Abstract
The insulin-sensitizer pioglitazone exerts its cardiometabolic benefits in type 2 diabetes (T2D) through a redistribution of body fat, from ectopic and visceral areas to subcutaneous adipose depots. Whereas excessive weight gain and lipid storage in obesity promotes insulin resistance and chronic inflammation, the expansion of subcutaneous adipose by pioglitazone is associated with a reversal of these immunometabolic deficits. The precise events driving this beneficial remodeling of adipose tissue with pioglitazone remain unclear, and whether insulin-sensitizers alter the lipidomic composition of human adipose has not previously been investigated. Using shotgun lipidomics, we explored the molecular lipid responses in subcutaneous adipose tissue following 6months of pioglitazone treatment (45mg/day) in obese humans with T2D. Despite an expected increase in body weight following pioglitazone treatment, no robust effects were observed on the composition of storage lipids (i.e., triglycerides) or the content of lipotoxic lipid species (e.g., ceramides and diacylglycerides) in adipose tissue. Instead, pioglitazone caused a selective remodeling of the glycerophospholipid pool, characterized by a decrease in lipids enriched for arachidonic acid, such as plasmanylethanolamines and phosphatidylinositols. This contributed to a greater overall saturation and shortened chain length of fatty acyl groups within cell membrane lipids, changes that are consistent with the purported induction of adipogenesis by pioglitazone. The mechanism through which pioglitazone lowered adipose tissue arachidonic acid, a major modulator of inflammatory pathways, did not involve alterations in phospholipase gene expression but was associated with a reduction in its precursor linoleic acid, an effect that was also observed in skeletal muscle samples from the same subjects. These findings offer important insights into the biological mechanisms through which pioglitazone protects the immunometabolic health of adipocytes in the face of increased lipid storage.
Highlights
Adipose tissue is the primary site for fat storage and quantitatively the most important energy reservoir in the body
A wide inter-individual variability was observed for many lipid classes and, principal component analyses (PCA) of each major structural family of lipids revealed that much of the variance in adipose lipid species was driven by between-subject differences (Figure 2B)
The results of the current study demonstrate that the clinical benefits seen in type 2 diabetes (T2D) patients treated with pioglitazone are accompanied by robust compositional changes in adipose tissue glycerophospholipids, with minimal alterations observed in other lipid classes
Summary
Adipose tissue is the primary site for fat storage and quantitatively the most important energy reservoir in the body. The coordinated expansion and breakdown of adipose lipid stores is crucial to the dynamic regulation of circulating nutrient availability and plays a central role in the control of whole-body metabolism. Excessive nutrient storage in adipose tissue (i.e., obesity) promotes adipocyte dysfunction, inflammation, and insulin resistance and is strongly implicated in the etiology of type 2 diabetes (T2D; DeFronzo, 2004). The molecular effects of pioglitazone are primarily mediated through the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), a transcriptional regulator of adipocyte differentiation and lipid storage which is highly abundant in adipose tissue (Spiegelman, 1998). As a result of this mode of action, pioglitazone paradoxically causes weight gain ( fat mass) despite improving dyslipidemia, insulin sensitivity, and glycemic control (Miyazaki et al, 2001; Shadid and Jensen, 2003)
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