WISP-1 in Obesity and Metabolic Dysfunction: The Modulatory Role of Exercise Training- A Narrative Review

Introduction

Obesity is a global health challenge associated with numerous comorbidities, including insulin resistance, chronic inflammation, type 2 diabetes, and cardiovascular diseases (1-3). The prevalence of obesity has increased dramatically in recent decades, prompting intensified efforts to better understand the molecular and physiological mechanisms underlying its pathophysiology and to identify effective therapeutic strategies (4-6). Among these mechanisms, adipose tissue derived factors, known as adipokines, have garnered significant attention due to their regulatory role in metabolic homeostasis and inflammatory processes (6, 7). WNT1-inducible signaling pathway protein 1 (WISP-1), a member of the CCN family of matricellular proteins, has recently emerged as a molecule of interest in obesity research. WISP-1 is expressed in multiple tissues, including adipose tissue, and has been implicated in extracellular matrix remodeling, inflammatory signaling, and metabolic regulation (8). Accumulating evidence indicates that circulating WISP-1 levels are positively associated with markers of adiposity, insulin resistance, and chronic low grade inflammation (9). However, much of the current evidence is observational or derived from experimental models, and definitive mechanistic conclusions in humans remain limited.

Exercise training is widely recognized as a cornerstone intervention for managing obesity and improving metabolic health. Regular physical activity contributes to enhanced insulin sensitivity, improved body composition, and reduced systemic inflammation (10). Exercise has also been shown to influence adipokine secretion profiles, suggesting a potential interaction between physical activity and WISP-1 regulation (11). Nevertheless, the extent to which exercise directly modulates WISP-1 expression, and whether such changes mediate improvements in metabolic outcomes, remains incompletely understood. Recent studies have explored the effects of aerobic training, resistance exercise, and high-intensity interval training (HIIT) on circulating WISP-1 levels in individuals with obesity and related metabolic disorders. Although several interventions report reductions in serum WISP-1 concentrations following structured exercise programs, findings are not entirely consistent, and study designs often involve small sample sizes and short intervention durations (11-13). Furthermore, variability in participant characteristics including; age, sex, metabolic status, and comorbid conditions; may influence reported outcomes. Importantly, while reductions in WISP-1 are frequently observed alongside improvements in insulin sensitivity and inflammatory markers, the available data primarily support associative relationships rather than established causality (13). Therefore, careful interpretation of these findings is warranted.

Given the emerging but still evolving evidence, this narrative review aims to synthesize and critically evaluate current findings regarding the relationship between exercise training and WISP-1 levels in individuals with obesity. In addition to summarizing existing studies, this review highlights methodological limitations, identifies gaps in mechanistic understanding, and discusses the clinical relevance of WISP-1 modulation in the context of exercise based interventions.

WISP-1 and Obesity

WISP-1, or WNT1-inducible signaling pathway protein 1, is a matricellular protein that plays a key role in the regulation of cellular processes such as proliferation, migration, differentiation, and survival (8). Part of the CCN protein family, WISP-1 is expressed in various tissues, including adipose tissue, where it functions as an adipokine. Accumulating evidence suggests that WISP-1 levels may be elevated in individuals with obesity, particularly in visceral adipose tissue, and may be associated with systemic inflammation and metabolic dysregulation (9, 14).

The role of WISP-1 in metabolic disorders has attracted increasing attention, particularly its potential involvement in obesity-related complications. Mechanistically, WISP-1 is proposed to interact with key signaling pathways, including WNT/β-catenin, which may influence adipogenesis, inflammation, and extracellular matrix remodeling (14). However, it is important to note that most evidence is associative or derived from experimental models, and definitive mechanistic conclusions in humans remain limited. Elevated WISP-1 levels have been observed alongside increased inflammatory markers, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) (15), which are central to obesity induced chronic inflammation. These cytokines have been implicated in the impairment of insulin signaling and metabolic regulation, suggesting that WISP-1 may contribute, alongside other factors, to a pro-inflammatory and metabolically dysregulated state in obesity (7).

Recent studies have highlighted the potential of WISP-1 as a biomarker for obesity-related complications. For example, elevated serum WISP-1 levels have been reported in individuals with type 2 diabetes, cardiovascular disease, and certain cancers, although the predictive utility and causative role remain under investigation (16). In the context of exercise, WISP-1 has emerged as a potentially modifiable factor. Interventional studies suggest that exercise training may reduce circulating WISP-1 levels in obese individuals, often alongside improvements in insulin sensitivity, body composition, and inflammatory markers (11, 12). However, the extent to which these changes are direct or mediated by broader metabolic adaptations is not fully clear.

Despite these advances, many questions remain regarding the regulation of WISP-1 in obesity and its precise role in mediating the effects of exercise. Heterogeneity in study populations, exercise modalities, intensity, and duration, as well as small sample sizes, limit the ability to draw definitive conclusions. Understanding the mechanisms underlying WISP-1 modulation by exercise may provide important insights, but further well designed studies are needed to establish its causal role and potential as a therapeutic target.

