Adipose tissue autophagy related gene expression is associated with glucometabolic status in human obesity

Abstract

Adipose tissue autophagy (AT) is associated with human obesity and increased metabolic risk. Recent findings establish a role for autophagy in lipid metabolism. Here, we compared the expression of autophagy-related and lipolysis genes in human abdominal subcutaneous AT (SCAT) in overweight/obese subjects (n = 17) with or without impaired glucose tolerance in comparison with lean normal glucose tolerant individuals (n = 9), and investigated the association between AT autophagy and lipolysis. Human multipotent adipose-derived stem cells (hMADS) were used to investigate the effect of pharmacological HSL inhibition on changes in the autophagic flux. The expression of autophagy-related genes (ATG) 5, 7 and 12 in SCAT was significantly higher (p = 0.043, p = 0.015, p = 0.004, respectively) in overweight/obese compared to lean men, while expression of the classical lipases HSL (p = 0.092) and ATGL (p = 0.084) tended to be lower. ATG12 mRNA was positively correlated with BMI (r = 0.407, p = 0.039). ATG7 mRNA correlated positively with waist/hip ratio (WHR) (r = 0.420, p = 0.041), 2 h glucose concentration (r = 0.488, p = 0.011) and insulin (r = 0.419, p = 0.033). Multiple linear regressions revealed that ATG7 gene expression was positively related to 2 h glucose, independent of BMI, WHR and insulin. Gene expression interaction analysis showed that ATG7 mRNA negatively correlated with HSL (p<0.01) and ATGL mRNA expression (p<0.01). In line, treatment of differentiated hMADS with an HSL inhibitor increased LC3 accumulation, a marker of increased autophagic flux. Collectively, the present study demonstrated that a low expression of classical lipases in abdominal SCAT is accompanied by an increased expression of ATGs in overweight/obese subjects, which seems to be mainly related to glucose tolerance.

Cathepsin gene expression in abdominal subcutaneous adipose tissue of obese/overweight humans

“…Recently, we showed that increased expression of autophagic genes (i.e. ATG 5–12 and 7) in human subcutaneous AT, was associated with an impaired glucometabolic status [ 4 ]. Lysosomal degradation of the autophagic cargo is the final stage of autophagy.…”

Leptin stimulates autophagy/lysosome-related degradation of long-lived proteins in adipocytes

“…4,5 In adipose tissue, how autophagy is dys-regulated remains unsettled, with a general agreement that autophagy genes are overexpressed in adipose tissue, particularly in depots and in obesity sub-types that are more associated with metabolic dysfunction. [6][7][8] Yet, although autophagy, particularly in chronic diseases, may be regulated also at the gene expression level, 9,10 much more is known about its more rapid regulation by post-translational modifications and proteinprotein interactions. Indeed, while two independent groups suggested that autophagic activity (i.e., 'flux') is inhibited in adipose tissue, 11,12 at least four groups, including our own, provided evidence that the elevated gene expression of autophagy genes in adipose tissue manifests by increased autophagic flux.…”

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“…The ATG12 mRNA has been positively correlated with raised BMI. More significant correlation has also been reported between ATG7 mRNA with waist/hip ratio (WHR) 57 . Further, altered endogenous glucocorticoid metabolism, including 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which generates active cortisol from cortisone, and 5α-reductase (5αR), has also been reported in obesity.…”

“…The lipophagy dys-regulation (inhibition of adipose tissue autophagy), is associated with human obesity 55 . High levels of glucagon, lesser insulin, lower amino acid availability are some of the factors to activate autophagy, through modulation of mTORor/and Akt-dependent pathways 56 .…”