Metabolic heterogeneity of obesity

Multi-organ-system insulin resistance is the key pathogenic driver of obesity-related metabolic complications and diseases, such as atherogenic dyslipidemia, metabolic dysfunction-associated steatotic liver disease and type 2 diabetes. However, there is considerable heterogeneity in insulin sensitivity among people with obesity. Some are considered to have metabolically healthy obesity, with normal insulin sensitivity in conjunction with normal fasting blood glucose, oral glucose tolerance, plasma lipid profile and intrahepatic triglyceride content. In this Review, we discuss metabolic differences at the cellular, organ-system and systemic levels between people with metabolically healthy and metabolically unhealthy obesity; we also discuss heterogeneity in the therapeutic effects of weight reduction. A better understanding of the differences between metabolically divergent groups and the physiological responses to weight loss can help identify the factors responsible for the link between excess adiposity and metabolic dysfunction and disease.