MOTS-c Mitochondrial Peptide Rises With Insulin Resistance, Not Obesity Alone

Mitochondrial Open Reading Frame of the 12S rRNA type-c (MOTS-c) is a 16-amino-acid peptide encoded within mitochondrial DNA that regulates skeletal muscle function, glucose metabolism, and energy homeostasis. Given its potential relevance to obesity-related metabolic dysfunction, this Turkish study is among the first clinical investigations of circulating MOTS-c in relation to body weight, insulin resistance, inflammation, and endothelial function in humans.

The cross-sectional case-control study enrolled 85 adults at a tertiary care hospital between January and May 2022. Forty-eight participants had obesity (BMI ≥ 30 kg/m²) and 37 had normal BMI (18.5–24.9 kg/m²). Individuals with type 2 diabetes, hypertension, cardiovascular disease, kidney disease, smoking, or pregnancy were excluded. Serum MOTS-c, insulin, hs-CRP, and ADMA were measured by ELISA after an 8-hour fast. HOMA-IR was calculated from fasting glucose and insulin. Statistical analyses included t-tests, Mann-Whitney U tests, Pearson/Spearman correlations, and multiple regression.

The primary result was that serum MOTS-c levels did not differ significantly between the obesity and normal-BMI groups (14.33 ± 3.76 pg/mL vs. 13.67 ± 3.44 pg/mL; p = 0.395). This null finding held in sex-stratified subgroup analyses. By contrast, the obesity group had significantly elevated fasting glucose, HbA1c, HOMA-IR, hs-CRP, and ADMA — confirming expected metabolic and vascular abnormalities. MOTS-c showed no correlation with hs-CRP or ADMA across the full cohort.

However, the most clinically noteworthy finding emerged from correlation and multiple regression analyses: MOTS-c levels correlated positively and significantly with HOMA-IR (p < 0.05). Multiple regression confirmed that both HOMA-IR and age were independent predictors of MOTS-c — higher insulin resistance associated with higher MOTS-c, while older age associated with lower MOTS-c. This pattern suggests MOTS-c may be upregulated as a compensatory adaptive response to insulin resistance, attempting to restore metabolic homeostasis.

The age-related decline in MOTS-c is consistent with longevity literature linking reduced mitochondrial peptide signaling to aging phenotypes. If MOTS-c rises to counteract insulin resistance but falls with age, older individuals with insulin resistance may be uniquely vulnerable — lacking sufficient MOTS-c compensation. This has implications for understanding metabolic decline in aging and for potential therapeutic strategies using MOTS-c analogs. Limitations include the small sample size, cross-sectional design, single-center recruitment, and the predominance of female participants (74%), which limits generalizability.