What distinguishes adipose tissue of severely obese humans who are insulin sensitive and resistant?

Abstract

Purpose of review: Despite a strong correlation between obesity and insulin resistance, 25% of severely obese (BMI >40) individuals are insulin sensitive. In this review, we will examine the factors in adipose tissue that distinguish the two groups, as well as reasons for believing the insulin-sensitive group will be less disease prone.

Recent findings: Obesity has been linked to the metabolic syndrome with an increase in visceral (intra-abdominal) compared to subcutaneous fat. Recent studies in which adipose tissue of insulin-sensitive and insulin-resistant patients with severe obesity were compared indicate that the insulin-resistant group is also distinguished by increases in oxidative stress and decreases in AMP-activated protein kinase (AMPK) activity. In contrast, changes in the expression of genes for SIRT1, inflammatory cytokines, mitochondrial biogenesis and function, and the two α-isoforms of AMPK showed more depot variation. Studies of how these and other changes in adipose tissue respond to bariatric surgery are still in their infancy.

Summary: Available data suggest that increases in oxidative stress, decreases in AMPK activity and SIRT1 gene expression, depot-specific changes in inflammatory, mitochondrial and other genes distinguish adipose tissue of insulin resistant from insulin-sensitive individuals with severe obesity.

FIGURE 1

Pathophysiology of adipose tissue in an obese, insulin-resistant individual. Adipose tissue consists of the adipocyte and cells present in the stroma including those in the microvasculature, resident macrophages, and other inflammatory cells taken up from the circulation. It is assumed that mononuclear cells taken up are predominantly converted to type 1 macrophages that produce inflammatory cytokines. As discussed in the text, decreases in AMPK and SIRT1 activity, such as that found in the adipose tissue of insulin-resistant patients with massive obesity, very likely contribute to these events. An early occurrence is presumably a decrease in lipid droplet proteins that simultaneously diminish fatty acid deposition and increase free fatty acid (FFA) releases from the lipid droplet. This could account for observed increases of FFA and reactive oxygen species in the cytosol of the adipocytes; however, this remains to be proven.

FIGURE 2

Hypothetical mechanisms for the activation of inflammasomes in adipose tissue of obese insulin-resistant individuals (adapted with permission [30]). The identity of the factor(s) that decrease AMPK activity in cells in which inflammasomes are found is uncertain, although oxidative stress could be a factor. Not shown here is that activation of caspase 1 in the inflammasome complex cleaves and presumably inactivates SIRT1. ULK1, a regulator of the autophage lysosome is phosphorylated and activated by AMPK.