Altered autophagy in human adipose tissues in obesity.
BACKGROUND
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.


METHODS
Paired omental (Om) and subcutaneous (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 with intraabdominal fat accumulation. Both adipocytes and stromal-vascular cells contribute to the expression of autophagy genes. An 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 omental 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 co-occur with insulin resistance but precede the occurrence of obesity-associated morbidity.
Department of Clinical Biochemistry, National Institute of Biotechnology Negev, Ben-Gurion University of the Negev, Beer-Sheva, 84103, Israel.
Julia
J
Kovsan
Matthias
M
Blüher
Tanya
T
Tarnovscki
Nora
N
Klöting
Boris
B
Kirshtein
Liron
L
Madar
Iris
I
Shai
Rachel
R
Golan
Ilana
I
Harman-Boehm
Michael R
MR
Schön
Andrew S
AS
Greenberg
Zvulun
Z
Elazar
Nava
N
Bashan
Assaf
A
Rudich
D000273:Adipose Tissue / Q000473:pathology*; D000328:Adult; D001343:Autophagy / Q000502:physiology*; D015415:Biomarkers; D001706:Biopsy; D015153:Blotting, Western; D015992:Body Mass Index; D015331:Cohort Studies; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000473:pathology*; D009852:Omentum / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D050151:Subcutaneous Fat / Q000473:pathology; D014015:Tissue Banks
D015415:Biomarkers; D012333:RNA, Messenger