WISP-1 and insulin resistance

WISP-1 is a protein from the CCN family that regulates various cellular processes, including inflammation, growth, and fibrosis. Evidence from observational and experimental studies indicates that WISP-1 may be associated with insulin resistance and metabolic disturbances, although causality in humans has not been firmly established (9, 17, 18). Several potential mechanisms have been proposed: WISP-1 may stimulate inflammatory processes in adipose tissue and muscle, partly through increases in TNF-α and IL-6, which can interfere with insulin signaling (14). WISP-1 is suggested to influence key insulin signaling pathways, including PI3K/Akt and MAPK, which are central to glucose and lipid metabolism (9, 14, 19). Overactivation of these pathways in experimental models has been associated with decreased insulin sensitivity, but human evidence remains largely associative. WISP-1 acts as a fibrotic factor, promoting extracellular matrix production and tissue remodeling in adipose tissue, muscle, and liver (20, 21). This may indirectly impair insulin responsiveness, but the extent to which WISP-1 independently drives fibrosis versus reflecting systemic metabolic stress is unclear (9, 19)

Furthermore, WISP-1 is linked to fat metabolism and distribution, particularly in visceral fat and the liver, which are key contributors to insulin resistance in obesity and type 2 diabetes (22, 23). In individuals with metabolic disorders, elevated WISP-1 is frequently observed alongside inflammatory and fibrotic changes, suggesting a multifaceted association with metabolic dysregulation, although direct causal pathways remain to be conclusively demonstrated (23, 24).

Exercise interventions have been reported to modulate WISP-1 levels, with aerobic, resistance, and high-intensity interval training often resulting in reductions in circulating concentrations, concomitant with improvements in insulin sensitivity and inflammatory markers. Nevertheless, differences in study design, population characteristics, intervention type, and duration limit the generalizability of these findings, and causality cannot be inferred with certainty (23).

Overall, WISP-1 appears to be a multifactorial mediator associated with insulin resistance and obesity related metabolic disturbances. While exercise may influence WISP-1, current evidence primarily supports associative relationships, emphasizing the need for longitudinal and mechanistic studies to clarify its physiological and therapeutic relevance.

Effects of exercise training on WISP-1 levels

Emerging evidence suggests that physical activity may influence circulating WISP-1 levels in individuals with obesity and related metabolic conditions. Aerobic exercise, resistance training, and high-intensity interval training (HIIT) have all been studied, with many interventions reporting reductions in serum WISP-1, often accompanied by improvements in insulin sensitivity, body composition, and inflammatory markers (12, 13).

For example, circuit resistance training in individuals with type 2 diabetes and obesity was associated with decreased WISP-1 and WISP-2 levels, along with reductions in TNF-α and improvements in insulin resistance (12). Similarly, aerobic training in obese men with type 2 diabetes appeared to reduce serum WISP-1 concentrations and associated inflammatory markers, although sample sizes were limited and intervention durations relatively short (25). HIIT and moderate intensity continuous training (MICT) in obese individuals have been reported to lower WISP-1, with some studies suggesting a more pronounced effect with HIIT, but heterogeneity in population characteristics and exercise protocols complicates interpretation (13).

In overweight and obese girls, both interval aerobic and continuous aerobic training were associated with reductions in serum WISP-1 and TNF-α, although the magnitude of effect differed slightly by training modality (26). Resistance training in obese men also appeared to reduce WISP-1 and WISP-2 levels, alongside improvements in body composition and insulin sensitivity (27). Generally, these findings suggest that WISP-1 may be responsive to physical activity, but the extent and consistency of these effects remain uncertain.

It is important to note several limitations in the current literature. Many studies are limited by small sample sizes, short intervention durations (typically 8-12 weeks), heterogeneous populations, and variations in exercise modality, intensity, and adherence. Additionally, while reductions in WISP-1 frequently co-occur with improvements in metabolic markers, causality cannot be inferred, and it remains unclear whether changes in WISP-1 mediate or merely reflect broader metabolic adaptations.

Despite these limitations, the observed associations provide preliminary support for the potential of WISP-1 as a modifiable factor in exercise interventions. Future research should aim to include larger, well controlled trials with standardized exercise protocols, longitudinal follow up, and mechanistic assessments to determine whether exercise induced modulation of WISP-1 contributes directly to improvements in metabolic health. In summary, while exercise training appears to influence WISP-1, current evidence predominantly supports associative relationships, highlighting the need for further investigation to clarify mechanistic links and potential clinical implications.

Solid arrows indicate observed associations in human intervention studies, including reductions in WISP-1 after aerobic, resistance, or HIIT exercise, along with improvements in insulin sensitivity, inflammation, and overall metabolic health. These associations do not confirm direct causality. Dashed arrows represent proposed mechanistic pathways that remain under investigation, including modulation of WNT/β-catenin signaling, extracellular matrix (ECM) remodeling, and adipose tissue adaptations.

