Factors regulating subcutaneous adipose tissue storage, fibrosis, and inflammation may underlie low fatty acid mobilization in insulin-sensitive obese adults

Abstract

Although the rate of fatty acid release from adipose tissue into the systemic circulation is very high in most obese adults, some obese adults maintain relatively low rates of fatty acid release, which helps protect them against the development of systemic insulin resistance. The primary aim of this study was to identify factors in adipose tissue that may underlie low vs. high rates of fatty acid mobilization in a relatively homogeneous cohort of obese adults. We measured systemic fatty acid rate of appearance (FA Ra) via C-palmitate isotope dilution, and we obtained subcutaneous abdominal adipose tissue samples from 30 obese adults (BMI: 38 ± 1 kg/m, age: 30 ± 2 yr) after an overnight fast. We then measured insulin sensitivity using a hyperinsulinemic-euglycemic clamp. Confirming our previous work, insulin sensitivity was inversely proportional to FA Ra ( = 0.50; < 0.001). Immunoblot analysis of subcutaneous adipose tissue samples revealed that, compared with obese adults with high FA Ra, those with low FA Ra had lower markers of lipase activation and higher abundance of glycerol-3-phosphate acyltransferase, which is a primary enzyme for fatty acid esterification. Microarray and pathway analysis provided evidence of lower fibrosis and lower SAPK/JNK pathway activation in obese adults with low FA Ra compared with those with high FA Ra. Our findings suggest that alterations in factors regulating triglyceride storage in adipose tissue, along with lower fibrosis and inflammatory pathway activation, may underlie maintenance of a relatively low FA Ra in obesity, which may help protect against the development of insulin resistance.

Adipokinome Signatures in Obese Mouse Models Reflect Adipose Tissue Health and Are Associated with Serum Lipid Composition

“…There was an accumulation of proteins found to be related to or involved in fibrosis-associated processes in obob mice, compared to the controls. This is consistent with the excess accumulation of adipose tissue extra cellular matrix (ECM) components and IR in obesity [28], and to a recent observation of the ECM organization and assembly markers that were increased in obese humans with a high serum FFA mobilization from adipose tissue [29].…”

Plasma ferritin concentration is positively associated with in vivo fatty acid mobilization and insulin resistance in obese women

“…This study was part of a larger investigation of the relationship between FA mobilization and insulin resistance in obese adults. Some of the methods for this study have been reported elsewhere (Van Pelt et al, 2017) but are briefly repeated here for convenience.…”

“…Participants were studied after an overnight fast during the follicular phase of their menstrual cycle. We collected a baseline blood sample and a subcutaneous abdominal adipose tissue sample, under local anaesthetic (Van Pelt et al, 2017). The rate of appearance of FA in the systemic circulation (FA Ra) was assessed using 13 C-palmitate isotope dilution as detailed elsewhere (Van Pelt et al, 2017).…”

“…We collected a baseline blood sample and a subcutaneous abdominal adipose tissue sample, under local anaesthetic (Van Pelt et al, 2017). The rate of appearance of FA in the systemic circulation (FA Ra) was assessed using 13 C-palmitate isotope dilution as detailed elsewhere (Van Pelt et al, 2017). Briefly, after collecting the baseline blood and adipose tissue samples, 13 C-palmitate was infused at a rate of 0.04 mol kg −1 min −1 for 1 h. After 45 min, we collected three blood samples separated by 5 min for the determination of the tracer-to-tracee ratio (TTR) of 13 C/ 12 C-palmitate in plasma for subsequent FA Ra calculations (Patterson, Zhao, & Klein, 1998).…”

“…Accumulating evidence suggests that dysregulated iron homeostasis contributes to metabolic dysfunction in obesity (Gabrielsen et al, 2012;Moreno-Navarrete et al, 2014;Orr et al 2014), but the mechanisms linking iron and metabolic health remain incompletely understood (Fernández-Real, McClain, & Manco, 2015). High rates of adipose tissue lipolysis and fatty acid (FA) release into the systemic circulation are associated with insulin resistance in obesity (Van Pelt, Guth, Wang, & Horowitz, 2017), and some ex vivo/in vitro evidence indicates that iron increases lipolysis in adipocytes (Chirumbolo et al, c 2018 The Authors. Experimental Physiology c 2018 The Physiological Society 2015; Rumberger, Peters, Burrington, & Green, 2004).…”