Adipose Tissue Expandability as a Link Between Nutrition and Obesity-Related Metabolic Risk: Insights from Bariatric...

Adipose tissue expandability refers to the capacity of white adipose tissue to store excess energy safely while preserving metabolic homeostasis. This adaptive response takes place via both an increase in adipocyte number (hyperplasia) and size (hypertrophy). Healthy expansion requires coordinated angiogenesis, extracellular matrix remodeling, and functional adipose stem and progenitor cells. Within this conceptual framework, when expandability is limited-due to genetic factors, aging, or chronic overnutrition-adipocyte hypertrophy predominates, which is hypothesized to trigger hypoxia, endoplasmic reticulum stress, chronic low-grade inflammation, and fibrosis. These changes are proposed to form a physical and metabolic barrier that compromises further safe lipid storage, potentially driving the spillover of surplus lipids to ectopic sites: the liver (promoting steatosis and hepatic insulin resistance), skeletal muscle (intramyocellular lipid accumulation and impaired glucose uptake), and pancreas (β-cell dysfunction and reduced insulin secretion). Lipotoxic intermediates such as diacylglycerols and ceramides activate protein kinase C isoforms and may impair insulin receptor signaling, thereby contributing to systemic insulin resistance. The clinical correlate is a spectrum of metabolic disorders including type 2 diabetes, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, and cardiovascular disease. Understanding the determinants of adipose tissue expandability-from adipose stem cell function and angiogenesis to fibrosis and immune cell infiltration-provides a framework for identifying individuals at risk despite normal body weight and for developing targeted therapies that restore healthy adipose tissue expansion. The aim of this narrative review is to analyze how nutritional factors shape adipose tissue expandability and how limitations in expandability drive obesity-related metabolic disease. To this end, we leverage bariatric surgery as a physiological model illustrating how weight loss reduces lipid overflow while intrinsic adipose tissue expandability may remain incompletely restored.