Background <p>Cold-induced thermogenesis (CIT) mediated by brown adipose tissue (BAT) and skeletal muscle holds therapeutic utility for obesity, but relative tissue contribution to CIT-driven metabolic flexibility (MetF) and its correlation to insulin resistance remain undefined across diverse ethnicities.</p> Objective <p>This study aimed to investigate ethnic differences in cold-induced MetF and its link to insulin sensitivity in Chinese and Asian Indian individuals with overweight.</p> Design <p>Forty-one participants with pre-metabolic or metabolic syndrome of two ethnic groups (31 Chinese, 10 Indian), with an average body mass index (BMI) of 27.5 kg/m² underwent whole-body calorimetry following 1-h cold exposure (~14.5 °C) and oral glucose tolerance test (OGTT) in a crossover design. Resting metabolic rate (RMR), respiratory exchange ratio (RER), carbohydrate oxidation (COX), and fat oxidation (FOX) were assessed. Blood glucose and insulin were measured to assess insulin sensitivity.</p> Results <p>Asian Indians had significantly higher fasting insulin levels and lower insulin sensitivity than Chinese participants. Chinese participants had greater increase in energy expenditure and a more pronounced fuel switch (RER, COX and FOX) with cold. For Chinese individuals, better cold-induced MetF was independently associated with lower fasting insulin and insulin resistance, even after adjusting for age, sex, and body fat. This association was not observed in Asian Indians.</p> Conclusion <p>Significant ethnic differences exist in the association of CIT-driven MetF to insulin resistance. Chinese individuals exhibited robust MetF-insulin sensitivity correlation, whereas Asian Indians showed a blunted response without such independent association. This suggests that ethnicity-specific strategies targeting MetF are crucial for addressing metabolic health disparities.</p>