Bidirectional regulation between mitochondrial metabolic reprogramming and epigenetic modifications in renal tubular epithelial cell injury of diabetic kidney disease.

Obesity has become one of the most challenging non-communicable diseases of the 21st century. A pooled analysis of 3–663 population-representative surveys covering 222 million children, adolescents, and adults showed that the global obese population exceeded one billion in 2022, with a continued rise in most countries since 1990 (). Under current trends, an estimated 3.8 billion adults are projected to be overweight or obese by 2050, with the fastest increases concentrated in low- and lower-middle-income countries (). Chronic low-grade inflammation of adipose tissue is a core pathological feature of obesity and is now considered deeply involved in obesity-related metabolic dysfunction and multi-organ comorbidities (). The prevalence of chronic pain is markedly higher in people with obesity than in the general population. A systematic review and meta-analysis demonstrated that adults with BMI ≥ 30 kg/m² report greater pain intensity than normal-weight controls, whereas the overweight group (BMI 25–30 kg/m²) does not differ significantly from controls, suggesting a clinical “BMI threshold effect” (). Imaging evidence from 32–409 abdominal MRI scans in UK Biobank further supports a dose–response relationship between both visceral and subcutaneous adipose tissue and multisite and widespread chronic pain, with stronger effect sizes in women (). A cross-sectional analysis of the All of Us cohort showed that the additive predictive value of waist/hip circumference together with inflammatory markers (CRP, IL-6, leptin) for chronic pain was significant only in women, indicating sexual dimorphism in adipose–inflammation interactions (). Evidence also links metabolic syndrome (MetS) to chronic pain. A scoping review of 28 observational studies found that MetS is enriched among individuals with migraine, spinal pain, fibromyalgia, and general chronic pain, and that the two conditions are bidirectionally associated (). The STEP 9 phase III randomized controlled trial provided direct clinical evidence: in patients with concurrent obesity and knee osteoarthritis, 68-week semaglutide treatment produced concurrent and significant improvements in body weight and knee WOMAC scores (). These findings support the clinical tractability of a “weight loss–anti-inflammation–analgesia” axis.