The Insulin-Sensitizer Pioglitazone Remodels Adipose Tissue Phospholipids in Humans

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.

Persistent Inflammatory Lipotoxicity Impedes Pancreatic β-cell Function in Diet-Induced Obese Mice Despite Correction of Glucotoxicity

“…5H ) in HFD mice. Furthermore, even though TAGs and DAGs make up a significant portion of total lipids in other tissues (e.g., adipose tissue [54] or liver [55]), these lipids were generally not as abundant in pancreatic islets ( Fig. 5A ).…”

“…6A – 6D ). Phosphatidylserine (PS), an inner phospholipid that is externalized in states of metabolic stress and apoptosis [56], and phosphatidic acid (PA), the obligate precursor for all glycerophospholipids [54], tended to decrease in HFD-feeding conditions in terms of absolute ( Fig. 5F ) and relative abundance ( Supp.…”

From an Apple to a Pear: Moving Fat around for Reversing Insulin Resistance

“…This specialized tissue is a connective tissue consisting of specialized cells called adipocytes and other types of cells. The health of AT is critical in terms of metabolic disorders, as it plays essential metabolic roles as will be discussed in Section 2 [ 9 ]. Dysfunctional AT can cause different pathologies and metabolic diseases, including IR and cardiovascular disorders (CVDs).…”

Frontiers in metabolic physiology grand challenges

“…Adipose tissue of obese type 2 diabetic humans treated with pioglitazone was the focus of another study. Findings demonstrated that pioglitazone protects the immunometabolic health of adipocytes through selective remodeling of the glycerophospholipid pool, characterized by a decrease in lipids enriched for arachidonic acid, such as plasmanylethanolamines and phosphatidylinositols ( Palavicini et al, 2021 ). At the other end of the species’ spectrum, studies examined molecular mechanisms mediating food-induced reinforcement in the model system C. elegans .…”