Abbreviations: WISP-1, Wnt1-inducible signaling pathway protein-1; HIIT, high-intensity interval training; ECM, extracellular matrix; TNF-α, tumor necrosis factor-alpha; IL-6, interleukin-6.

Mechanisms of WISP-1 reduction by exercise training

Exercise training reduces WISP-1 levels through a variety of interrelated mechanisms that impact metabolic and inflammatory pathways. These mechanisms include:

1. Reduction in Adipose Tissue Mass: Exercise promotes weight loss and reduces visceral and subcutaneous adipose tissue, leading to a decrease in adipokine secretion, including WISP-1. Adipose tissue is a primary site of WISP-1 expression, and its reduction directly correlates with lowered WISP-1 levels (13, 25, 27).
2. Improved Insulin Sensitivity: Physical activity enhances insulin sensitivity by increasing glucose uptake in skeletal muscles and reducing insulin resistance. Lower insulin resistance is associated with decreased WISP-1 levels, as WISP-1 is implicated in pathways that exacerbate insulin resistance (25, 27).
3. Anti-inflammatory Effects: Regular exercise reduces chronic low-grade inflammation, characterized by lower levels of pro-inflammatory cytokines such as TNF-α and IL-6. Since WISP-1 expression is positively regulated by inflammation, its levels decrease as the inflammatory milieu improves (25).
4. Modulation of the WNT/β-catenin Pathway: Exercise affects the WNT/β-catenin signaling pathway, which is involved in adipogenesis and WISP-1 regulation. Modulating this pathway reduces WISP-1 expression and its downstream effects on adipocyte differentiation and inflammation (13).
5. Improvement in Body Composition: Exercise-induced improvements in lean body mass and reductions in fat mass contribute to the modulation of adipokine profiles, including WISP-1. Enhanced muscle mass increases the secretion of anti-inflammatory myokines, which may further suppress WISP-1 expression (10).
6. Exercise Intensity and Type: Different exercise modalities, such as high-intensity interval training (HIIT), moderate-intensity continuous training (MICT), and resistance training, have been shown to variably influence WISP-1 levels. HIIT, in particular, may have a more pronounced effect due to its impact on metabolic rate and inflammatory cytokine profiles (13).

These mechanisms highlight the multifaceted effects of exercise training on WISP-1 levels and underscore the importance of physical activity as a non-pharmacological intervention for improving metabolic health in obese individuals.

Clinical Implications

Understanding the impact of exercise on WISP-1 levels has significant clinical implications:

1. Non-Pharmacological Management: Exercise serves as a cost-effective and accessible intervention for reducing WISP-1 levels and improving metabolic health.
2. Biomarker Potential: Monitoring WISP-1 levels could provide insights into the efficacy of exercise interventions and the progression of metabolic disorders.
3. Tailored Exercise Programs: Personalized exercise regimens targeting WISP-1 regulation could enhance therapeutic outcomes for obese individuals.

Few studies have directly examined the relationship between exercise and WISP-1 levels. Further research is needed to validate these findings in larger and more diverse populations. The molecular pathways linking exercise to WISP-1 modulation remain unclear and warrant deeper investigation. Studies exploring the sustained impact of exercise on WISP-1 levels and its clinical significance are necessary.

Conclusion

Exercise training appears to be a promising strategy for modulating circulating WISP-1 levels and potentially improving obesity related inflammation and metabolic dysfunction. Evidence from human studies suggests that aerobic, resistance, and HIIT may reduce WISP-1 concentrations, often in parallel with improvements in insulin sensitivity, body composition, and inflammatory markers such as TNF-α and IL-6. However, the current literature is limited by small sample sizes, short intervention durations, heterogeneous populations, and variations in exercise modality, intensity, and adherence. As a result, causal relationships between exercise-induced changes in WISP-1 and improvements in metabolic health remain to be fully established. Future research should focus on well-controlled, longitudinal studies with larger and more diverse populations, standardized exercise protocols, and mechanistic investigations to clarify whether changes in WISP-1 contribute directly to metabolic improvements. Such studies could inform the development of optimized exercise interventions targeting WISP-1 and provide insight into its potential role as a biomarker or therapeutic target in obesity and related metabolic disorders.

Author Contributions

F. D. & A. A. were equally involved in writing, editing, and methodology, and checked and approved the final draft of the manuscript.

Conflict of Interest

The authors declare that they have no conflict of interest.

Data Availability Statement

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

Ethical Considerations

No ethical approval was required for this study because it is a narrative review of published studies and did not involve animal experimentation or human participants.

AI declarations

Artificial intelligence tools were not used for data analysis or interpretation. AI assistance was limited to language editing and formatting during manuscript preparation.

Funding

This research did not receive a specific grant from any funding agency in the public, commercial, or not-for-profit sectors.