REGULATION OF ADIPOCYTE AND ADIPOSE TISSUE METABOLISM IN OBESITY RELATED INFLAMMATION AND METABOLIC DISORDERS
Location: Human Nutrition Research Center on Aging
Title: Altered autophagy in human adipose tissues in obesity
| Kovsan, Julia - |
| Bluher, Matthias - |
| Tarnovscki, Tanya - |
| Kloting, Nora - |
| Kirshten, Boris - |
| Madar, Liron - |
| Shai, Iris - |
| Golan, Rachel - |
| Harman-Boehm, Ilana - |
| Schon, Michael - |
| Greenberg, Andrew - |
| Elazar, Zvulun - |
| Rudich, Assaf - |
Submitted to: Journal of Clinical Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 5, 2010
Publication Date: February 1, 2011
Citation: Kovsan, J., Bluher, M., Tarnovscki, T., Kloting, N., Kirshten, B., Madar, L., Shai, I., Golan, R., Harman-Boehm, I., Schon, M.R., Greenberg, A., Elazar, Z., Rudich, A. 2011. Altered autophagy in human adipose tissues in obesity. Journal of Clinical Endocrinology and Metabolism. 96(2):E268-277.
Interpretive Summary: Autophagy is a cellular process that regulates fat storage and breakdown in cells. In animals and humans fat is stored with different anatomic locations called fat depots. We investigated whether factors associated with autophagy were increased within intra-abdominal (deep within the belly) and subcutaneous (just under the skin) fat depots. We found that more autophagy factors were expressed within intra-abdominal fat depots of certain people as compared to others. Additionally, we found that those individuals whom had increased expression of autophagy factors in their intra-abdominal fat were more resistant to the anti diabetic actions of the hormone insulin. These studies suggest that the expression of autophagy factors may promote insulin resistance and risk of developing diabetes which will be explored in future studies.
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 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.