Is metabolically healthy obesity shaped by inflammation, gender differences, and fat distribution?

Abstract

The obesity epidemic continues to challenge global cardiovascular (CV) health, but not all obesity is equal. Emerging evidence underscores that distinct obesity phenotypes—particularly metabolically healthy vs unhealthy profiles—confer differential CV risks. Recent large-scale studies have revealed that even metabolically healthy obesity (MHO) is associated with an increased risk of adverse CV events, particularly in the context of socioeconomic disadvantage. Central is the role of chronic low-grade inflammation, termed “metaflammation”, which can persist even in the absence of overt metabolic syndrome and is shaped by both gender and fat distribution. Epicardial and visceral adiposity contribute to this pro-inflammatory state and are strongly associated with conditions such as heart failure and atrial fibrillation. Notably, aging and hormonal changes, particularly in women, may destabilize MHO status, increasing CV vulnerability over time. This overview calls for a paradigm shift in cardiometabolic care, moving beyond anthropometric parameters toward a more refined assessment that incorporate inflammatory biomarkers, fat distribution and sex-specific factors. Recognizing these underlying biological and phenotypic differences enables more accurate CV risk stratification and supports the development of precision-based therapeutic strategies. Ultimately, understanding not just who is at risk, but why, is essential to improving prevention and outcomes across diverse populations facing the burden of obesity.

Keywords: Cardiovascular risk; Epicardial adipose tissue; Inflammation; Metabolically healthy obesity; Metaflammation; Obesity; Sex differences; Visceral fat

Core Tip: Obesity is not a uniform condition but comprises multiple phenotypes with distinct cardiovascular (CV) risks. The concept of metabolically healthy obesity is increasingly challenged by evidence of low-grade inflammation, ectopic fat accumulation, and adipose dysfunction. Inflammation, particularly in visceral and epicardial fat, plays a central role in driving subclinical CV damage, even in the absence of overt metabolic disease. Postmenopausal women are especially vulnerable due to hormonal shifts and fat redistribution. Integrating fat phenotype, inflammatory biomarkers, and sex-specific factors is essential for precise cardiometabolic risk management and targeted prevention, moving beyond body mass index-based assessments.