Work

Systemic MOTS-c levels are increased in adults with obesity in association with metabolic dysregulation and remain unchanged after weight loss

Year: 2025

Type: article

Abstract: • Circulating MOTS-c levels are increased in obese adults compared to lean controls. • BMI and HOMA-IR are primary independent determinants of circulating MOTS-c in obesity. • Circulating MOTS-c exhibits a nonlinear relationship with insulin resistance suggesting compensatory response to metabolic stress. • MOTS-c levels and HOMA-IR remain unchanged despite weight loss 6 months after bariatric surgery. • Adipose tissue MOTS-c expression does not correlate with its circulating levels. MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a mitochondrial-derived peptide and regulator of metabolic homeostasis. Although its role in glucose and lipid metabolism is emerging, changes in circulating MOTS-c with obesity remain unclear. We hypothesized that circulating MOTS-c concentrations would be altered in obese vs. lean adults in associations with altered metabolic and inflammatory markers. Circulating MOTS-c levels, metabolic parameters, and inflammatory markers were compared between 22 lean controls and 32 obese participants scheduled for bariatric surgery. Longitudinal changes in weight, MOTS-c levels, and metabolic markers were also analyzed in 10 of the obese patients before and 6 months after bariatric surgery. Additionally, adipose tissue MOTS-c expression was assessed by immunofluorescence in lean kidney donors (n = 6) and obese (n = 14) subjects. Circulating MOTS-c levels were significantly higher in obese compared to lean individuals (273 ± 56 vs. 223 ± 50 pg/mL; P < 0.01). BMI and HOMA-IR independently predicted elevated MOTS-c levels ( P = 0.035 and P = 0.032, respectively). MOTS-c showed a biphasic relationship with HOMA-IR, rising sharply above HOMA-IR of ∼ 6.6 mmol/L×µU/mL. Adipose tissue MOTS-c did not differ between the groups or correlate with circulating MOTS-c. Despite significant BMI improvements post-surgery ( P < 0.001), circulating MOTS-c levels remained unchanged ( P = 0.913). Circulating MOTS-c levels are elevated in obesity, exhibiting a nonlinear relationship with BMI and insulin resistance. MOTS-c may represent a compensatory metabolic response in obesity and insulin-resistant states, highlighting its potential as a clinical biomarker. This preliminary exploratory study warrants validation in larger and independent cohorts.

Source: Journal of Clinical & Translational Endocrinology

DOI: 10.1016/j.jcte.2025.100429