Chronic pain is a highly prevalent, yet poorly understood, condition. It is estimated that 50 million adults (20.9 %) in the United States experience chronic pain. 17.1 million patients report that living with a chronic pain condition has caused a substantial restriction of daily activities.[29] Chronic pain impacts patients physically, psychologically, and socially, often leading to a significant decline in quality of life.[7].

Previous studies have demonstrated a positive correlation between chronic pain and body mass index (BMI).[6] Emerging evidence shows, however, that body fat may be a better indicator for pain risk than body mass.[37] This is not unexpected, since growing research suggests that high levels of adiposity, traditionally associated with a high BMI, is also associated with chronic inflammation,[9] and chronic inflammation may well be a key contributor to chronic pain.[20].

Adipokines are hormones specifically synthesized and released by adipocytes.[4], [13] The first adipokine, leptin, was discovered in 1994 and more than 600 adipokines have since been identified.[17] Monocytes and macrophages from the adipose tissue, as well as adipocytes, also secrete a wide spectrum of cytokines.[3], [38] Many of these adipose-derived factors are implicated in the modulation of inflammation and may as well constitute the link between fat tissue and chronic pain. Certain adipokines (e.g. leptin and resistin) and cytokines (e.g. IL-1β, TNFα, IL-6) are known to be pro-inflammatory, whereas other adipokines (e.g. adiponectin) and cytokines (e.g. IL-4 and IL-10) have anti-inflammatory effects.[13], [27], [38] Moreover, the inflammation marker C-Reactive Protein (CRP) was shown to be related to visceral fat mass.[36].

Individuals with more adipose tissue may release more pro-inflammatory adipokines such as leptin, predisposing them to chronic pain. In addition, an excess of adiposity has been rather shown to cause dysregulation of adipokine and cytokine secretion, with an imbalance between pro-inflammatory and anti-inflammatory factors. Fat tissue accumulation has indeed various impacts upon inflammation function of its distribution. In this respect, visceral adipose tissue is more strongly associated with inflammation than subcutaneous adipose tissue.[2] BMI is limited as an indirect measure of adiposity and gives no information about fat tissue distribution. Given this, it is pertinent to adopt more comprehensive methods to quantify body fat distribution, such as the waist-to-hip ratio (WHR),[12] hip circumference (HC), or waist circumference (WC). These parameters control for additional causes of an elevated BMI, including increased muscle mass, bone density, and metabolic disorders that alter typical patterns of adipose distribution.[25].

Beyond the adipose-related paracrine modulation of chronic inflammation, the increased metabolic demand from more adipose tissue is thought to trigger hypoxia and oxidative stress, thereby contributing to chronic pain through non-inflammatory mechanisms.[22].

Although fat mass and distribution, as well as fat tissue-related inflammation are renowned as factors influencing chronic pain, their exact relationship is not well established. Moreover, sex-dependent variability of these correlations was never performed in a single study.

To bridge fat mass and distribution with the intensity of chronic pain, evaluated through the participants’ self-reported pain ratings, we performed a cross-sectional study, evaluating fat tissue-related inflammatory spectrum (CRP, IL-6, leptin, resistin) concomitantly with fat mass as reflected by WC and HC at participants of both sexes and different ages from the All of Us database. By further exploring the associations of various pain-related prognostic factors, we hoped to contribute with additional detail to this topic.