The study pooled data from several small trials and found that people with type‑2 diabetes have lower blood levels of the mitochondrial peptide MOTS‑c, while people who are obese (especially with a BMI over 28) tend to have higher levels. MOTS‑c also showed a modest positive link with total and LDL cholesterol. These patterns suggest MOTS‑c could act as a biomarker for metabolic health, but the research is still early and the tests aren’t widely available for everyday use.

MOTS-c is known as mitochondrial open reading frame (ORF) of the twelve S c, produced by a small ORF-encoded peptides (SEPs) in mitochondrial 12S rRNA region. There is growing evidence that MOTS-c has a strong relationship with the expression of inflammation- and metabolism-associated genes and metabolic homeostasis, and even offering some protection against insulin resistance (IR). However, studies have reported inconsistent correlations between different population characteristics and MOTS-c levels. This meta-analysis aims to elucidate MOTS-c levels in physiological and pathological states, and its correlation with metabolic features in various physiological states. We conducted a systematic review and meta-analysis to synthesize the evidence of changes in blood MOTS-c concentration, and any association between MOTS-c and population characteristic. The Web of Science, PubMed, EMBASE, CNKI, WANGFANG and VIP databases were searched from inception to April 2023. The statistical analysis was summarized using the standardized mean difference (SMD) and 95% confidence interval (95% CIs). Pearson correlation coefficient was used to analyze the correlation and generate forest plots through a random-effects model. Additional analyses as sensitivity and subgroup analyses were performed to identify the origins of heterogeneity. Publication bias was retrieved by means of a funnel-plot analysis and Egger's test. All related statistical analyses were performed using Revman 5.3 and Stata 15 statistical software. There are 6 case-control studies and 1 cross-sectional study (11 groups) including 602 participants in our current meta-analysis. Overall analysis results showed plasma MOTS-c concentration in diabetes and obesity patients was significantly reduced (SMD = - 0.37; 95% CI- 0.53 to - 0.20; P < 0.05). After subgroup analysis, the present analysis has yielded opposite results for MOTS-c changes in obesity (SMD = 0.51; 95% CI 0.21 to 0.81; P < 0.05) and type 2 diabetes mellitus (T2DM) (SMD = - 0.89; 95% CI - 1.12 to - 0.65; P < 0.05) individuals. Moreover, the correlation analysis was performed to identify that MOTS-c levels were significantly positively correlated with TC (r = 0.29, 95% CI 0.20 to 0.38) and LDL-c (r = 0.30, 95% CI 0.22 to 0.39). The subgroup analysis results showed that MOTS-c decreased significantly in patients with diabetes (SMD = - 0.89; 95% CI- 1.12 to - 0.65; P < 0.05). In contrast, the analysis result for obesity persons (BMI > 28 kg/ m²) was statistically significant after overweight people (BMI = 24-28 kg/ m²) were excluded (SMD = 0.51; 95% CI 0.21 to 0.81; P < 0.05), which is completely different from that of diabetes. Publication bias was insignificant (Egger's test: P = 0.722). Circulating MOTS-c level was significantly reduced in diabetic individuals but was increased significantly in obesity patients. The application of monitoring the circulating levels variability of MOTS-c in routine screening for obesity and diabetes is prospects and should be taken into consideration as an important index for the early prediction and prevention of metabolic syndrome in the future. PROSPERO registration number CRD42021248167.