Altered Autophagy in Human Adipose Tissues in Obesity

Abstract

Context Autophagy is a housekeeping mechanism, involved in metabolic regulation and stress response, shown recently to regulate lipid droplets biogenesis/breakdown and adipose tissue phenotype. Objective We hypothesized that in human obesity autophagy may be altered in adipose tissue in a fat depot and distribution-dependent manner. Setting and Patients Paired omental (Om) and sc adipose tissue samples were used from obese and nonobese (n = 65, cohort 1); lean, sc-obese and intraabdominally obese (n = 196, cohort 2); severely obese persons without diabetes or obesity-associated morbidity, matched for being insulin sensitive or resistant (n = 60, cohort 3). Results Protein and mRNA levels of the autophagy genes Atg5, LC3A, and LC3B were increased in Om compared with sc, more pronounced among obese persons, particularly if with intraabdominal fat accumulation. Both adipocytes and stromal-vascular cells contribute to the expression of autophagy genes. The increased number of autophagosomes and elevated autophagic flux assessed in fat explants incubated with lysosomal inhibitors were observed in obesity, particularly in Om. The degree of visceral adiposity and adipocyte hypertrophy accounted for approximately 50% of the variance in Atg5 mRNA levels by multivariate regression analysis, whereas age, sex, measures of insulin sensitivity, inflammation, and adipose tissue stress were excluded from the model. Moreover, in cohort 3, the autophagy marker genes were increased in those who were insulin resistant compared with insulin sensitive, particularly in Om. Conclusions Autophagy is up-regulated in adipose tissue of obese persons, especially in Om, correlating with the degree of obesity, visceral fat distribution, and adipocyte hypertrophy. This may precede the occurrence of obesity-associated morbidity.

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