for sham analysis following the same procedure. This model recapitulates the SSCT thickening and fibrosis found in CTS patients. 48 retired breeder New Zealand White mature rabbits (Charles River Laboratories) (24 females, 24 males) were used, as CTS is an age-related disease with its peak incidence in humans aged 45–55. For this reason, we used mature rabbits with an average age of 2.6 years (range: 0.9–4.3), including males 2.8 years (1.2–4.3) and.

Rabbits were randomly divided into four groups of 12 (6 females and 6 males in each group). The groups were fed a STD or a HFD and SSCT fibrosis was induced by dextrose injections which drives SSCT thickening (CTS) or saline injections (Sham) as previously described22. Groups were designated as follows: STD+Sham, STD + CTS, HFD+Sham, and HFD + CTS (Fig. 1). Rabbits in the STD groups were acclimated for a week on STD and then received the CTS or Sham injections as described below. STD rabbits continued the STD for an additional 6 weeks prior to sacrifice. HFD group rabbits were acclimated for a week and fed HFD for 12 weeks prior to injections to develop metabolic dysfunction, based on previous studies of HFD in rabbits30–32. The HFD rabbits then received CTS or Sham injections and continued the HFD for an additional 6 weeks prior to sacrifice. (Fig. 1). In all groups immediately after sacrifice, one forepaw was harvested for histology and the other for SSCT gene expression analysis. Metabolic dysfunction was assessed by measuring hyperglycemia, hypercholesterolemia, and hypertriglyceridemia dysfunction as described below73. Three rabbits died during the study. One STD-fed female during the study at 1.5 weeks of unknown causes and two HFD-fed rabbits (one female and one male) died during the study at 5.5 weeks post CTS induction died from liver failure, associated with the HFD.

Diet

The STD group was fed a standard rabbit diet (Laboratory Rabbit Diet HF 5326, CA) that consisted of 12% water, 14.5% protein, 23% fiber, and 3.8% fat. The HFD (Teklad Custom Diet TD.200785, ENVIGO, IN) was the STD supplemented with 0.5% cholesterol and 4% peanut oil, as previously reported24,25,30,31. Water and food were not restricted during this study.

CTS induction

Using our established rabbit model of CTS, a small incision was made with direct vision while under rabbits were under anesthesia. For CTS and sham induction, the carpal tunnels of both forepaws were injected with either 0.1 ml of 10% dextrose solution (CTS) or 0.1 ml of 0.9% saline (Irrigation, Baxter, IL) (Sham), using a 30-gauge needle. As per the protocol two injections were given 1 week apart. Each injection was made inside the synovium around the middle digit flexor digitorum superficialis tendon, as described previously23,71.

Metabolic dysfunction assessment

Blood samples were taken at sacrifice. Rabbits were fasted overnight and blood was taken from the marginal ear vein. Blood samples were centrifuged at 3,000 rpm for 20 min at 4 °C, and the supernatant was collected as serum. Samples were sent to IDEXX BioAnalytics (Columbia, MO) for analysis of total cholesterol, triglyceride, glucose, and insulin levels in the serum (IDEXX BioAnalytics Case # 82497-2021).

Histology

The tissue was harvested so that an axial section at the wrist level was visible after bone removal. The SSCT was fixed in a 4% paraformaldehyde solution for approximately one week, embedded in paraffin, and sectioned into 4-µm-thick slices. Sections were stained with hematoxylin-eosin and observed under a light microscope (All-in-One Fluorescence Microscope BZ-X800, Keyence, IL, RRID: SCR_019119).

Image analysis

Tissue images were evaluated using ImageJ software (ImageJ, National Institutes of Health; http://imagej.nih.gov/ij/, RRID: SCR_003070) by double blind observers. The distance between the flexor digitorum superficialis (FDS) and flexor digitorum profundus (FDP) was measured and determined to be the SSCT thickness, as described in previous studies23,74 (Fig. 3). The average values of the thickness measured by two observers were used for analysis.

Quantitative real-time polymerase chain reaction (PCR)

After sacrifice, total RNA was extracted from the SSCT of one forepaw using Trizol reagent (Invitrogen Life Technologies, NY). The cDNA was obtained from 100 ng of total RNA by reverse transcription using an iScriptTM cDNA Synthesis Kit (Bio-Rad, CA). Gene expression of 96 fibrosis-associated genes were evaluated using a PCR array kit (RT2 Profiler™ PCR Array Rabbit Fibrosis PANZ-120Z, Qiagen) by quantitative real-time PCR using a Thermal Cycler (Bio-Rad Laboratories, CA, RRID: SCR_019152). The average values of the results in triplicate were used for analysis. Data was normalized to the geo-mean of housekeeping genes Acta2, Actb, Gapdh, Ldha, and LOC100346936.

Statistics

Sample size and power

Based on previous studies using this model, a sample size of 6 rabbits per group is required to achieve 80% power to detect a difference in means of 0.15 mm between groups in the FDS-FDP distance, assuming an overall within group standard deviation of 0.08 mm23. Additionally, to perform separate analyses within each sex, each group was fully powered with 6 males and 6 females, for a total of 12 rabbits per group (48 rabbits total). This analysis is powered for 2-way Anova assessments.

Analysis

Statistical analyses were performed using BlueSky Statistics v7.5 software. Separate analyses were performed for males and females. Within each sex subset, the effects of CTS induction (no vs. yes) and diet (HFD vs. STD) on SSCT thickness and gene expression level was evaluated using two-way analysis of variance (ANOVA). For blood test results, mean values were calculated for each diet group and sex and compared using two-way ANOVA. Holm-Bonferroni post-doc tests were completed. P-values less than 0.05 were considered statistically significant.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Material 1 (126.9KB, pdf)

Acknowledgements

This study was supported by NIH-NIAMS R01AR076347 and the Mayo Clinic.

Author contributions

T. Kuroiwa, P. Amadio, and A. Gingery formulated the concept and designed the research; T. Kuroiwa, A. Gingery, H. Lui, K. Nakagawa, R. Wan, and E. Adam performed the experiments; T. Kuroiwa, N, Iida, K. Nishimura, and C. Desrochers acquired the data; T. Kuroiwa, D. Larson, PC. Amadio and A, Gingery analyzed and interpreted the data. All authors were involved in drafting and revising the manuscript. All authors have read and approved the final submitted manuscript.

Data availability

The data that supports the findings of this study are available in the methods and/or supplementary material of this article.

Declarations

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Peter Amadio, Email: pamadio@mayo.edu.

Anne Gingery, Email: gingery.anne@mayo.edu.

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Data Availability Statement

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