The prevalence of obesity and obesity-related metabolic comorbidities are rapidly increasing worldwide, placing a huge economic burden on health systems. Excessive nutrient supply combined with reduced physical exercise results in positive energy balance that promotes adipose tissue expansion. However, the metabolic response and pattern of fat accumulation is variable, depending on the individual’s genetic and acquired susceptibility factors. Some develop metabolically healthy obesity (MHO) and are resistant to obesity-associated metabolic diseases for some time, whereas others readily develop metabolically unhealthy obesity (MUO). An unhealthy response to excess fat accumulation could be due to susceptibility intrinsic factors (e.g., increased likelihood of dedifferentiation and/or inflammation), or by pathogenic drivers extrinsic to the adipose tissue (e.g., hyperinsulinemia), or a combination of both. This review outlines the major transcriptional factors and genes associated with adipogenesis and regulation of adipose tissue homeostasis and describes which of these are disrupted in MUO compared to MHO individuals. It also examines the potential role of pathogenic insulin hypersecretion as an extrinsic factor capable of driving the changes in adipose tissue which cause transition from MHO to MUO. On this basis, therapeutic approaches currently available and emerging to prevent and reverse the transition from MHO to MUO transition are reviewed.
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